Ibuprofen: Pharmacology, Therapeutics and

Side Effects
.
K.D. Rainsford

Ibuprofen: Pharmacology,
Therapeutics and
Side Effects
K.D. Rainsford
Biomedical Research Centre
Sheffield Hallam University
Sheffield
United Kingdom

ISBN 978-3-0348-0495-0 ISBN 978-3-0348-0496-7 (eBook)

DOI 10.1007/978-3-0348-0496-7
Springer Heidelberg New York Dordrecht London
Library of Congress Control Number: 2012951702

# Springer Basel 2012

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This book is respectfully dedicated to
Professor Stewart Adams OBE
and his colleagues for their discovery
of ibuprofen 50 years ago and its
implementation in the therapy
of pain and inflammatory conditions.

Professor Stewart Adams, BPharm, PhD,

DSc(hc), OBE
.
Foreword

I am very pleased to write the foreword to this book, since Professor Rainsford
over the years has written extensively and expertly on ibuprofen. It is difficult now
to look back to 1953 when I first began to think about the possibility of finding
a non-corticosteroid drug for the treatment of rheumatoid arthritis (RA). It was
a forbidding prospect, for little was known about the disease process and nothing
about the mode of action of aspirin (aspirin being effective in very high doses
in RA).
After several disappointing and non-productive years we finally discovered the
“propionics”, and selected ibuprofen, which we estimated would potentially be
the best tolerated. In 1969 as a prescription drug, ibuprofen started slowly because
the recommended dose of 600–800 mg/day was too low for the effective treatment of
the rheumatic diseases and well below the now usual doses of 1,200–1,800 mg/day.
Later studies showed ibuprofen was an effective analgesic in many painful
conditions in doses up to 1,200 mg/day, and in 1983 it was approved as a non-
prescriptive (OTC) analgesic. It is perhaps these differences between the
prescription and non-prescription doses which have led to the mistaken view that
at the lower doses ibuprofen is only an analgesic.
A most satisfying aspect of ibuprofen has been its good tolerance, always a
major aim of our research, and one of the reasons for its ever increasing world-wide
use since 1969.
Nottingham, UK Stewart Adams
October 2011

vii
.
Preface

Ibuprofen is probably one of the most successful drugs used worldwide for the
treatment of mild to moderate pain and various inflammatory conditions. Since its
initial discovery half a century ago in December 1961 by Dr. (now Professor)
Stewart Adams, the late Dr. John Nicholson and Mr. Colin Burrows of the Boots
Co. Nottingham (UK) (see photo), ibuprofen has been developed in a wide variety
of oral and parenteral formulations for use in an amazing variety of indications. My
chapter on the “History and Development of Ibuprofen” written in the first mono-
graph (which I also edited) on this drug details the twists and turns that took place in
the discovery and development of ibuprofen from initial humble beginnings. It is a
great tribute to Stewart Adams and his colleagues that their insight and persistence
enabled the pharmacological activities of ibuprofen to be discovered and clinical
potential to be realized at a time when little was known about inflammatory
processes, let alone the techniques for quantifying clinical responses in arthritic
and other painful inflammatory conditions. Indeed, it was only through screening
several thousand compounds for anti-inflammatory, analgesic, and antipyretic
activity in what were then relatively newly established animal models in guinea
pigs and rats that the pharmacological activity of ibuprofen was identified, and
found to be uniquely active compared with other compounds including that of
aspirin, a reference standard employed at the time. These discoveries were essen-
tially made on an empirical basis. It was a decade or so later before the discovery of
prostaglandins and their actions in regulating inflammation. Also, it took longer
before assays for detecting anti-inflammatory activity based on prostaglandin
synthesis inhibition were developed, conditions understood and then refined as
well as validated for screening potential therapeutic agents.
In the process of the early clinical trials with ibuprofen, initially in patients with
rheumatoid arthritis, using the approach of cautious introduction using relatively
low doses of the drug, that its efficacy and safety were appreciated. Later on, higher
doses were found necessary for optimal effects, and proved relatively safe after
long-term usage. This, and evidence from toxicological studies and extensive
clinical investigations, showed that ibuprofen was safer as or more effective than

ix
x Preface

the established non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, indo-

methacin, and phenylbutazone).
As detailed in this book, ibuprofen has since been proven to be one of the safer
NSAIDs. This is such that it has been used extensively as a standard for comparison in
the large number of clinical trials of newly developed agents. These trials are
reviewed here, and although some newer drugs (e.g., coxibs) have been found to
have fewer gastrointestinal (GI) adverse effects, their margin of improved GI safety is
relatively small, and this improvement has not come without other safety issues (e.g,.
cardiovascular reactions) or added costs to healthcare budgets or the individual.
One of the great successes with ibuprofen was its introduction in a low dose
(1,200 mg/day) form for over-the-counter (OTC), non-prescription sale in the UK
(in 1983), USA (in 1984) and now in 82 countries worldwide. Large-scale clinical
and epidemiological studies have shown that this OTC form of the drug is relatively
safe in the GI tract compared with aspirin and other NSAIDs, and is comparable in
GI safety with paracetamol (acetaminophen), yet without the risks of liver toxicity
seen with the latter. This is not to say that OTC ibuprofen is without adverse effects.
As reviewed in this book, development of these untoward actions is now well-
understood, and most reactions, though discomforting to some degree, are minor
and preventable, or at least are reversible upon with drawing the drug (indicating
reversibility of toxic mechanisms).
This book also reviews the disposition and unique modes of action of ibuprofen.
Studies on the pharmacological properties of ibuprofen have advanced in parallel
with understanding of the cell and molecular biology of inflammatory processes,
especially those underlying neuro-pathological reactions in pain and neurodegen-
erative diseases and cancer-related inflammatory reactions. Consequently, much
interest has been shown in the past two decades or so in the potential for ibuprofen
to prevent conditions such as Alzheimer’s and atherosclerotic dementias,
Parkinson’s disease and neural injuries, as well as colo-rectal, mammary, and
some other cancers. While these developments are undoubtedly exciting, there
are, however, extensive investigations which will have to be performed to under-
stand when ibuprofen should be employed in the various stages of these chronic and
complex conditions, and at what dose(s). Indeed, special formulations of ibuprofen
may need to be developed to ensure optimal biodisposition of the drug (e.g.,
localized delivery in the colon in colo-rectal cancer) or prolonged pharmacokinetics
for specific applications in different chronic diseases (e.g., in cystic fibrosis) or
special patient groups (young and the elderly) in which long-term safe use is
required.
Recently, there has been much commercial and clinical interest in developing
and use of combinations of ibuprofen with other drugs (e.g., paracetamol, codeine,
caffeine) and some natural products. The objective of many drug combinations has
been to raise the “analgesic ceiling” to achieve greater or more sustained acute pain
relief. While in many cases the “jury may still be out” on most of these claims, there
are already some indications of potential therapeutic benefits of the drug
combinations in certain painful conditions, while still retaining the relative safety
benefits of ibuprofen (at least at OTC dosages). Further investigations will be
Preface xi

required with some of these ibuprofen–drug mixtures to establish optimal

conditions for their application and use in specific indications.
This book is intended for a broad readership for anyone interested in the
properties, actions, and uses of ibuprofen. It is intended that this book be written
in a more general style to reflect interest in it by a broad readership. There are
several concepts that are presented diagrammatically but with sufficient detail such
that key points are emphasized. For more in-depth information, the reader is
referred to the specialist book “Ibuprofen: A Critical Bibliographic Review”
(1999; 2nd edition in preparation), edited by myself.
This book would not have been possible without the privileged collaboration and
valuable advice of my long standing research colleagues, among them Dr. Brian
Callingham (University of Cambridge, UK), Professor Michael Whitehouse (Uni-
versity of Queensland & Griffiths University, Queensland, Australia), Professors
Walter Kean and Richard Hunt and the late Watson Buchanan (McMaster Univer-
sity, Hamilton, Ontario, Canada).
I would also like to record my appreciation of advice of research colleagues in
pharmaceutical companies that produce and market ibuprofen who have often given
me valuable information on this drug, and access to their drug safety databases
without prejudice. Among these, I have been privileged to have advice and receive
important historical information from the discoverer of ibuprofen, Professor Stuart
Adams, OBE, to whom this book is dedicated.
My thanks to Dr. Hans-Detlef Klüber of Springer Basel AG (formerly Birkhäuser
Verlag), Basel, Switzerland for his idea that has led to this book based on a review I
published (Inflammopharmacology, 2009;17:275–342), and his long-standing and
valuable help and collaborations.
I would like to record my appreciation for invaluable secretarial support to
Veronica Rainsford-Koechli and to Alexander and William Rainsford for their
expert preparation of the figures and tables in this book.
Sheffield, UK K. D. Rainsford
10 December 2012
.
Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Introduction of Ibuprofen for Non-Prescription (OTC) Use . . . . . 2
1.3 Experience at Prescription Level Dosage . . . . . . . . . . . . . . . . . . 3
1.4 Scope and Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2 Biodisposition in Relation to Actions . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1 Key Aspects of the Pharmacokinetics and Biodisposition
of Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.1 Impact of Variability in Pharmacokinetics . . . . . . . . . . . . 11
2.2 Plasma/Serum Concentrations Relevant to Onset
of Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.2.1 Dental Pain Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.2.2 Induced Pain Models . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.2.3 Applicability to Other Acute Pain States . . . . . . . . . . . . . 25
2.3 Antipyresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.4 Therapeutically-Relevant Concentrations
in Rheumatic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.4.1 Plasma/Serum Levels in Arthritic Diseases . . . . . . . . . . . 28
2.4.2 Accumulation in Synovial Fluids . . . . . . . . . . . . . . . . . . 30
2.4.3 Rectal Administration in Adults and Children . . . . . . . . . 33
2.5 Pharmacokinetics in Children . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.5.1 Juvenile Idiopathic (Rheumatoid) Arthritis . . . . . . . . . . . 40
2.5.2 Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.5.3 Patent Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . 42
3 Mechanisms of Inflammation and Sites of Action of NSAIDs . . . . . 43
3.1 Pathways of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.2 Link of Pharmacokinetics to Pharmacodynamics . . . . . . . . . . . . 45
3.3 Relation of Analgesic Effects to COX-1
and COX-2 Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

xiii
xiv Contents

3.4 Multiple Modes of Anti-inflammatory Activities . . . . . . . . . . . . 50

3.4.1 Pain Control Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3.4.2 Antipyretic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
4 Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.1 Dental Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.2 Pain Relief at OTC Dosages . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.3 Treatment of Pain in Osteoarthritis and Related
Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.4 Paediatric Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.4.1 Acute Fever in Children . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.4.2 Juvenile Idiopathic (Rheumatoid) Arthritis . . . . . . . . . . . 75
5 Drug Derivatives and Formulations . . . . . . . . . . . . . . . . . . . . . . . . 77
5.1 Dexibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
5.2 Combinations with Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.3 Ibuprofen–Codeine Combinations . . . . . . . . . . . . . . . . . . . . . . . 81
5.4 Ibuprofen–Paracetamol Combination . . . . . . . . . . . . . . . . . . . . . 83
5.5 Amino Acid and Salt Formulations . . . . . . . . . . . . . . . . . . . . . . 87
5.6 Topical Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
6 General Safety Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
6.2 Pharmacokinetic Aspects of Importance
in the Safety of Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
6.3 Pharmacokinetic Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
6.4 Pharmacokinetics in Oriental Compared with Caucasian
Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
6.5 Influence of Disease States on PK of Ibuprofen . . . . . . . . . . . . 101
6.6 ADRs and Safety in Prescription-Level Doses . . . . . . . . . . . . . 102
6.7 Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
6.8 Outcomes from Large-scale Clinical Trials . . . . . . . . . . . . . . . 104
6.9 Adverse Events Attributed to Ibuprofen at Non-prescription
(OTC) Dosages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
6.10 ADR Risks in Oriental Populations . . . . . . . . . . . . . . . . . . . . . 113
6.11 Potential Concerns with Chinese Traditional and Herbal
Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
6.12 Adverse Events and Safety in Paediatric Populations . . . . . . . . 119
7 Gastro-Intestinal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7.1 Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
7.2 GI Risks in Coxib Studies at Prescription Doses . . . . . . . . . . . . . 130
7.3 GI Symptomatic Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . 134
7.4 GI Events at OTC Dosages . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
7.5 GI Safety in Paediatric Populations . . . . . . . . . . . . . . . . . . . . . . 135
7.6 Reducing GI Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Contents xv

8 Cardiovascular Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

8.1 Disease-related Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
8.2 Heightened Concerns from the Coxib Studies . . . . . . . . . . . . . . . 142
8.3 Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
8.4 Recent Clinical Trials and Meta-Analyses . . . . . . . . . . . . . . . . . 152
8.4.1 Individual Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
8.5 Interaction of Ibuprofen with the Anti-platelet
Effects of Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
8.6 Effects in Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
8.7 Congestive Heart Failure and Cardio-Renal Effects . . . . . . . . . . 162
8.8 Balancing CV and GI Risks of NSAIDs . . . . . . . . . . . . . . . . . . . 162
9 Renal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
10 Hepatic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
11 Other Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
11.1 Hypersensitivity Reactions and Asthma . . . . . . . . . . . . . . . . . . 169
11.2 Cutaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
11.3 Risk of Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
12 Global Assessment of Adverse Reactions and Human
Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
12.1 Initial Basis for Approval for OTC Sale in UK and USA . . . . . 175
12.2 Experience in the UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
12.3 Cases of Poisoning in UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
12.4 Limitations on Analgesic Pack Sizes in UK . . . . . . . . . . . . . . . 180
12.5 Concerns About Misuse of Analgesics in USA . . . . . . . . . . . . . 180
13 Overall Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
13.1 Spontaneous ADRs and Toxicity . . . . . . . . . . . . . . . . . . . . . . . 183
13.2 Benefit/Risk Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
13.3 Assessment of Risks and Procedures for Their Reduction . . . . . 185
13.4 Examples of Advice for Ibuprofen Packages and PILs . . . . . . . 187
14 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
.
Abbreviations and Explanations

5-HT 5-Hydroxytryptamine (serotonin)

Acetaminophen Paracetamol [synonym]
ADR Adverse drug reaction
AE Adverse event
AIA Aspirin intolerant asthma
ALT Alanine amino transferase (syn SGPT)
ASA Acetyl-salicylic acid (= aspirin)
AST Aspartate amino transferase (syn SGOT)
ATP Adenosine monophosphate
AUC Area under the curve
b.d. bis die (twice a day)
B-cell Bursar-derived or -like lymphocyte
BK Bradykinin
cAMP Cyclic adenosine monophosphate
CB Cannabinoid (receptor)
CGRP Calcitonin gene-related peptide
CHD Coronary heart disease
CI Confidence interval
Cl Clearance
Cl/F Fractional clearance
CLASS Celecoxib Long-term Arthritis Safety Study (clinical trial)
Cmax Maximal concentration
CNS Central nervous system
COSTART Coding symbols for a thesaurus of adverse reaction terms
COX Cyclo-oxygenase
COX-1 Cyclo-oxygenase-1 [isoform]
COX-2 Cyclo-oxygenase-2 [isoform]
Cp Plasma concentration
CSM UK Committee on the Safety of Medicines (now MHRA)
CTM Chinese traditional medicines
CV Cardio-vascular

xvii
xviii Abbreviations and Explanations

CYP-2C19 2C19 isoform of Cytochrome P450

CYP-2C8 2C8 isoform of Cytochrome P450
CYP-2C9 2C9 isoform of Cytochrome P450
CYP-2C9*1, *2 or *3 2C9 Genetic variants 1, 2 or 3 of the isoform of
Cytochrome P450
CYP450 Cytochrome P450
DDD Defined daily dose
DRG Dorsal root ganglion
EC50 Concentration for half-maximal effect
EEG Electro-encephalograph(y)
EMA (EMEA) European Medicines (Evaluation) Agency
eNOS Endothelial nitric oxide synthase
EP (receptor) E-Prostaglandin receptor(s)
EP Evoked potential(s)
ER Extended release
FDA US Food and Drug Administration
FP (receptor) F-Prostaglandin receptor(s)
GCP Good clinical practice
GI Gastrointestinal
GI Gastro-intestinal
GLU Glutamate
GSL General sales list [direct to public sale]
GU Gastric ulcer
HAQ Health assessment questionnaire
HR Hazard rate
i.p. intra-peritoneal
i.r. intra-rectal
IBU Ibuprofen
ICH International Committee for Harmonization of clinical
trials
IE Intensity estimates (of pain responses)
IkB Inhibitor of nuclear factor kappa B
IL Interleukin
IL-1, -6, -8 Interleukins 1, 6 or 8
iNOS Inducible nitric oxide synthase
IP (receptor) I-Prostaglandin, or prostacyclin receptor(s)
JIA Juvenile inflammatory arthritis, or juvenile rheumatoid
arthritis (JRA)
Ka Absorption rate constant
kel or Ke Elimination rate constant
LC-MS Liquid chromatography–mass spectrometry
LFT Liver function tests
LT Leukotriene
MHRA UK Medicine and Healthcare Products Regulatory
Agency
Abbreviations and Explanations xix

MI Myocardial Infarction
MMP Matrix metalloproteinase(s)
MRT Mean (or median) residence time
MTT Mean transit time
N Number of subjects or patients
NA Noradrenaline (norepinephrine)
NFkB Nuclear factor kappa B
NGF Nerve growth factor
NMDA N-methyl-D-aspartate (glutamate receptor)
NN Non-narcotic
nNOS Neuronal nitric oxide synthase
NNT Number needed to treat
NO Nitric oxide
NOS Nitric oxide synthase
NP Non-prescription
NS (NSAID) Non-selective (COX-inhibitory) NSAID
NSAIDs Non-steroidal anti-inflammatory drugs
OA Osteoarthritis
OH• Hydroxyl radical(s)
ONOO• Peroxy-radical(s)
OR Odds ratio
OTC Over-the-counter (sale) or non-prescription
P- or P-only Prescription
p.r.n. pro re nata (as required)
PAR Pain relief (score(s))
PD Pharmacodynamic(s)
PDA Patient ductus arteriosus
PG Prostaglandin
PGD2 Prostaglandin D2
PGE2 Prostaglandin E2
PGF2a Prostaglandin F2a
PGH2 Prostaglandin G/H synthase
PGI2 Prostaglandin I2 or prostacyclin
PID Pain intensity difference
PK Pharmacokinetic(s)
pKa negative logarithm of the dissociation constant
Plasma or serum Refers to the medium in which drug concentrations are
measured
PMN Polymorphonuclear leucocytes (neutrophils)
PPIs Proton pump inhibitors
q.i.d. quarter in die (4 times a day)
R(-) R enantiomer
RA Rheumatoid arthritis
rac Racemic (mixture) or racemate
xx Abbreviations and Explanations

RR Relative risk
S(+) S (+) enantiomer (syn. dexibuprofen)
SD Standard deviation
SEM Standard error of the mean
Serotonin 5-Hydroxytryptamine
SGOT Serum glutamate oxaloacetate transaminase (syn AST)
SGPT Serum glutamate pyruvate transaminases (syn ALT)
SP Substance P
SPID Sum of pain intensity difference(s)
SR Sustained release
t.i.d. ter in die (3 times a day)
t1/2 Half-life of elimination
T-cell or Th Thymus-derived lymphocyte
TIA Transient ischaemic attack
tmax Time at peak maximal concentration
TNFa Tumour necrosis factor-a
TOTPAR Total pain relief
TRIAD Tri-organ (gastro-intestinal, liver and caradiovascular)
toxicity
TRPC Therapeutically relevant plasma concentrations
TxA2 Thromboxane A2
TxB2 Thromboxane B2
VAS Visual analogue scale
VD Volume of distribution
VD/F Fractional volume of distribution
VIGOR Vioxx Gastrointestinal Outcomes Research Study
(clinical trial)
WOMAC Western Ontario McMaster University Assessment
Chapter 1
Introduction

It is now half a century since ibuprofen was discovered to have anti-inflammatory

properties by Dr (now Professor) Stewart Adams at the Boots Company in
Nottingham (UK) (Rainsford 2011). Since then, ibuprofen has evolved to be
amongst the most widely-used analgesic–antipyretic–anti-inflammatory drugs
today. It is available in nearly all countries in the world as both a prescription and
over-the-counter sale drug for treating a wide variety of painful and inflammatory
conditions, although its principal approved application is the for the treatment of
mild–moderate pain, including musculo-skeletal conditions, headache/migraine,
fever, and accidental injuries. As an over-the-counter sale remedy it is registered
for sale in 82 countries worldwide. It probably ranks after aspirin and paracetamol
in non-prescription over-the-counter (OTC) use for the relief of symptoms of acute
pain, inflammation, and fever, although the patterns of use of these analgesics vary
considerably from country to country worldwide. Of these three analgesics, OTC
ibuprofen is probably the least toxic, being rarely associated with deaths from
accidental or deliberate misuse, or with serious adverse reactions. Indeed, it has
been described as “the mildest NSAID with the fewest side-effects, and has been in
clinical use for a long time” (General Practice Notebook; http://www.gpntebook.co.
uk, accessed 1/12/2011).

1.1 Background

Ibuprofen was initially introduced in the UK in 1969, and afterwards during the
1970s worldwide, as a prescription-only medication, where it was recommended to
be prescribed at up to 2,400 mg per day (and even at a higher dose in the USA) for
the treatment of musculo-skeletal pain and inflammation as well as other painful
conditions (Rainsford 1999a). During the 1970s, it was the most frequently
prescribed drug for use either as a first-line NSAID or in place of aspirin, indo-
methacin, or phenylbutazone for treatment of arthritic conditions. The experience
during and after this period showed it had a reputation for good efficacy and lower

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 1

DOI 10.1007/978-3-0348-0496-7_1, # Springer Basel 2012
2 1 Introduction

gastrointestinal adverse effects. Initially, the drug was used in low doses ranging
from 400 to 1,200 mg per day and, with latitude and experience, by physicians’
cautious dose-escalation proceeded to the current recommended dosage of
2,400 mg per day (Rainsford 1999a, 2009; Kean et al. 1999).

1.2 Introduction of Ibuprofen for Non-Prescription

(OTC) Use

The emphasis on the initial cautious use of ibuprofen was one of the hallmarks of
its early success and the development of confidence in its safe use (Rainsford 1999a).
It was following a long period of safety evaluation of prescription-level dosage
of ibuprofen for treating rheumatic conditions that the Boots Company Ltd.
(Nottingham, UK) applied for and was granted a licence in 1983 to market ibuprofen
as a non-prescription (NP) drug for over-the-counter (OTC) sale (or General Sales
Listing, GSL) at a daily dose of up to 1,200 mg. In the following year, the Upjohn
Company in collaboration with the Boots Company was granted a licence by the US
Food and Drug Administration (FDA) to market ibuprofen as an OTC drug in the
USA. The decision by the FDA was predicated on the basis of the drug having a
proven record of safety, for at that stage it was given that the drug was efficacious in
the treatment of pain and associated inflammatory conditions (Paulus 1990).
Following these two successful introductions of ibuprofen for NP-OTC use,
there followed approvals in a large number of countries worldwide. Overall, the
drug is licensed for OTC use in 27 European and 55 non-European countries,
making a total of 82 countries worldwide. In contrast to some other NSAIDs,
ibuprofen has never had its licence revoked or suspended for reasons relating to
safety or other factors concerned with the use of this drug.
A major competitor to ibuprofen has been paracetamol (acetaminophen),
especially in the OTC field but also, as discussed later, in therapy of osteoarthritis.
In non-prescription OTC use for paediatric use, both ibuprofen and paracetamol are
equally effective in controlling fever, but there are recent data to suggest that
combination of these two drugs may be particularly useful in severe febrile or
painful conditions. It appears that ibuprofen and paracetamol have differing modes
of action, and ibuprofen is the more potent of the two for anti-inflammatory
activities. It is possible that they may have additive or synergistic analgesic effects.
Claims by those advocating paracetamol are that this drug is associated with
lower gastrointestinal (GI) and renal adverse reactions than observed with ibupro-
fen. For OTC use, these differences are minimal or nonexistent (Rainsford et al.
1997, Rainsford 2009). At higher prescription doses as used in arthritis therapy, the
consensus is that the differences in GI adverse reactions are relatively low, while
renal adverse reactions may be more prevalent in patients taking ibuprofen. A major
issue with paracetamol is hepatotoxicity especially when taken in the range of 3–4 g
daily long-term and with alcohol. The situation with regard to consumption of
alcohol and the use of paracetamol in patients with alcoholic liver disease or signs
1.3 Experience at Prescription Level Dosage 3

of alcohol abuse is quite serious. Mild to moderate hepatic reactions have been
observed infrequently with high prescription doses of ibuprofen, but rarely with
NP-OTC doses of this drug.
In some countries (e.g., USA, UK, Australia) where naproxen and ketoprofen are
marketed for OTC use, these have been competitors for ibuprofen. Both these drugs
are more potent as anti-inflammatory agents and prostaglandin inhibitors than
ibuprofen, and are associated with higher risk of upper GI adverse reactions at
prescription doses. Naproxen tends to be used as a second-line drug for treatment of
primary dysmenorrhoea where aspirin, ibuprofen, and paracetamol are found to be
less effective. Ketoprofen is favoured by some for more severe joint pain in arthritic
disease.
Overall, ibuprofen has withstood competition and challenges over the four
decades since its introduction as a prescription drug, and in the period of over
two decades since it was introduced for over-the-counter sale.

1.3 Experience at Prescription Level Dosage

Over the years, there have been many challenges to ibuprofen, some from concerns
about safety including the occurrence of some very rare serious adverse reactions
[e.g., Stevens-Johnson and Lyell’s (toxic epidermal necrolysis) syndromes, renal or
cardiovascular failure, necrotising fasciitis] as well as some that are more common
to the class of NSAIDs. Most recent of these have been cardiovascular (CV)
conditions that were highlighted by the occurrence of fatal and non-fatal
myocardial infarction and cardio-renal symptoms in patients receiving the newer
class of NSAIDs, the coxibs (rofecoxib, valdecoxib and to some extent celecoxib
(Östör and Hazleman 2005; Rainsford 2005a). This had the effect of regulatory
agencies worldwide examining the potential of all NSAIDs to cause CV and cardio-
renal symptoms, an aspect that is still of concern for some of the coxibs and some
NSAIDs.
There have also been many challenges from newer NSAIDs, particularly the
wave of some 20–30 new NSAIDs introduced in the period of 1970s–1980s and the
much celebrated introduction of the selective cyclooxygenase-2 (COX-2) inhibitors
(“coxibs”) that appeared in 1999 following the discovery of COX-2 as the main
prostaglandin synthesising enzyme expressed in inflammation and pain pathways
(Rainsford 2007). Surprisingly, one-half to two thirds of the NSAIDs introduced to
the clinic since the 1970s have been withdrawn from the market, mostly due to
unacceptable and unpredictable toxicities (Rainsford 1987). So in a sense, ibupro-
fen has survived these challenges both from the point of view of competition from
the newer drugs and the inevitable negative impact of the failures or associations
with other drugs that have raised safety issues (e.g., the CV risks raised by the
coxibs). Mostly, these issues have concerned prescription-only NSAIDs, although
those sold OTC like ibuprofen may also have been affected by these issues.
4 1 Introduction

1.4 Scope and Objectives

This book aims to bring together key salient and clinically important published data
and information on the safety and efficacy of ibuprofen at both prescription (up to
2,400 mg per day) and non-prescription or OTC (1,200 mg per day) doses. While
the focus of attention is on consideration of the application of the lower OTC doses
of the drug for wider use in the population, the data on prescription-level dosage is
useful for showing the safety potential of the drug and the important issues of what
happens when OTC doses might be exceeded.
The main emphasis in this review is on the scientific evidence for safety of
ibuprofen at OTC dosage (1,200 mg per day), since this is the central issue that is
recognised in the evaluation of the drug for OTC sale. The safety profile of
ibuprofen at prescription-level (P-level) doses (>1,200 mg per day; usually
1,800–2,400 mg per day) is reviewed and evaluated as an indication of what can
be considered the upper limits of toxic actions of the drug. It is not expected that the
public taking the drug at the recommended OTC doses would experience adverse
reactions observed at prescription level, but this may be considered as an indicator
of safety at the upper limit or extreme of dosage. Based on this evidence and that for
the efficacy of the drug, including that in relation to its competitors, an assessment
of the benefit/risk profile of ibuprofen is considered and the risks are presented.
This review also focuses on the modes of action of ibuprofen especially in
relation to its pharmacokinetics, recent concepts of inflammatory processes, and
clinical indications.
Chapter 2
Biodisposition in Relation to Actions

Like most NSAIDs, ibuprofen has multiple actions including the inhibition of
prostaglandin (PG) production, and these activities underlie the clinical effects
that are linked to its pharmacokinetic (PK) properties (Rainsford 1996, 1999b,
2009). In this chapter, the principal PK and pharmacodynamic (PD) properties
that are relevant to the analgesic and anti-inflammatory activities of ibuprofen are
considered.

2.1 Key Aspects of the Pharmacokinetics

and Biodisposition of Ibuprofen

The form of ibuprofen sold OTC has a racemic chemical structure. This arises from
the position of the methyl moiety that is attached to the 2-carbon atom (i.e., adjacent
to the carboxyl group) (Fig. 2.1).
The commercially available drug is composed of a 50:50 mixture of the R(
)-
and S(þ)- enantiomers (or isomers) (Fig. 2.1).
The existence of the racemic mixture was not appreciated in the early chemical
development of the drug, but studies on the metabolism and identification of the
prostaglandin synthesis (PG) inhibitory activities (Adams et al. 1976; Rainsford
1999a, b) showed that S(þ)-ibuprofen was a potent inhibitor and R(
)-ibuprofen
was a relatively weak inhibitor of PGs. Since the original observations concerning
the selectivity of the two enantiomers on the production of PGs (Adams et al. 1976),
it is now known that this effect is achieved by the selective actions on different
components of inflammatory pathways. The major pathways of metabolism of
racemic [i.e., R(
)- and S(þ)]-ibuprofen involved (a) conversion of about
40–60 % or the R(
) form to the S(þ) antipode, (b) oxidative conversion catalysed
by cytochromes P450 of the tert-butyl side chain to hydroxyl or carboxyl moieties,
and (c) conjugation with glucuronic acid catalysed by glucuronyl transferases or
with taurine by aminoacyl transferases (Fig. 2.2). Relatively small quantities

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 5

DOI 10.1007/978-3-0348-0496-7_2, # Springer Basel 2012
6 2 Biodisposition in Relation to Actions

H CH3 H CH3
H3C OH
OH
CH3
O
O H3C
CH3
S(+)-Ibuprofen R-(-)-Ibuprofen

Fig. 2.1 Chemical structures of the R(
)- and S(þ)- isomers of ibuprofen (Nichol 1999). The
ibuprofen molecule has a chiral centre at carbon-2 of the propionic acid group. This leads to the
formation of two optical isomers or enantiomers. The (þ) form (originally described as d- or
dextro-) has the S- configuration. The (
) form (comprising the l- or leavo-) has the R-configura-
tion (Ghislandi et al. 1982).

(circa 4 %) of ibuprofen glucuronides are formed in isolated cell systems (Koga

et al. 2011; Buchheit et al. 2011) and in subjects who have taken repeated oral doses
of ibuprofen (Castillo et al. 1995), which are excreted in urine (Ikegawa et al. 1998).
The half-lives of the S(þ)-ibuprofen, 2-hydroxylated or carboxylated glucuronides
are approximately 3.7 h, while the R(
)-ibuprofen acyl glucuronides are about
1.7 h (Johnson et al. 2007). The S-acyl-glutathione, but not the glucuronides,
appears to have the capacity to be reactive in transacylation reactions in vitro
(Grillo and Hua 2008). The acylation of plasma and other proteins from ibuprofenyl
glucuronide occurs to a limited extent, but is not appreciable and appears short-
lived (Vanderhoeven et al. 2006).
Ibuprofen is rapidly, and almost completely, absorbed from the upper gastro-
intestinal tract. As shown in Fig. 2.3 (Dewland et al. 2009), the plasma concentra-
tion profiles of ibuprofen can vary according to the drug formulation (Ceppi Monti
et al. 1992; Brocks and Jamali 1999; Lötsch et al. 2001; Dewland et al. 2009;
Cattaneo and Clementi 2010). Thus, sodium salt or solubilised (poloxamer)
formulations of ibuprofen are more rapidly absorbed than the acid (Dewland
et al. 2009). Most other formulations of ibuprofen, including extended- or
sustained-release types, show similar and near complete bioavailability compared
with the immediate-release forms (Brocks and Jamali 1999).
Comparing the plasma profiles of the R(
)- and S(þ)-enantiomers of ibuprofen
(Figs. 2.3 and 2.4) shows that following the plasma profile of the S(þ)-ibuprofen
lags behind that of the R(
)-isomer, whether the drug is taken as the racemic
mixture (a) or and the separate R(
) isomer (c) compared with the S(þ) isomer (b).
This lag of the S(þ)- form is considered to be a consequence of the metabolic
conversion of the R(
)- to S(þ) forms (Rudy et al. 1992; Brocks and Jamali 1999;
Graham and Williams 2004; Fig. 2.4; Table 2.1).
A typical set of quantitative pharmacokinetic parameters for the R(
)- and S(þ)-
isomers of racemic ibuprofen taken orally by healthy human volunteers at an OTC
dose of 400 mg is shown in Table 2.1. Here, it is evident that the rate of elimination
kel, of S(þ) ibuprofen is lower than that of the R(
)-enantiomer and this may reflect
the combination of longer t1/2, and lower clearance of the S(þ) enantiomer com-
pared with that of the R(
) antipode. The Cmax, AUC and mean residence time
(MRT) for S(þ) ibuprofen are all greater than that of the R(
) enantiomers,
2.1 Key Aspects of the Pharmacokinetics and Biodisposition of Ibuprofen 7

Fig. 2.2 Metabolism of the PG (COX) inactive R(
)-ibuprofen to the COX-inhibitory or active
S(+)-antipode catalysed by 2-aryl-proprionyl-coenzyme A epimerase (Reichel et al. 1997) and
subsequent oxidative reactions and glucuronidation. About 40–60 % of the R(
) ibuprofen is
converted to the S(+), whereupon there may be addition of glucuronic acid to form acyl- (i.e.
carboxyl-) glucuronides and hydroxylation of the tert-butyl side chain to form 1-, 2- or 3-hydroxyl-
ibuprofen metabolites, and subsequently 3-carboxy-ibuprofen from 3-hydroxy-ibuprofen (Brocks
and Jamali 1999; Graham and Williams 2004). The formation of the hydroxyl- and carboxy-
metabolites is catalysed by cytochromes P-450. The carboxy-metabolite may be subsequently
glucuronidated to form the acyl-glucuronides Holmes et al. (2007). All these metabolites appear to
be pharmacologically inactive, and these metabolic pathways constitute detoxification of the drug.
Additionally, a disopyramide metabolite has been identified in human urine by NMR and MS
hyperspectroscopy (Crockford et al. 2008), but the metabolic origins and fate of this are unknown.
Mixed triglyceride derivatives (termed hybrid lipids) of ibuprofen have been identified (Williams
et al. 1986), and are synthesised following the formation of the ibuprofen thioester of coenzyme A
through a corruption of the short-medium fatty acyl coenzyme A synthetic pathway. These
metabolites are present in small quantities relative to other triglycerides in liver cells, adipose
tissue, and plasma, and they have slow turnover (Brocks and Jamali 1999; Graham and Williams
2004). Little is known about the pharmacological activity of these hybrid triglycerides
8 2 Biodisposition in Relation to Actions

Fig. 2.3 Mean plasma concentration profiles of racemic ibuprofen (determined by LC-MS) follow-
ing oral ingestion of a single dose of: (a) 2  200 mg tablets of ibuprofen acid [“standard ibuprofen”
in the figure, i.e., Nurofen®], (b) 2  256 mg tablets of sodium dihydrate ibuprofen [“sodium
ibuprofen”, with the equivalent mass of ibuprofen to that in (a)], and (c) 2  200 mg ibuprofen
acid in which is incorporated 60 mg poloxamer as a solubilising excipient [“ibuprofen/poloxamer”].
The sodium ibuprofen achieved the shortest tmax of 35 min and higher Cmax of 41.47 mg/mL,
compared with that of standard ibuprofen (acid) with a tmax of 90 min and Cmax of 31.88 mg/mL,
while the ibuprofen/poloxamer had a tmax of 75 min and a Cmax of 35.22 mg/mL, which was a shorter
time interval but little difference in Cmax compared with the latter. The bioavailability of ibuprofen
from all these formulations was similar [expressed as AUC0–inf (range 117–122 mg/h/mL) and
AUC0–4 (range 115–120 mg/h/mL)], and amounted to approximately 100 %. Redrawn and reproduced
with permission from Dewland et al. (2009) under the terms of BMC Open Access

reflecting the increase in formation of the S(þ) over the R(
) antipode. Overall,
these data confirm the dynamic formation of the S(þ) enantiomer from R(
)
ibuprofen in accordance with the mechanism of inversion as shown in Fig. 2.4.
This emphasises the importance of the enantiomeric conversion of ibuprofen for the
actions of this drug on prostaglandin-related inflammation.
Ibuprofen is extensively metabolised in humans to hydroxyl, carboxyl, and
glucuronyl metabolites which are pharmacologically inactive (Brocks and Jamali
1999; Graham and Williams 2004; Holmes et al. 2007). Ibuprofen glucuronide can
also form irreversibly bound drug–protein adducts in vitro, including those to
albumin (Castillo et al. 1995). The stability and reactivity of these different adducts
is not known.
Like that of other NSAIDs, ibuprofen displays extensive (~99 %) binding to
plasma proteins (Brocks and Jamali 1999; Graham and Williams 2004). Thus, there
is a relatively low volume of distribution of the drug of approximately 10–20 l in
adult volunteers (Table 2.1) as well as in patients. The non-linear PKs of ibuprofen
at high doses are due to saturation of plasma protein binding.
Simulations of the rate of absorption on the relative tmax of the enantiomers of
ibuprofen in the presence and absence of pre-systemic inversion support the view
2.1 Key Aspects of the Pharmacokinetics and Biodisposition of Ibuprofen 9

Fig. 2.4 Mean serum concentrations of S(+) ibuprofen (open circles) or R(
) ibuprofen
(open squares) with time after oral intake by healthy human volunteers of 600 mg S(+) ibuprofen
(a), 600 mg of R(
) ibuprofen (b), or 800 mg of the racemate (c). Note the appearance of S(+)
ibuprofen following that of the R(
) isomer both after intake of R(
) ibuprofen (b) and the
racemic mixture (c). The studies were undertaken using a stable deuterium isotope methodology
(Rudy et al. 1992). Modified from Rudy et al. (1992) with the tracing of the internal standard of
S-D4-ibuprofen shown in red. Reproduced according to the proprietary rights and permission of
The Journal of Pharmacology and Experimental Therapeutics

Table 2.1 Pharmacokinetic parameters for oral ibuprofen (400 mg)

Data analysis S-ibuprofen R-ibuprofen
Non-compartmental analysis
Ke (h
1) 0.359  0.128 0.538  0.087*
t1/2 (h) 2.18  0.83 1.33  0.25
tmax (h) 1.64  0.71 1.59  0.77
Cmax (mg/mL) 19.0  4.7 17.8  3.3
AUC (mg/h/mL) 75.0  27.1 52.2  11.5*
AUMC (mg/h/mL) 328  229 155  72*
MRT (h) 4.08  1.52 2.86  0.79*
Cl/F (L/h) 2.90  0.73 4.00  0.85*
Vd/F (L) 8.61  2.63 7.46  1.22
Compartmental analysis
Vd/F (L) 6.28  2.2
Ka (h
1) 1.08  0.95
Ke (h
1) 0.50  0.22
*Indicates statistically significant difference at P < 0.05. Values are means + SD. From
Suri et al. (1997a)

that a pre-systemic process predominates in the chiral inversion of ibuprofen. This

pre-systemic inversion of ibuprofen takes place in the GI tract.
As shown in Fig. 2.5, there is approximate linearity in the values of Cmax and
AUC with dosage of ibuprofen.
10 2 Biodisposition in Relation to Actions

Fig. 2.5 Relationships between dose of ibuprofen and the Cmax and AUC of the R(
) and S(þ)
enantiomers

The synovial compartment is considered a site of action, and several studies have
shown the accumulation of either racemic ibuprofen or its enantiomers in the
synovial fluid of arthritic patients requiring aspiration of synovial effusions of the
knee (Whitlam et al. 1981; Gallo et al. 1986; Day et al. 1988; Cox et al. 1991;
Seideman et al. 1994; Elmquist et al. 1994; Dominkus et al. 1996). The accumula-
tion of ibuprofen occurs to about 40–60 % of the concentration of the drug in
plasma or serum. The tmax in synovial fluid of both enantiomers lags approximately
2 h behind that in serum or plasma. The mean rate constants for ibuprofen transfer
into and out of the synovial fluid are 0.91 and 0.34 h
1 respectively (Seideman et al.
1994). The mean S:R ratio of AUC in synovial fluid is 2.1 compared with 1.6 in
plasma, with a linear relationship between the two (Day et al. 1988). The protein
content (mostly albumin) is a major contribution to ibuprofen kinetics into synovial
fluid as the drug is strongly bound to synovial fluid, though not to the extent of that
in plasma (Whitlam et al. 1981; Gallo et al. 1986; Cox et al. 1991).
Since the pathways in the CNS underlie the antipyretic and analgesic properties
of NSAIDs, including ibuprofen, the potential for uptake of ibuprofen enantiomers
into the CSF was studied by Bannwarth et al. (1995). They found that the AUC0–8h
of the R and S enantiomers in CSF were 0.9 % and 1.5 % respectively of those in
plasma, which reflects the higher unbound fraction of the S enantiomer in plasma.
2.1 Key Aspects of the Pharmacokinetics and Biodisposition of Ibuprofen 11

As in the synovial fluid compartment, the peak ibuprofen enantiomer concentrations

are present in CSF later than in plasma, and are attributed to passive transport of drug
into the CSF. Higher concentrations of ibuprofen enantiomers were present in the
CSF than could be accounted for on the basis of the unbound concentration in plasma.
The S:R ratios of ibuprofen enantiomers in CSF was found to be 2:1, similar to that of
unbound drug in plasma but higher than in the synovial fluids suggesting that the
outward kinetics of the enantiomers determines the ratio of R:S in the CSF
compartment.
These studies on the kinetics and disposition of ibuprofen and its enantiomers in
synovial fluids and the CNS form an important basis for understanding the analge-
sic actions of the drug in these compartments.

2.1.1 Impact of Variability in Pharmacokinetics

The pharmacokinetic (PK) variations with individual NSAIDs may constitute an

important reason for their differing toxicities and occurrence of ADRs in different
organ systems. A concept of the TRIAD toxicity may be postulated to show these
inter-relationships between PK and PD or relatively toxicity of NSAIDs, as shown
in Fig. 2.6.
The pathways of oxidative metabolism of ibuprofen are shown in Fig. 2.1. These
principally involve the cytochromes P450 2C9 (CYP-2C9), CYP-2C8 and 2C19
participating in the oxidation of the alkyl side chain to hydroxyl and carboxyl
derivatives. These cytochromes are coded by a gene cluster on chromosome 10q24
(Mo et al. 2009). CYP-2C9 is probably the most abundant of these three
cytochromes, and metabolises about 20 % of clinically used drugs of a wide variety
of pharmacological classes (amounting to some 120 in all) (Mo et al. 2009). With
such wide substrate specificity, it is not surprising that there are extensive drug
interactions at the level of CYP-2C9 as well as CYP-2C19. The S(þ) and R(
)
isomers have approximately the same kinetic constants for hydroxylation at their
2-or 3-position (Hamman et al. 1997).
Differential metabolism of S(þ) and R(
) ibuprofen occurs as a result of CYP-
2C9, CYP-2C19 and CYP-2C8, with these being referred to as S(þ) ibuprofen and
R(
)-ibuprofen hydroxylase activities respectively (Kirchheiner et al. 2002). Of the
allelic frequencies of these CYP isoenzymes, the three ascribed to CYP-2C9
comprise the wild type CYP-2C9*1 which is characterised by an arginine at
codon 359 on the gene. In the variant CYP-2C9*2, this arginine is replaced by
cysteine, and in the variant CYP-2C9*3 the isoleucine-359 is replaced by leucine.
In vitro studies and human PK studies have shown that CYP-2C9*2 has only
slightly less activity than that of the wild type CYP2C9*1, whereas that of
CYP-2C9*3 is 10–30 % less so (Kirchheiner et al. 2002). In comparisons of the
pharmacokinetics of the S(þ) enantiomer, the rates of clearance were found to
12 2 Biodisposition in Relation to Actions

Fig. 2.6 Postulated inter-relationships between differences in PK of NSAIDs and their propensity
to develop toxicity or ADRs. Based on Rainsford et al. (2008a, b)

parallel the enzymic activity, with subjects having the CYP-2C9*1/*2 and *3/*3
variants having 27 % and 53 % less clearance than those with the wild type *1/*1
genotype (Kirchheiner et al. 2002). For other NSAIDs (e.g., celecoxib, diclofenac)
there is either increased or decreased clearance in individuals with these isoforms.
These aspects are discussed in Sect. 6.3 on “Pharmacokinetic Variations”. Thus,
overall it can be stated that there is marked variation in the PK of ibuprofen and
other NSAIDs according to the CYP-2C9 status.
Single nucleotide polymorphism studies in 45 populations worldwide have
highlighted the global variation that occurs in different populations in the
CYP2C8 and CYP2C9 functional haplotypes (Speed et al. 2009). It has been
suggested from these studies that global variation in these cytochromes may
account for the substantial variations in drug metabolism, response, and toxicity.
One such example of the functional impact shows that increased risks of interna-
tional normalisation ratio (INR) may be seen in patients receiving warfarin who
have the *2 and *3 variants of CYP2C9 system (Lindh et al. 2005).
As far as other indications of the significance of CYP polymorphisms, studies by
Pachkoria et al. (2007a, b) have examined the role of CYP-2C9 and CYP-2C19
polymorphisms for associations with drug-induced idiosyncratic reactions. While
arguably liver reactions from NSAIDs have been associated with abnormalities of
phase 1 and phase 2 metabolism, the studies by Pachkoria et al. (2007a, b) have
failed to establish if polymorphisms of CYP-2C9 or CYP-2C19 are associated with
liver disease.
2.2 Plasma/Serum Concentrations Relevant to Onset of Analgesia 13

In summary, the key pharmacokinetic properties of ibuprofen (Rainsford 2009)

include:
1. Depending on the particular formulation there are relatively fast rates of absorp-
tion of the drug, with subsequent “first pass” liver phase 1 and phase 2 metabo-
lism to well-characterised (a) phenolic and carboxylic acid derivatives via
CYP-2C8, CYP-2C9 and CYP-2C19 activities, and (b) subsequent conjugation
with glucuronic acid and taurine (a minor metabolite).
2. The overall biodisposition of ibuprofen is a consequence of high plasma protein
binding and low volume of distribution, but with the capacity to be accumulated
in appreciable quantities in inflamed compartments where there is need for
anti-inflammatory/analgesic activity (synovial fluids, CSF), but not in those
sites in which side-effects occur (Brune 2007).
3. Ibuprofen has a relatively short plasma elimination half-life, and although
prolonged in liver and renal diseases this is not so appreciable as to be a factor
accounting for a high frequency of adverse events. Indeed, the longer t½ has been
suggested as a factor accounting for low incidence of serious GI events (bleed-
ing, peptic ulcers) (Henry et al. 1996, 1998; see Chap. 7).
4. Ibuprofen exhibits approximately linear kinetics to within 1,200 mg dosage, or
near compliance with predictable kinetics.
5. Chronic disease states (arthritis) have relatively little impact on the overall
kinetics of ibuprofen. However, acute surgical pain reduces the plasma
concentrations of R(
) and S(þ)-ibuprofen, which may arise from the stressful
conditions of the surgery (Jamali and Kunz-Dober 1999). This has been
suggested as evidence for considering dosage adjustment in the therapy of
acute surgical pain on the basis of allowance for increasing dosage to meet
adequate pain control. However, other studies reviewed in the next section
suggest that 400–600 mg ibuprofen produces adequate pain control in dental
surgery, with in some reports evidence of superiority over paracetamol
(1,000 mg) (see Chap. 4).
6. The t½, AUC, Vd, and clearance kinetics of conventional ibuprofen tablets are
consistent with the usual dosage regime of either 400 mg t.i.d. for OTC use or
400–800 mg t.i.d. or q.i.d. as appropriate for prescription use to 2,400 mg daily.
Extended release formulations that have been developed could enable twice
daily dosage to limits of 1,200 mg/day OTC or 2,400 mg/day prescription
requirements.

2.2 Plasma/Serum Concentrations Relevant

to Onset of Analgesia

One of the basic tenets of pharmacology is that drug molecules exert influence on
cells or molecules in order to produce a pharmacological response (Rang et al.
2003; Brunton et al. 2008). To achieve this, drugs must penetrate or be present in
14 2 Biodisposition in Relation to Actions

defined concentrations adjacent to cells to enable them to interact with specific

receptors (Rang et al. 2003). The properties governing the concentration of drugs at
their receptors depend on the physicochemical properties that underlie their
properties of absorption, distribution, metabolism, and elimination (ADME)—
their pharmacokinetics (PK). Thus, it is axiomatic that for understanding the
therapeutic actions of drugs it is necessary to be able to quantify the amount of
drug (or metabolite[s]) in the circulation, i.e., in blood or plasma/serum, and to
determine their “free” (i.e., unbound form) or active concentration (Brunton et al.
2008). The situation for the non-steroidal anti-inflammatory drugs (NSAIDs) and
non-narcotic analgesics (NN analgesics) is complicated, because these drugs have
multiple modes of action and varying potencies as anti-inflammatories, and specifi-
cally, as pain-relieving agents (Rainsford 1996). Thus, differentiating the quantita-
tive actions or potencies of these agents depends on knowledge of the amounts of
drugs that are in the circulation, and thence how much of the drugs will penetrate to
their sites of action (Orme 1990). Plasma concentrations of NSAIDs can be
correlated to their clinical effects when certain criteria (analytical methodology,
principles of distribution equilibrium, and other PK properties and specific
mechanisms of their actions) are known (Orme 1990). Ranges of plasma
concentrations for their therapeutic and toxic effects are well-established for
many drugs, and particularly for NSAIDs and NN analgesics that are used in the
relief of acute and chronic pain (Orme 1990; Rainsford 1996; Suri et al. 1997a;
Graham and Scott 2003).
In order to derive values of the therapeutically relevant plasma concentrations
(TRPC) of ibuprofen, information was derived from published studies in various
acute and chronic (arthritis) studies and acute experimental pain models in humans,
in which plasma concentrations of the racemic or enantiomeric forms of the drug
were compared with therapeutic response, comprising the relief of pain symptoms
or the pharmacological actions as attributed to the S(þ) and R(
) in reducing
circulating levels of the cyclo-oxygenase products.
Attempts to model therapeutically-relevant drug concentrations are governed by
(a) the respective PK parameters at which pain responses can be directly related,
(b) the contribution of the individual enantiomer concentrations to their pharmaco-
dynamic (PD) activity (assuming the fact that the S(þ) isomer is the relevant
enantiomers for both pain relief and prostaglandin synthesis inhibitory actions),
and (c) the impact of different painful conditions on both the PK of ibuprofen and
the analgesic responses.
In modelling of the data on PK in relation to PD from published studies it is
possible to take two approaches: (1) select data at the earliest period when there is
significant increase in plasma concentrations and relate this to the development of
the analgesic response, or (2) to select data on the plasma concentrations of the
drug, Cp, at the lowest effective dose of the drug (400 mg) and relate this to
analgesic activity; the latter occurs mostly after the peak concentrations of the
drug. Using data derived from the third molar dental surgery pain model, it has been
possible to identify the earliest significant analgesic activity from ibuprofen 400 mg
at 0.5 h associated with serum concentrations of 17.5 mg/mL of racemic ibuprofen.
2.2 Plasma/Serum Concentrations Relevant to Onset of Analgesia 15

In less severe inflammatory conditions than observed in dental surgery it is

established that the lowest dose of 200 mg ibuprofen can be effective in relieving
symptoms of mild pain (headache, colds, acute injuries). Under these circumstances,
lower TRPC is anticipated. Thus, in considering the TRPC of ibuprofen, it is
important to identify the degree of pain and inflammation accompanying the respec-
tive painful conditions.
A central question concerning the therapeutics of ibuprofen is: what concen-
trations of the drug in plasma are required to achieve analgesic and/or anti-
inflammatory activity? This question can be divided into several parts:
1. What are the minimal concentrations required to achieve analgesic effects?
2. Do these minimal concentrations and the other pharmacokinetic (PK) parameters
of ibuprofen differ in various pain states?
3. What is the relationship between the individual enantiomer concentration and
the development of analgesia?
4. What is the relationship between inhibition of ex vivo production of prostaglandins
(via COX-1 and COX-2 inhibition) and plasma concentrations of ibuprofen (in
racemic or enantiomeric forms), and how does this relate to the analgesic activity of
the drug?
5. What are the relevant plasma concentrations of ibuprofen (in racemic or enan-
tiomeric forms) at which pain relief and anti-inflammatory activities are
achieved in arthritic pain conditions?
Since ibuprofen is chemically a diastereoisomeric equal mixture of R(
) ibu-
profen and S(þ) ibuprofen (Brocks and Jamali 1999; Rainsford 2009), it is impor-
tant to consider the respective contribution of the S(þ) enantiomer, since this is
considered the “active” form of the drug as it is the more potent inhibitor of the two
of prostaglandin synthesis (Rainsford 2009). This effect of ibuprofen is amongst the
principal modes of action of the drug in controlling pain, but other activities
underlie other anti-inflammatory effects of the drug which contribute to pain
reduction (Rainsford 2009). Following absorption, about 40–60 % of the R(
)
enantiomer is metabolised principally in the liver to the S(þ) form, so that about
80–90 % of the ingested drug is in the active S(þ) form.
Thus, from the point of view of estimating the TRPC of ibuprofen, it is possible
to consider the amounts in circulation of both the racemic [i.e., R(
) þ S(þ)] forms
as well as the S(þ) enantiomer as being therapeutically relevant. Indeed, one
estimate (Brocks and Jamali 1999) claims that attainment of the SþR (i.e., racemic)
concentration range of 11–30 mg/mL 1 h post-dose was needed for complete pain
relief in a study by Laska et al. (1986). However, the procedures used to calculate
this and the dose of drug were not specified. In the study by Laska et al. (1986), the
conditions for estimating the range of plasma or serum concentrations required for
pain relief in various painful conditions have been determined.
The PK and pharmacodynamic (PD; analgesia) data used for the analysis
described here were selected from relevant literature, and models for understanding
the relationships between ibuprofen concentrations and therapeutic responses have
either been discussed or derived from these data. It should be noted that there have
16 2 Biodisposition in Relation to Actions

been several reviews published on the general PK/PD properties of ibuprofen in

which general aspects of the relationships between PK properties and therapy have
been reviewed. These articles do not, however, address the central issues posed by
the above question.
Most of the data reviewed in relation to questions (1) to (4) are derived from
studies using the acute dental pain model, in which pain responses and analgesic
activity of ibuprofen have been determined in double-blind, placebo controlled trials.
In many respects, this is about the most satisfactory clinical pain model of acute pain
which has a pronounced local inflammatory component. Analgesic activity is usually
achieved in this model at the lowest dose of 400 mg ibuprofen (sometimes even
200 mg), and thus pain relief is at doses within those recommended for non-
prescription pain relief. It is possible to accurately quantify the analgesic effects in
this model using well-established methodology. There have been several studies
reported in which plasma or serum concentrations have been related to analgesic
activity, using either the third molar dental extraction model or that following
induction of acute pain from locally applied stimuli. Comparisons of the analgesic
responses in these different acute pain models are useful for discriminating the
varying analgesic responses in a quantitative and time-dependent manner.

2.2.1 Dental Pain Model

The third molar extraction model, or variants thereof, has proven the most reliable
and sensitive method for determining the acute pain relief afforded by analgesics,
whether narcotic or non-narcotic (Dionne 1998; Moore et al. 2011a, b).
Most dental pain studies in which racemic ibuprofen has been administered
within 30 min of pain show onset of analgesic activity within 30 min and peak
activity at 2–3 h post drug administration (Cooper 1984; Cooper et al. 1989; Dionne
and Cooper 1978, 1999; Laska et al. 1986; Jain et al. 1986; Seymour et al. 1991,
1996, 1998, 1999; Walker et al. 1993a; Jones et al. 1997; Averbuch and Katzper
2003; Barden et al. 2004; Malmstrom et al. 2004; Schleier et al. 2007; Daniels et al.
2009, 2011; Figs. 2.7 and 2.8).
The analgesic activity from ibuprofen is usually accompanied by reduction in
oedema in the inflamed tissues around the area of extracted tooth (Dionne and
Cooper 1999; Bjørnsson et al. 2003). Some studies have compared the time-course
of analgesia by ibuprofen with serum/plasma concentrations of the drug (Laska
et al. 1986; Jones et al. 1997; Hersh et al. 2000a; Fig. 2.8). In one study, there were
no significant correlations between efficacy measures and the PK parameters
comprising Cmax, tmax or AUC following a single dose of 400 mg ibuprofen
(Jones et al. 1997).
The study by Laska et al. (1986) (Fig. 2.8) was the first study designed to
compare serum concentrations with analgesic response following 400, 600 or
800 mg ibuprofen in patients with moderate to severe pain after third molar
extraction. The authors found that serum levels correlated with global analgesic
response measured by the sum of pain intensity difference (SPID) scores, but the
2.2 Plasma/Serum Concentrations Relevant to Onset of Analgesia 17

Fig. 2.7 Time-courses of the mean pain scores (determined from 100 mm visual analogue scales)
(SEM) in randomised-controlled studies in which patients undergoing third molar surgery
received treatment with placebo (small dashed line) ibuprofen 400 mg as a liquid in soft gelatin
capsules (continuous line) or ibuprofen 400 mg tablets (dashed line) in a double-dummy array.
Statistically significant differences from 1 to 6 hr between the values for ibuprofen and placebo
(P < 0.05). Note that these were apparent at, or after, 30 min of treatment. Redrawn from
Seymour et al. (1991), reproduced with permission of Wiley Blackwell for the British Journal of
Clinical Pharmacology

Fig. 2.8 Redrawn from Laska et al. (1986) with modifications showing calculations of effective
doses and serum concentrations (i.e., A, A,0 B, B0 , C, and C0 respectively) as shown in the figure

correlation coefficients (r ¼ 0.28, 0.34, and 0.26 for the three dose levels of 400,
600, or 800 mg) appeared rather low. This was probably due to the doses employed
being at the upper limit for near maximal response; the doses of 600 and 800 mg
being at the upper limit for response (Fig. 2.8). It is noteworthy that most other
18 2 Biodisposition in Relation to Actions

studies on the effects of ibuprofen in the third molar dental pain model have shown
that effective doses for analgesia were 400 mg, with a few at 600 mg ibuprofen.
Given these limitations, it is possible to use the information in this study by
Laska et al. (1986) to give some estimates of relevant therapeutic concentrations of
ibuprofen. There are several approaches which can be employed:
1. Taking data on serum concentrations at the earliest point at which there is a
statistically significant difference in analgesic activity (i.e., pain intensity differ-
ence scores) (see Fig. 2.8), gives a time of 0.5 h. The right side graph in Fig. 2.8,
gives values for the serum concentrations for the 400 mg dose of approximately
17.5 mg/mL, for the 600 mg dose 24.8 mg/mL and the highest dose of 800 mg
gives 28.8 mg/mL.
2. Taking the maximal serum concentrations of ibuprofen at 1 h those for the 400 mg
dose would approximate to 27 mg/mL; at the 600 mg dose this would be 42 mg/mL
and at the 800 mg dose about 45 mg/mL ibuprofen. This would seem at variance
with the previously mentioned statement by Brocks and Jamali (1999) that the
S þ R (i.e., racemic) concentration range is 11–30 mg/mL 1 h post-dose.
3. If data for the onset of analgesia for 15 and 20 min period were available, it
might be possible to derive an earlier time estimate of the serum concentrations
at this period which might be statistically significant. By visual inspection of the
graphs in Fig. 2.8, an approximate estimate of 10 mg/mL of ibuprofen appears to
coincide with reduction in pain at about 15–20 min.
The study by Schou et al. (1998), showed that the pain intensity difference (PID)
and pain relief (PAR) scores were dose-related, with the peak of these scores at
2–3 h. Compared with PK values for the drug, it is evident that the peaks of pain
relief follow those for the peak plasma levels.
Dose–response effects of ibuprofen 50–400 mg on pain parameters have been
shown in the dental pain model by Schou et al. (1998) (Fig. 2.9). An estimate of the
number of patients with at least 50% pain relief from the percent maximum of
TOTPAR and SPID values has been derived from meta-analyses by McQuay and
Moore (2007). Using a similar approach, Li Wan Po (2006) calculated
dose–response data from a large study in 258 Danish patients, in which the analge-
sic effects of 50–400 mg ibuprofen were compared (see Fig. 2.9). The 50%
pain responses calculated by Li Wan Po (2006) are shown in Fig. 2.9. These data
show there is a linear dose–response in the analgesic parameters ranging from 50
to 400 mg ibuprofen. Thus, using doses of 2  200 mg or 400 mg ibuprofen
in comparisons of PK of ibuprofen with the time-course of analgesia from
rac-ibuprofen lysinate (Nelson et al. 1994) would appear to show that the earliest
significant pain relief is evident at 30 min, at which there is a significant plasma
concentration of R(
) and S(þ) ibuprofen (Lötsch et al. 2001; Fig. 2.10). This time
point may be used to derive the effective therapeutic concentrations required for the
earliest onset of effects of the racemic drug. This would appear to be approximately
25–30 mg/mL for the racemate, 15 mg/mL for the S(þ) isomer and 14 mg/mL for the
R(
) isomer (see Fig. 2.10), based on the extrapolation of the time to reach specific
concentrations. At least by 1 h (tmax) the Cmax value can be confidently used for
calculations of the therapeutically-relevant concentrations at tmax.
2.2 Plasma/Serum Concentrations Relevant to Onset of Analgesia 19

Fig. 2.9 Dose–response of ibuprofen in the third molar dental pain model in which the percentage
of patients showing greater than 50 % pain relief is shown in relation to data of Schou et al. (1998)
on the sum of pain intensity difference (SPID) (open circle) and total rain relief (filled circle).
These data show that doses of 200 mg and 400 mg produce >50 % pain relief. Re-drawn from: Li
Wan Po (2006). Reproduced with permission of John Wiley and Sons, publishers of the British
Journal of Clinical Pharmacology. PLA Placebo

R-ibuprofen S-ibuprofen

1x400 mg Ibuprofen 1x400 mg Ibuprofen

25 (Test) (Test)
Plasma concentration

20

15

10

0
0 2 4 6 8 10 0 2 4 6 8 10
Time (hr) Time (hr)

Fig. 2.10 Time-course of plasma concentrations of ibuprofen enantiomers following 400 mg

ibuprofen lysinate (test) tablets. From Lötsch et al. (2001), reproduced with permission of John
Wiley and Sons, publishers of the British Journal of Clinical Pharmacology

A possible confounder of these estimates might be the time of intake of the drug
in relation to surgery. This suggestion arises from the observations by Jamali and
Kunz-Dober (1999), who showed that when ibuprofen 200 mg or 600 mg was taken
following third molar surgery there was about a 2-h delay in the mean time to peak
concentrations. The S(þ) ibuprofen serum concentrations were more markedly
affected than those for the R(
) enantiomers. If the drug was taken prior to surgery,
then the tmax for both enantiomers was 1 h for both doses, and this is within the
range of the tmax in normal volunteers.
20 2 Biodisposition in Relation to Actions

Plasma concentration (µmol 1–1)

0.3
Threshold difference (watts) 200

0.2

0.1 100

0.0

–0.1 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (h) Time (h)

Fig. 2.11 Time-course of pain responses from laser-induced pain applied to right hand dorsum
(left graph) compared with the plasma concentrations of the prostaglandin synthesis inhibitory S
(+)-ibuprofen active enantiomer (right graph). The pain threshold differences (mean  SEM,
watts; left graph) and plasma concentrations (mmol/L; right graph) are shown following intake of
400 mg (filled square) or 800 mg (open square) ibuprofen, or placebo (open circle) in the pain
measurements. Reproduced from Nielsen et al. (1990) with permission of John Wiley and Sons,
publishers of the British Journal of Clinical Pharmacology

2.2.2 Induced Pain Models

A number of studies have been performed in which the nociceptive responses

induced by various peripheral stimuli have been employed to investigate the
analgesic responses to ibuprofen but without investigating the time-course of
plasma concentrations of ibuprofen (see Walker and Carmody 1998; Walker et al.
1993a; Growcott et al. 2000; Sycha et al. 2003).
Amongst the first studies in which plasma ibuprofen concentrations were
compared with the time course of analgesic response was a model of pain from
the laser-induced stimulus applied to the dorsum (C7-dermatome) of the right hand,
investigated by Nielsen et al. (1990). In a double-blind, placebo-controlled,
three-way crossover study, these authors compared the effects of 400 mg and
800 mg racemic ibuprofen tablets. The results of this study (Fig. 2.11) show that
the peak plasma concentrations of ibuprofen enantiomers were evident at 1.4–1.5 h,
while the peak of analgesia occurred at 3 h. This shows that there is a clear
differentiation between the absorption of ibuprofen and the later onset of analgesic
effects. The use of the earliest onset of analgesia in relation to drug concentration as
applied previously does not appear applicable in this case. However, the relation-
ship between analgesia and peak concentrations of ibuprofen can be established
using Cmax (at tmax) of the S(þ) and R(
) enantiomers. Unfortunately, values for
R(
) ibuprofen were not stated. Thus, the concentrations of S(þ) ibuprofen peaked
at 1.2–1.5 h, these being 18.2 mg/mL (from a 400 mg dose) and 27.8 mg/mL (from a
800 mg dose) respectively.
Kobal et al. (1994) investigated the effects of ibuprofen 400 mg and 800 mg on
the EEG activity over three positions (Fz, Cz, Pz) in response to application of two
2.2 Plasma/Serum Concentrations Relevant to Onset of Analgesia 21

pulses of CO2 applied to the right nostril while the left nostril was stimulated with a
stream of dry air. The volunteers recorded the intensity of painful stimuli by visual
analogue scales (VAS). This so-called chemo-somatosensory model is in the expe-
rience of the author of this report so objectionable that it is difficult to determine
whether the responses are due to painful stimuli from cold CO2 per se or are a result
of reflex irritation. The peak plasma concentrations of racemic ibuprofen were
obtained at 90 min after intake, and were 28 mg/mL (after a dose of 400 mg) and
41.7 mg/mL (after a dose of 800 mg) respectively. There did not appear to be any
time-course data available in this study. The pain intensity estimates did not reach a
level of significance, so the experimental design would appear to be somewhat
flawed.
Another approach by the same group (Hummel et al. 1997) using a modification
of the above CO2 nasal irritation system in which pulsed stimuli were employed to
compare the effects of proprietary tablets of racemic ibuprofen 400 mg and 800 mg
with an effervescent formulation of the same doses of the drug in a randomised,
double-dummy crossover study. The authors also performed a comprehensive
plasma concentration profile of ibuprofen, with both enantiomers being measured.
The plasma concentrations of R(
) and S(þ) ibuprofen were greater overall at
earlier time intervals in the subjects that received the effervescent ibuprofen
preparation than in those that received the tablet formulation. Using measurements
of EEG components, there did not appear to be any consistent dose-related changes
upon intake of ibuprofen tablets, but there was a more pronounced increase in
latencies with the two doses of the effervescent preparation. A reduction in intensity
estimates (IE) of pain recorded by the subjects was evident at 15 and 60 min with
both doses of the effervescent preparation, while the tablet preparations showed
more delayed response. Using data at 15 min intervals on the plasma concentrations
of R(
) and S(þ) ibuprofen, the means  SD at 15 min were 25.33  5.65 mg/mL
and 22.11  4.57 mg/mL (for 400 mg effervescent ibuprofen), and 40.56  14.64
mg/mL and 35.62  12.62 mg/mL (for the 800 mg effervescent ibuprofen) respec-
tively. By comparison, the plasma concentrations of R(
) and S(þ) ibuprofen
following intake of tablets were 6.42  6.32 mg/mL and 5.51  5.43 mg/mL (for
400 mg tablets), and 12.54  8.3 mg/mL and 10.85  7.8 mg/mL (800 mg tablets)
respectively. This study with an effervescent formulation of ibuprofen raises the
possibility that salts of ibuprofen which have fast onset of action (e.g., see
Geisslinger et al. 1989; Ceppi Monti et al. 1992; Seibel et al. 2004; Jamali and
Aghazadeh-Habashi 2008) may give lower estimates of the TRPC from ibuprofen.
Given that the lowest dose of the effervescent preparation gave significant
changes in pain Intensity estimates at 15 min, it is possible to conclude that the
effective therapeutic concentrations for analgesia were 25 mg/mL (R(
) ibuprofen)
and 22 mg/mL (S(þ) ibuprofen). Assuming that the analgesic effect is due to the
S(þ) enantiomer, then the effective therapeutic concentration of these enantiomer
is in the range of 22 mg/mL. By comparison with data (Table 2.2) in the third molar
extraction studies (e.g., of Jamali and Kunz-Dober 1999) a lower dose of 200 mg
ibuprofen tablets produced effective plasma concentrations which were 1/4 of those
in the CO2-pain model [i.e., ~4–5 mg/mL of the S(þ) or R(
) isomer]. Comparing
these results suggests that the effective therapeutic concentration varies according
Table 2.2 Plasma serum concentrations of ibuprofen in analgesia models
22

Time at Earliest Earliest

earliest sig Corresponding maximal Cpmax time AUC (0
t)
Author (year) Pain model Dose (mg) analgesia (h) conc (mg/mL) (mg/mL) Tmax (h) t ¼ h (mg/L/h)
Laska et al. (1986) Third molar extraction 400 0.5 17.5 27 1
600 0.5 24.8 42 1
800 0.5 28.8 45 1
Nelson et al. (1994) Third molar extraction 400 (lysinate) 0.5
Lötsch et al. (2001) 400 (different 25–30(rac)
formulations)
15[S(+)] ~20 1
14[R(
)] ~18 1
Jamali and Third molar extraction 200 N/A N/A 6.3 1 [S(+)] 5.6 (0–2)
Kunz-Dober 3.9 6 Before Surg. 1.6
(1999) After Surg.
6.1 1 [R(
)] 5.5 (0–2)
5.3 6 Before Surg. 2.1
After Surg.
600 N/A N/A 14.5 1 [S(+)] 14.2 (0–2)
11.1 4 Before Surg. 7.2
After Surg.
14.8 1 [R(
)] 14.1
13.4 4 (0–2)
Before Surg. 1.8
After Surg.
Nielsen et al. (1990) Laser beam applied to 400 3 18.2[S(+)] 1.4–1.5
right hand dorsum 800 3 27.8[S(+)] 1.2–1.5
2 Biodisposition in Relation to Actions
2.2 Plasma/Serum Concentrations Relevant to Onset of Analgesia 23

to the type and severity of the painful stimulus, given that the inflammatory pain in
the third molar extraction model is appreciably greater than the CO2-stimulus
model.
An elegant quantitative approach to relating the PK of ibuprofen to pain
responses in an analgesic model was developed by Suri et al. (1997a). These authors
employed the tooth pulp electrical stimulation model, and quantified the pain
response by subjective pain ratings (PR) and pain evoked potentials (EP) following
electrical pulp stimulation. Racemic ibuprofen 400 mg was administered, and the
serum concentrations of the enantiomers were determined. The pharmacokinetic
data was modelled to the effects of the drug treatments on the maximal responses,
Emax, of these two pain parameters. There were clear time-related responses on both
pain-related parameters and these coincided, or nearly so, with the development of
the peak serum concentrations of S(þ) ibuprofen (Fig. 2.12). A model integrating
plasma concentrations of S(þ) ibuprofen (measured by Lötsch et al. 2001;
Fig. 2.12) with PKs for pain ratings (EC50 set to 24.37 mg/mL) and evoked potential
(EC50 set to 8.71 mg/mL) using data from Suri et al. (1997a) was developed by
Lötsch et al. (2001), and this is shown in Fig. 2.13. This model shows several
important phenomena and details:
1. Plasma concentrations of S(þ) ibuprofen peak and are ahead of the peak
pain-related parameters. Thus, peak concentrations of S(þ) ibuprofen occur at
1 h, while that of the evoked potentials is at 2 h and the subject-assessed pain
ratings follow at a peak at 3 h. The latter extends for a longer period, and the
AUC for the pain ratings extends over a much longer period that that of the
evoked potential.
2. These time-course data suggest that the S(þ) ibuprofen requires penetration to
brain sites to modify the EEG pain-related responses ahead of the full subjective
pain response.
3. Given that the EC50 for pain ratings is 24.37 mg/mL then it would be safe to
assume this value approximated to 24 mg/mL as the effective therapeutic con-
centration. The lower value of the EC50 being 8.71 mg/mL reflects greater
sensitivity of the electrical or EEG responses compared with the corresponding
value for pain ratings, as well as in the data from the third molar surgical pain
model discussed previously.
In conclusion, the data summarised in Table 2.2 and Figs. 2.12 and 2.13 from
third molar and the pain-evoked models show that:
(a) Plasma concentrations of racemic ibuprofen at which pain responses are
detected from 400 mg oral dosage form are ~18–27 mg/mL while those of the
active S(þ) isomer after 200 mg of the racemate are ~14 mg/mL and after
400 mg of this are 25 mg/mL.
(b) There is a clearly a trend for the peak ibuprofen (racemic or S(þ) forms) to
precede the development of the analgesic pain responses to the drug.
(c) Given that 400 mg ibuprofen is about the lowest effective dose of the drug in
the third molar pain model, then the effective therapeutic plasma/serum
24 2 Biodisposition in Relation to Actions

Fig. 2.12 Relationships between objective evoked potentials and subjective pain ratings in
subjects who had pain from tooth pulp stimulation and treatment with ibuprofen 400 mg tablets.
Comparison of pharmacokinetics of ibuprofen enantiomers (a) with pain response (b) and (c)
2.2 Plasma/Serum Concentrations Relevant to Onset of Analgesia 25

Fig. 2.13 Prediction of time course of plasma concentrations of ibuprofen related to simulated
time course of analgesic effects determined from pain ratings and evoked potentials following
electrical pulp stimulation and intake of racemic ibuprofen. Data from Suri et al. (1997a); figure
reproduced with permission and redrawn from Lötsch et al. (2001)

concentrations may be approximated to about 25 mg/mL. However, the lower

dose of 200 mg might also be considered effective in some pain states, giving a
lower estimate of the effective therapeutic plasma concentration of the S(þ)
isomer of ~15 mg/mL (Jamali and Kunz-Dober 1999). Since this parameter has
been derived from only one study and does not have corroborating evidence
such as provided from data using 400 mg of racemic ibuprofen (Table 2.2), then
caution should be employed using this extrapolated value.

2.2.3 Applicability to Other Acute Pain States

There do not appear to be any published studies comparing plasma/serum levels of

ibuprofen with development of pain or analgesia. There is a considerable number of
studies in which the time-course of analgesic response to ibuprofen has been
compared with placebo. Thus, time- and dose-dependent effects of 200 or 400 mg
ibuprofen in migraine headache show statistically-significant changes after 1–2 h,
ä

Fig. 2.12 (continued) evoked potentials (EP) following tooth pulp stimulation. Integration of
ibuprofen concentrations with the percent decrease in pain produces the expected hysteresis loop
(figure not shown). a Plasma concentrations of S(+)-ibuprofen (filled circle) and R(
)-ibuprofen
(open circle) after 400 mg rac-ibuprofen tablets. b Effects of ibuprofen on subjective pain
responses recorded by subjects after tooth pulp stimulation. c Effects of ibuprofen on objective
brain recordings of evoked potentials in subjects following tooth pulp stimulation. Redrawn from
Suri et al. (1997a). Reproduced with permission of the publishers Dustri-Verlag Dr Karl Feistle
GmbH & Co KG, Deisenhofen, Germany
26 2 Biodisposition in Relation to Actions

depending on the pain parameters that were measured (Codispoti et al. 2001).
Similar results have been observed in tension-type or migraine headaches (Lange
and Lentz 1995; Schachtel et al. 1996; Sandrini et al. 1998; Packman et al. 2000;
Diener et al. 2004), acute sore throat or tonsillitis (Schachtel et al. 1988, 1994,
2007; Boureau 1998), dysmenorrhoea (Zhang and Li Wan Po 1998), and other
acute conditions (Kean et al. 1999). Suffice it to say that based on the established
PK properties of 200 and 400 mg racemic ibuprofen, it would be expected that the
therapeutic concentrations of the drug (racemic, or S(þ)) required for treating these
acute pain states would be of the same order as those mentioned in the previous
section.

2.3 Antipyresis

As a component of inflammation, fever is a very good index of systemic as well as

central nervous system reactions to inflammogens, even though the mechanisms
involved centre around leucocyte activation and the effects of pyrogens (principally
interleukins 1 and 6 and tumour necrosis factor–a) on hypothalamic pathways
leading to PGE2 production. Thus, a model of antipyretic effects of NSAIDs,
including ibuprofen, focuses principally on the direct inhibition of hypothalamic
PGE2, and may with some drugs involve reduction in pyrogens generated from
activated leucocytes via, in the case of ibuprofen, inhibition of signalling pathways
within these cells (Rainsford 2009).
Trocóniz and co-workers (2000) developed a PK/PD model from studies on two
formulations of racemic ibuprofen in healthy adults and febrile children. The
population PD model they developed established on EC50 [the plasma concentra-
tion that elicits half maximal drug effect, or Emax] for reduction of temperature at
6.18 mg/mL. Thus, for the purposes of comparison with analgesic effects (e.g., Suri
et al. 1997a) this could be employed at the effective therapeutic drug concentration.
Another model for the PK/PD of racemic ibuprofen was developed by Garg and
Jusko (1994) based on data of Walson et al. (1989) in febrile children. Using data
based on 5 and 10 mg/kg doses, the profiles of plasma concentration of racemic
ibuprofen and mean temperature showed that peak levels of the drug were achieved
at approximately 1 h and coincided with the decline in temperature, which reached
a maximum at 2–6 h. As with the pattern of analgesia, the actions of the drug peak
after the maximal drug concentrations. Using a kinetic model in which the change
in response with time dR/dt was related to plasma concentrations, Cp, thus:


dR/dt ¼ km ð1
Cp = Cp þ IC50
kout R

Where IC50 is the plasma ibuprofen concentration producing 50 % reduction in

fever, km is the zero order rate of synthesis, and kout the first order degradation, both
hypothetical parameters.
2.4 Therapeutically-Relevant Concentrations in Rheumatic Diseases 27

Reconstructing this equation after fitting of the data of Walson et al., the IC50
was determined to be 10.1 mg/mL. This value is of interest, since it falls within the
range of concentrations required for effects in analgesic systems (Table 2.2).
To determine the concentrations of the ibuprofen enantiomers required for
antipyretic effects in children following treatment with 6 mg/kg of liquid racemic
ibuprofen, Kelley et al. (1992) found that the time for maximal effects of ibuprofen
(tmax.ef) was 183 min, with the time of maximal concentrations of both isomers and
the racemate being at approximately 1 h, showing again that the maximal effects
occur following the peak concentrations of the drug. The EC50 was not specifically
calculated by the authors, but the Cmax for total racemic ibuprofen was 26.67 mg/mL
and those for S(þ) ibuprofen were 13.8 mg/mL and for R(
) ibuprofen 13.39 mg/mL
respectively.

2.4 Therapeutically-Relevant Concentrations in Rheumatic

Diseases

Ibuprofen is used extensively for the relief of joint and other painful symptoms in
osteoarthritis (OA) or rheumatoid arthritis (RA). Most studies in which the PK of
ibuprofen has been investigated in patients with OA and RA show that the PK
properties are not appreciably different from normal volunteers (Aarons et al. 1983;
Grennan et al. 1983; Bradley et al. 1992; Rudy et al. 1992; Shah et al. 2001;
Rainsford 2009). Moreover, as many rheumatic patients are elderly, it is relevant
to consider the impact of age on PK of ibuprofen. Studies by Albert et al. (1984)
have shown that the PK of ibuprofen is not different from that in younger normal
volunteers.
As significant pain relief is evident in RA and OA with even a single low dose of
400 mg or 600 mg of racemic ibuprofen or multiple doses, it is possible to use
plasma/serum concentrations of the drug at these doses as a guide to establishing the
therapeutically-relevant serum or plasma concentrations of ibuprofen. Variability in
PKs and especially enantiomer concentrations is a known problem in patients with
RA (Geisslinger et al. 1993) and OA (Rudy et al. 1992). Aarons et al. (1983) found
that the values for Cmax of racemic ibuprofen at the first dose or after 7 or 14 days
treatment with 1,600 mg/day ibuprofen were (a) not significantly different from one
another, (b) approximately 27–29 mg/mL, and (c) coincided with reduction in VAS
estimates of pain and articular indices. There were no differences in the time of Cmax
(approximately 1 h) or other PK parameters with time of drug administration.
Geisslinger et al. (1993) observed that a 600 mg single dose of racemic ibupro-
fen in RA patients produced plasma concentration values of 20.3  5.3 mg/mL
S(þ) ibuprofen and 17.7 mg/mL R(
) ibuprofen at 2.4 and 2.3 h respectively.
Corresponding doses of ibuprofen 600 mg taken for 3 days by patients with OA
produced plasma values of 11.2 mg/mL for S(þ) ibuprofen and 8.8 mg/mL for R(
)
28 2 Biodisposition in Relation to Actions

ibuprofen, which are about 1/2 those observed by Geisslinger et al. (1993). The
lower dose of 300 mg/day ibuprofen produced values of 7.5 mg/mL S(þ) ibuprofen
and 6.5 mg/mL R(
) ibuprofen. These values are appreciably different from those
obtained at the higher 600 mg dose, suggesting that the values at 600 mg ibuprofen
may represent the upper concentrations in relation to dosage.
In a study in which OA patients received ibuprofen 600 mg t.i.d./day for 5 days,
the plasma Cmax for racemic ibuprofen was 31.1–35.6 mg/mL and was achieved at
tmax of 1.2–1.5 h (Shah et al. 2001).
Thus, as a rough approximation the upper limit therapeutically relevant concen-
tration of ibuprofen after administration of 600 mg of racemic drug would appear to
be in the range of 30 mg/mL of the racemate and approximately 10–20 mg/mL of the
pharmacologically active S (þ) isomer.
In summary, this section has highlighted procedures and studies that can be used
to derive values of the therapeutically relevant plasma concentrations (TRPC) of
ibuprofen. Data have been obtained from various acute and chronic (arthritis)
studies and acute experimental pain models in humans where the plasma (or
serum) concentrations of the racemic or enantiomeric forms of the drug were
compared with therapeutic response, comprising the relief of pain symptoms or
the pharmacological actions as attributed to the S(þ) and R(
) in reducing
circulating levels of the cyclo-oxygenase products. There is some variability in
the estimates of TRPC, as would be expected from different pain models and
methodologies for determining PK and PD.
It is suggested that the TRPC of racemic ibuprofen are at the upper end in the
range of 20–30 mg/mL and 10–15 mg/mL of S (þ) ibuprofen following 400–600 mg
ibuprofen, these doses being within the optimal for lowest dose of the non-
prescription (OTC) use of the drug normally employed for relief of acute pain
It should be emphasised that these data are only first-level approximations
derived from diverse models and pain states.

2.4.1 Plasma/Serum Levels in Arthritic Diseases

The PKs of ibuprofen in patients with osteoarthritis (OA) and rheumatoid arthritis
(RA) have been investigated by several authors (Brocks and Jamali 1999; Graham
and Williams 2004). In general, the main kinetic parameters do not differ apprecia-
bly between these patient groups and normal subjects (see Table 2.3 compared with
Table 2.1).
Comparing the clinical responses to ibuprofen in patients with OA (Table 2.3),
Bradley et al. (1992) showed that the trough serum concentrations of racemic
[i.e., R(
) þ S(þ)] or S(þ)-ibuprofen correlated with the Health Assessment
Questionnaire (HAQ) or physicians’ global assessments of pain relief respectively
(Table 2.4).
In patients with RA, there is a relationship between parameters of joint pain
and dose above 1,600 mg/day as well as the AUC (Table 2.5; Grennan et al. 1983).
2.4 Therapeutically-Relevant Concentrations in Rheumatic Diseases 29

Table 2.3 Pharmacokinetic parameters following administration of 300 or 600 mg of ibuprofen

as single or chronic doses to patients with osteoarthritis
Single Chronic Chronic
300 mg 600 mg 300 mg 600 mg overall
(n ¼ 8) (n ¼ 7) (n ¼ 21) (n ¼ 24) (n ¼ 45)
S(þ)-ibuprofen
AUCa (mg h/L) 42.9 (21) 74.3 (31) 54.4 (22) 81.4 (33)
CLS-1 (mL/min) 115.5 (53) 124.3 (45) 87.9 (31) 120.7 (64) 105.4 (53)
Cmax (mg/L) 11.1 (5.3) 13.8 (8.5) 12.7 (5.4) 18.2 (6.8)
Tmax (h) 2.0 (0.89) 1.9 (0.73) 2.1 (0.98) 2.0 (1.2)
Css.av (mg/L) 7.5 (3.2) 11.2 (4.4)
t1/2 (h) 2.0 (0.83) 3.5 (2.8) 3.1 (1.9) 3.0 (2.3) 3.1 (2.1)
R(
)-ibuprofen
AUCa (mg h/L) 27.7 (8.9) 56.6 (20) 35.9 (14) 55.5 (22)
CLR-1 (mL/min) 99.0 (32) 96.5 (27) 82.7 (39) 108.4 (55) 96.4 (49)
Cmax (mg/L) 10.5 (3.8) 16.4 (8.5) 12.0 (4.9) 18.7 (7.4)
Tmax (h) 1.9 (1.1) 2.3 (1.2) 1.7 (0.82) 1.6 (1.0)
Css.av (mg/L) 6.5 (3.1) 8.8 (3.4)
t1/2 (h) 1.7 (0.58) 2.3 (0.82) 2.8 (2.9) 2.9 (3.3) 2.9 (3.1)
Finv (%) 62.5 (9.9) 63.2 (5.8) 66.6 (12) 64.0 (13) 65.2 (12)
AUC S/R ratio 1.5 (0.42) 1.3 (0.30) 1.6 (0.61) 1.5 (0.42) 1.6 (0.51)
AUC area under the serum concentration–time curve from zero to infinity, CLS-1 clearance of
S-ibuprofen taking into account the inversion of R- to S-ibuprofen, Cmax maximum serum
concentration, Tmax time to Cmax, Css.av average steady state serum concentration, t1/2 half life,
Finv fraction of R-ibuprofen inverted to S-ibuprofen, n number of observations. From Bradley
et al. (1992)

Table 2.4 Serum concentrations of ibuprofen in patients with osteoarthritis of the hip or knee
Parameter S(þ)-Ibuprofen S(þ)-Ibuprofen
Dose 1,200 mg/day 2,400 mg/day
Av. Cp (0–6 h) mg/mL 7.5  3.2 11.2  4.4
Trough Cp (6 h) mg/mL 4.6  2.2 6.9  3.7
AUC (0–12 h) mg h/mL 67.2  34.0 98.7  43.6
Patients received rac-ibuprofen for 4 weeks. The AUC of S(+)-ibuprofen correlated with pain at
rest, Health Assessment Questionnaire (HAQ), improvement in HAQ disability and physician’s
global assessment, Trough concentrations of S(+)-ibuprofen correlated with HAQ disability and
physician’s global assessment. Similar associations were observed with R(
) and S(+) ibuprofen,
though no data was provided on the serum concentrations of R(
) ibuprofen. Data from Bradley
et al. (1992)

The values of Cmax and tmax are not different from one another at doses of
800–24,000 mg/day suggesting that the peak concentrations of ibuprofen are
unrelated to joint pain parameters or thermographic index. There is, however,
much greater variability in the plasma/serum concentrations of ibuprofen in
patients with RA. This is especially evident in the rates of inversion of R(
)- to
S(þ)-ibuprofen (Geisslinger et al. 1993).
30 2 Biodisposition in Relation to Actions

Table 2.5 Relationship between pharmacokinetic parameters for ibuprofen with clinical response
in patients with rheumatoid arthritis
Dose of ibuprofen (1 week)
800 mg/day 1,600 mg/day 2,400 mg/day
PK Parameters Placebo
Cmax (mg/mL) – 19.4  6.8 18.2  4.0 17.5  3.9
AUC (mg/mL/min) – 3,042  966 5,564  1,152 7,962  1,653
tmax (min) – 61.4  18.1 56.9  12.4 58.3  13.9
Clinical responses (vs. placebo)
VAS pain – NS <0.005 0.005
Articular index – NS <0.01 0.005
Pain scores – NS <0.05 0.02
Thermographic index 445.4  188.5 429  220.2 443.3  204.6 462  203.9
Arthritis patients (N ¼ 20 total) took either placebo or iIbuprofen in stated dosages four times
daily for 1 week in a double-blind, crossover study starting with a 2-day washout period in a
Latin-square sequence design
From: Grennan et al. (1983)

2.4.2 Accumulation in Synovial Fluids

There is appreciable accumulation of R/S (i.e. both R(
) and S(þ))-ibuprofen in

synovial fluids, with broad peaks occurring over a period of 2–6 h which follow the
peak plasma or serum concentrations (Glass and Swannell 1978; Mäkelä et al.
1981; Whitlam et al. 1981; Albert and Gernaat 1984; Gallo et al. 1986; Walker et al.
1993a; Davies 1998). It is generally agreed that ibuprofen readily partitions into
synovial fluid from plasma/serum, and that the total levels (Table 2.6) are about
one-half of those in synovial fluids (Whitlam et al. 1981; Graham 1988). The uptake
of ibuprofen into synovial fluids of arthritic patients is dependent upon the bound
drug in plasma; decrease in protein binding of the drug explains the total drug
concentrations in synovial fluids (Wanwimolruk et al. 1983).
The free concentrations in synovial fluids (0.19 mg/mL) do not differ signifi-
cantly from those in plasma (0.25 mg/mL) when corrected for protein content
(Whitlam et al. 1981) which is lower in synovial fluid, these data supporting the
concept that the synovial compartment is readily accessible to free plasma/serum
concentrations of the drug (Whitlam et al. 1981; Rau et al. 1989).
Gallo et al. (1986) found that the ratios of total ibuprofen concentrations in the
synovial fluid to those in plasma is about 1.24 according to time at 7 h following
single dose of 600 mg of the drug, and 0.52–1.46 at 3–12 h after three daily doses of
ibuprofen 1.8 g/day. The mean free total ibuprofen in synovial fluid ranged from
1.81 to 2.91 %, compared with that in plasma which is 1.54–2.53 %. Thus, there is
appreciable total and free R/S-ibuprofen that accumulates in synovial fluids of
Table 2.6 Pharmacological concentrations of ibuprofen and enantiomers in synovial or CSF compartments
Rate constant, k
1 AUC
Dose Enantiomer Compartment Concentration (mmol) (h) or MTT (h) (mg/mL/h) Author(s)
400–1,200 mg rac Syn fluid 4.0–63 Wallis and Simpkin (1983)
a
[0.6–1.6]
Syn tissue 126–150
800 mg rac Syn fluid 11S(+) Cox et al. (1991)
6.4R(
)
600 mg rac Syn fluid 9.7 S(+)b Geisslinger et al. (1993)
8.6 R(
)
400 mg S(+) Syn fluid 10.6(S+)c
40 mg/kg Children rac Syn fluid 20 K ¼ 0.45; 0.29 sp Elmquist et al. (1994)
JCAd MTT ¼ 2.22, 3.44
1,200 rac Syn fluid 3.3–4.9 S(+) Ki ¼ 0.29 110  28e Seideman et al. (1994)
K0 ¼ 0.36e
2.4–4.4 R(
) Ki ¼ 0.19 56  8
K0 ¼ 0.34
Blister fluid 2.4–6.0 S(+) Ki ¼ 0.22 116  43
K0 ¼ 0.77
R(
) Ki ¼ 0.14 73  32
K0 ¼ 0.20
2.4 Therapeutically-Relevant Concentrations in Rheumatic Diseases

800 rac Lumbar CSF 1.5 Bannwarth et al. (1995)

a
Free concentrations from estimates of free fraction ~0.026.
b
tmax ~ 2.4 h.
c
tmax ~ 2.3 h.
d
JCA children with juvenile chronic arthritis; data from Mäkelä et al. (1981).
e
Rate constants, k
1 (h) as Ki ¼ inward, K0 ¼ outward of synovial fluid or blister fluid values of Ki or K0 and AUCs of synovial fluids not significantly
different from blister fluids.
31
32 2 Biodisposition in Relation to Actions

arthritic patients, and clearly this will have therapeutic significance in relation to the
local anti-inflammatory and analgesic effects of the drug in pain control.
Rau et al. (1989) found that the synovial fluid concentrations of ibuprofen 4 h
after administration of 400 mg of the drug to patients with a mixture of
arthropathies having knee effusions were 9.4 mg/mL (45.6 mM), compared with
those in plasma at that time which were 15.45 mg/mL (75 mM), the ratios of synovial
fluid to plasma being 0.61. These are lower than those found by Gallo et al. (1986),
probably because of the earlier time interval. Most studies of the profiles of
ibuprofen (as well as other NSAIDs) in synovial fluids show they are somewhat
lower than the peak plasma concentrations, and the synovial fluid profiles follow
those of the plasma profiles (Graham 1988). Rau et al. (1989) did not find that the
pH of the synovial fluid was different than that of plasma (pH 7.4), and so the view
that the synovial fluid is more acidic than the plasma would appear to be challenged
by these data. It appears that the efflux of ibuprofen from the plasma into the
synovial fluid is by diffusion of plasma protein-bound drug (Day et al. 1988). There
is no evidence of time-dependent accumulation of the drug in plasma or synovial
fluids following repeated doses compared with single doses (Cox et al. 1991).
Estimates of the synovial exit rates have been determined for a number of
NSAIDs, and result in first-order kinetics of drug transport out of the synovial
space. The exit rate constants (ksp) are the sum of the rate constants for both
diffusion and lymphatic blood flow out of the synovial space (Elmquist et al.
1994). The mean residence times (MTTsynovial) can be calculated in relation to
the exit rate constants. Using partial-areas analysis, Elmquist et al. (1994) calcu-
lated the ksp for ibuprofen as 0.29 h
1 and the MTTsynovial 3.44 h. This indicates that
ibuprofen has an appreciable time of retention in synovial fluids. Moreover, this
was comparable with four other NSAIDs, i.e. diclofenac, etodolac, indomethacin
and tenoxicam, which had MTTsynovial values of 1.84–2.04 h, 5.29 h, 4.67 h and
4.03 h respectively.
Stereospecific disposition of ibuprofen enantiomers occurs into the synovial
fluids of arthritic patients, many of whom have synovitis or inflammation of their
knees (Table 2.6). In the disposition of the individual enantiomers, it has been found
that the concentrations of the S(þ) isomer as well as values of AUC S(þ) always
exceed those of the R(
) enantiomer (Day et al. 1988; Cox et al. 1991; Geisslinger
et al. 1993; Seideman et al. 1994), with similar selective accumulation being shown
in experimentally-induced skin suction blisters (Seideman et al. 1994). The patterns
of synovial fluid accumulation of the enantiomers follows that of the peak plasma
levels, with broad peaks of R(
) and S(þ) ibuprofen at about 2–4 h and extending
to about 12–15 h (Seideman et al. 1994), thus showing persistence of the
enantiomers in synovial fluids well past those of their peak plasma concentrations
(Fig. 2.14; Graham and Williams 2004).
2.4 Therapeutically-Relevant Concentrations in Rheumatic Diseases 33

Fig. 2.14 Pharmacokinetics of ibuprofen enantiomers in synovial fluids compared with plasma.
Redrawn from Graham and Williams (2004), which was based on data of Day et al. (1988)

2.4.3 Rectal Administration in Adults and Children

Ibuprofen, like other NSAIDs, has been employed in suppository formulations

principally for treatment of fever, musculo-skeletal pain, perioperative pain and
other painful conditions, principally in children (Viitanen et al. 2003; Yoon et al.
2008; Rainsford 2009). Ibuprofen suppositories are generally well-tolerated in
children, with the most common adverse reaction being diarrhoea (Hadas et al.
2011). NSAID suppositories are not widely used in certain parts of the world
(e.g., UK, USA) but are popular in some continental European countries. There is
considerable potential for their development for treating patients that have dyspep-
tic or other gastro-duodenal symptoms associated with NSAIDs. The properties of
drugs administered by the rectal route using suppositories are related to their being
in intimate contact with the rectal mucosa which is normally pH 7.2–7.4, a tissue
that has unique fatty acid metabolism with a lipoidal barrier (Florence and Attwood
1998). They present in contact with the mucous membrane of the rectal ampulla,
which comprises a layer of epithelial cells without villi (Florence and Attwood
1998). The main blood supply of importance to absorption through the rectal
mucosa is in the superior rectal or haemorrhoidal artery, while drug absorption
per se takes place through the venous network of the submucous plexus, which then
becomes the inferior, middle superior rectal veins, the latter being connected to the
portal veins, leading to transport of drugs direct to the liver. In contrast, the inferior
veins enter the inferior vena cava and thus bypass the liver. The proportion of drug
that is absorbed by these two venous routes depends on the extent to which the
suppository migrates in its original or molten form up the intestinal tract (Noro et al.
1982a, b). Thus, this use can be variable and so drugs administered rectally may not
bypass the liver (Florence and Attwood 1998).
34 2 Biodisposition in Relation to Actions

The factors influencing rectal absorption of drugs include (a) the melting point and
liquefaction properties of the suppository, and (b) physico-chemical and solubility
properties of the drug that initially influence contact of the drug with the mucosa
(Noro et al. 1982a, b; Bergogne-Bérézin and Bryskier, 1999). Aqueous solubility and
pKa of the drug influence absorption from “fat” based or liposoluble drugs. Viscosity
of the base and excipients or dispersants added to disperse the fat can influence
absorption (Noro et al. 1982b; Toshino et al. 1983). The rate-limiting step in drug
absorption for suppositories made from a fatty base is the partitioning of the dissolved
drug from the molten base, not the solubilisation of drug in body fluids (Florence and
Attwood 1998).
NSAIDs and paracetamol vary considerably in their rates of absorption when
administered rectally (van Hoogdalem et al. 1991; Yong et al. 2004). The
formulations of these drugs clearly are a major factor in influencing their absorption.
For example, addition of increasing amounts of lecithin can delay the rectal absorp-
tion of diclofenac (van Hoogdalem et al. 1991). The physico-chemical properties of
NSAIDs influence their absorption. Studies in rats have shown that ibuprofen is
strongly retained in a lipophilic base, so limiting absorption through rectal mucosal
membranes (Kaka and Tekle 1992). The inclusion of polyethylene glycols (PEG)
may slightly enhance absorption (Kaka and Tekle 1992), and menthol can also affect
properties of suppositories (Yong et al. 2004). It has been suggested that the relatively
small pore size in the rectal mucosa compared with that in the small intestinal
membrane may limit the rate and extent of absorption of ibuprofen (Kaka and
Tekle 1992). Despite this limitation, studies in rabbits by Hermann et al. (1993)
have shown that the AUC values for ibuprofen (as the lysine salt) when given rectally
are comparable with those when the drug is given intravenously. The ibuprofen acid
is absorbed more readily than the lysine salt, though this is dependent on the type of
excipient (Hermann et al. 1993).
Of the PK studies performed with rectally-administered ibuprofen, these show
that ibuprofen in adults is absorbed at rates that are nearly those of conventional
oral formulations of the drug (Aiache 1990; Kyllönen et al. 2005).
Eller et al. (1989) studied the bioavailability of ibuprofen from rectally- or
orally-administered sodium or aluminium salts of ibuprofen as solutions (pH 7.8)
or suspensions (pH 5.2) in eight normal healthy, non-obese, male subjects using a
randomised Latin square design The bioavailability for these forms was compared
with that of the orally-administered drug. In essence, the results showed that both
rectal formulations showed similar extent of bioavailability being about 60 % of the
oral formulation; the Cmax values being 62–67 %, and the tmax was longer. Both the
rectally-administered preparations were significantly less bioavailable as shown by
the AUC values (Table 2.7), and were relatively high, as were the Cmax values
compared with the oral solutions/suspensions. However, as expected, the tmax
values were longer for the rectally-administered preparation than for those taken
orally (Table 2.7). The serum elimination half-lives (t½) were almost identical for
the oral and rectal solutions, and about 1/3 lower with the oral suspension compared
with the former or the rectally-administered suspension.
2.4 Therapeutically-Relevant Concentrations in Rheumatic Diseases 35

Table 2.7 Bioavailability of rectal compared with oral solutions/suspensions of ibuprofen in

8 normal, non-obese male human volunteers
Treatment A Treatment B Treatment C Treatment D
Oral Rectal Rectal
Parameter Oral solution suspension solution suspension
Peak concentration (mg/mL) 80.7 (6) 28.7 (28) 50.3 (36) 19.2 (63)
AUC (mg/mL/h) 2.7
0–12 197.8 (12) 164.2 (21) 172.5 (36) 97.6 (73)
0–1 200.3 (12) 179.1 (30) 175.5 (36) 102.9 (74)
Peak time (h) 0.33 (30) 2.12 (28) 1.14 (36) 2.44 (45)
Mean residence time (h) 2.60 (12) 5.99 (23) 3.19 (6) 4.49 (24)
Terminal elimination rate 0.351 (11) 0.211 (19) 0.344 (6) 0.367 (22)
constant (h
1)
From Eller et al. (1989). Reproduced with permission of the publishers from Rainsford (2009)

The rectal solution showed greater bioavailability than the suspension and
achieved higher serum Cmax values than the suspension (Table 2.7). In addition,
the MRT was shorter for the rectal solution than the suspension.
These results showed that the sodium solution was the preferred salt to be used in
any fundamental considerations of suppository formulations. Głowka (2000) stud-
ied the enantiomeric pharmacokinetics in rabbits of suppositories of ibuprofen acid
and the lysine salt prepared in the lipophilic base Witepsol H-15. They observed
there was no pre-systemic inversion of R(
) to the S(þ) enantiomers; the S:R ratios
only increasing after about 1.5 h following administration of both formulations, and
being greater with the lysine salt. The AUCs were greater after administering
ibuprofen acid suppositories compared with the lysine salt, even though the latter
was more rapidly absorbed.
Kyllönen et al. (2005) investigated the R(
) and S(þ) pharmacokinetics of what
is now a widely used commercial suppository formulation of ibuprofen, Burana®
(Orion Pharma, Espoo, Finland). These investigations are amongst the most exten-
sively investigated, and involved studying the PKs of suppositories of ibuprofen in:
(a) nine full-term infants aged 1–7 weeks, (b) eight infants aged 8 to 25 weeks,
(c) seven infants aged 26–52 weeks, and (d) seven adults aged 20–40 years after
single-dose administration of approximately 19–20 mg/kg ibuprofen suppositories
and following induction of anaesthesia for minor general or orthopaedic surgery in
infants or lumbar disc surgery in adults.
The results (Table 2.8) show that ibuprofen was rapidly absorbed from the
suppository formulation in all age groups. The tmax in infants for the ratio of R/S
enantiomers of ibuprofen was 1.6–3.3 h, and the t½ for absorption was 1.9–2.9 h. In
four of the youngest group of infants (1–7 weeks; group 1), the tmax was similar to
that in those where the suppository was not fully retained in situ, even though the
Cmax values were about 40 % less than in the retained suppository group. The only
differences in tmax for R/S ibuprofen were observed in the adults (group 4) where
this was 3.3 h, and so was greater than in all the other groups (infants), which ranged
from 1.6 to 1.9 h.
36 2 Biodisposition in Relation to Actions

Table 2.8 Ibuprofen enantiomers after rectal administration. Pharmacokinetic variables of

(S)-(+)-,(R)-(
)- and (R,S)-()-ibuprofen following rectal administration of 20 mg/kg of racemic
ibuprofen
(S)-(+)-ibuprofen (R)-(
)-ibuprofen (R,S)-()-ibuprofen AUC ratio
Group 1 (n ¼ 5) suppository retained
Cmax (mg/L) 29.3  16.2 23.8  9.4 49.2  20.7 1.7  1.1
Tmax (h) 2.2  1.0b 1.8  1.3b 1.9  1.2b
Chronological t1/2 (h) 2.9  1.8 3.2  2.7 4.6  5.1
Physiological t1/2 (h) 5.8  3.5b 6.6  5.4b 8.9  10.1
AUC (mg/L  h) 159  81a 112  54 299  69a
Group 1 (n ¼ 4) suppository expelled
Cmax (mg/L) 12.4  6.4 13.4  8.1 25.7  14.2 1.6  1.4
Tmax (h) 1.9  0.9 1.9  0.9 1.9  0.9
Chronological t1/2 (h) 3.8  2.9 3.1  2.4 2.9  2.1
Physiological t1/2 (h) 7.8  5.8 6.3  5.1 6.0  4.4
AUC (mg/L  h) 66  40 54  48 108  83
Group 2 (n ¼ 8)
Cmax (mg/L) 38.5  20.7 40.0  21.8 75.6  44.6 1.1  0.2
Tmax (h) 1.6  0.7b 1.4  0.8b 1.6  0.7b
Chronological t1/2 (h) 1.7  0.4 2.2  0.7 1.9  0.5
Physiological t1/2 (h) 3.1  0.9 3.9  1.4 3.4  1.0
AUC (mg/L  h) 131  79 124  67 248  153
Group 3 (n ¼ 7)
Cmax (mg/L) 42.7  16.0 49.7  23.3 87.9  36.6 1.1  0.4
Tmax (h) 1.7  0.3b 1.6  0.7b 1.6  0.3b
Chronological t1/2 (h) 2.8  1.3 1.8  0.4 2.1  0.7
Physiological t1/2 (h) 4.6  2.3 2.9  0.7 3.6  1.3
AUC (mg/L  h) 180  98 167  56 339  136
Group 4 (n ¼ 7)
Cmax (mg/L) 30.1  12.5 30.1  9.9 63.8  20.4 0.9  0.1
Tmax (h) 3.5  0.8 2.9  1.0 3.3  0.8
Chronological t1/2 (h) 2.1  0.3 2.5  0.7 2.2  0.4
Physiological t1/2 (h) 2.1  0.3 2.5  0.6 2.2  0.4
AUC (mg/L  h) 160  65 177  59 334  123
Values are mean  SD. Only those patients in group 1 in whom the suppository was retained were
included in the comparisons between the groups 1 and 4.
a
Significantly (P > 0.05) different from the corresponding value in group 1 where the suppository
was expelled.
b
Significantly (P < 0.05) different from the corresponding value in group 4.
AUC ratio is the ratio of (S)-(+)-ibuprofen AUC to that of (R)-(
)-ibuprofen.
Reproduced from Kyllönen et al. (2005) with permission of the publishers of Paediatric
Anaesthesiology.

The ratios of the AUC values for the R/S, R(
) and S(þ) isomers were similar in
all the groups except, as expected, in the youngest infant group who had expelled
suppositories.
The values of tmax for R(
) ibuprofen ranged from 1.4 to 2.9 h. The highest
values of 2.9 h achieved in adults, in contrast to the range of values in infants of
2.5 Pharmacokinetics in Children 37

1.4–1.8 h. There were no significant differences in the values of tmax between the
infant groups. However, there were significant differences between the two older
infant groups, as well as with the adult group. Only in adults was the tmax of 3.5 h
greater for the S(þ) isomer than the R(
) enantiomer (1.6–2.2 h).
The ratios of the AUCs for R/S-ibuprofen was greater in the youngest infant
group, being 1.7 in those that had retained the suppositories, and 1.6 in the expelled
suppository groups, compared with those in all the other groups (0.9–1.1). This
indicates that there is a greater rate of conversion of R(
) to S(þ) ibuprofen from
suppositories, an observation which parallels that observed following oral adminis-
tration of the drug. The plasma elimination half-life (t½) of both the racemic
ibuprofen as well as the R(
) and S(þ) enantiomers was greater in the youngest
of the infant groups compared with those in others and adults, indicating slower
rates of elimination in young infants, perhaps as a consequence of ibuprofen-
metabolising enzymes not being fully developed in infants.
These studies show that rectal administration of ibuprofen is an easy and
effective way of achieving therapeutic plasma concentrations, especially in
children or in the perioperative or post-operative surgery. The slightly delayed
absorption of ibuprofen in adults may have been due to the stress of the more
extensive disc herniation surgery, contrasted with the minor surgery in children
where there were higher plasma half-lives in infants aged 1–7 weeks. Otherwise,
there do not appear to be any substantial differences in pharmacokinetics between
infants and adults from ibuprofen administered as a suppository formulation.

2.5 Pharmacokinetics in Children

Of the limited number of studies on the PKs of ibuprofen in children, the only
appreciable changes observed in paediatric populations have been found in young
children aged less than 5 years, where the clearance (CL/F) and volume of
distribution (Vd/F) may be less than that in adults or older children, and the plasma
half-life of elimination (t½) prolonged to about twice that in adults or older children
(Autret-Leca 2003; Jacqz-Aigrain and Anderson 2006).
There are, however, relatively few studies that have been performed in very
young children (Jacqz-Aigrain and Anderson 2006; Rainsford 2009). The limited
data suggest that the PK and pharmacodynamic (PD) properties of ibuprofen in
3–4 month to 12-year-old children may be similar to that of young-mid aged adults.
Variations in PK in most age groups >1–2 years might be related to differences in
growth rates, thus affecting body mass indices, and possibly gender, both of which
may influence developmental and hormonal regulation of drug metabolising
enzymes.
The PK and PD properties of ibuprofen in children >1–2 years are generally
believed to be related to that in adults. The few PK studies have been performed in
children in the <1–2 years age group are enough to conclude that, in general, the
PK properties are similar to those in adults. While relatively little is known about
PD properties in young children, it appears that dose-related pain relief is similar in
38 2 Biodisposition in Relation to Actions

Table 2.9 General pharmacokinetic properties of ibuprofen in children

Oral absorption t½: 0.3–0.9 h
tmax: 1–2 h
10 mg/kg ! Cmax: 44 mg/L
Protein binding 99 %
Active isomer S(+)
Plasma conc. S(+) children < S(+) adults
Metabolism CYP450 2C9 and 2C8
t½ 0.9–2.3 h
From Autret-Leca (2003) and Rainsford (2009)
Reproduced with permission of John Wiley and Sons, publishers of the International Journal of
Clinical Practice

young adults to that in younger children (Jacqz-Aigrain and Anderson 2006;

Rainsford 2009).
The population PK properties of ibuprofen in children (aged 6 months)
following oral administration are summarised in Table 2.9 (cf. Table 2.1 in adults),
from which it is apparent that these properties are similar to those in adults.
The data in Table 2.9 show that the mean (SD) values for many of these
parameters in children show remarkable consistency from the different studies, and
indicate that ibuprofen has, in general, predictable and reliable kinetic properties.
Furthermore, there is dose-related increase in plasma concentration Cp and to some
extent AUC values, but the kinetic constants reflected by t½ (or the inverse, kel)
suggest that there is little variation with dosage. There is also little variation of these
kinetic parameters with repeated dosage.
The PK properties of various formulations, including those given parenterally as
well as orally, are shown in Table 2.10. It is apparent that the t½ and Vd of ibuprofen
in patients receiving i.v. drugs is about 25-fold higher than from orally-administered
ibuprofen; yet there is the same order of elimination and distribution of oral ibuprofen
from an early age of about 0.5 year. In older subjects, the t½ and Vd are within the
range of those in adults. The rates of clearance are, greater in young children up to
about 5 years and decline in higher age groups, and are appreciably lower in i.v.-
administered infants (Table 2.10). Ibuprofen has a lower rate of glomerular filtration
in premature infants, so this may be a factor accounting for higher t½ and Vd in this
group compared with that in adults.
Some differences in stereospecific PK are apparent in children compared with
adults. Thus, in a study in 11 infants (6–18 months) the plasma levels of the S(þ)
enantiomer of ibuprofen were found to be lower than in adults, while the values for
t½ for R(
) and S(þ) ibuprofen were within the range of those expected in older
children or adults (Kauffman and Nelson 1992; see also Jacqz-Aigrain and
Anderson 2006). It is possible that the relatively low levels of S(þ) ibuprofen
would be an argument for advocating higher dosage of ibuprofen in infants.
However, it can at least be a reason for erring on the side of caution, especially if
the drug is give on a body-weight basis.
2.5 Pharmacokinetics in Children 39

Table 2.10 Pharmacokinetic parameter estimates for ibuprofen given by different routes to
paediatric patients
Age Formulation CL/F (mL/h/kg) V/F (L/kg) t1/2 (h)
Ibuprofen i.v. 2.06 (0.33) 0.062 (0.004) 30.5
22–31 weeksa i.v. 9.49 (6.82) 0.357 (0.121) 43.1 (26.1)
28.6 (1.9) weeksa Suspension 110 (40) 0.20 (0.09) 1.6 (0.4)
0.5–1.5 years Suspension 57.6 0.164 1.97
11 mo–11 years Suspension 80 (10)SE 0.16 (0.02)SE 1.44 (0.15)
3 mo–12 years Suspension 110 (10)SE 0.22 (0.02)SE 1.37 (0.09)
3 mo–12 years Suspension 140 (32) 0.27 (0.11) 1.4 (0.5)
5.2 (1.7) years Tablet 114 (26) 0.26 (0.1) 1.6 (0.4)
5.2 (2.5) years Suspension/ 71 (CV 24 %) Vc 0.06, Vp 0.1 –
4–16 years granules (4.05 L/h x 70 kg)
1 (CV 65 %)
Based on Jacqz-Aigrain and Anderson (2006).
Variability presented as standard deviation (SD), range (x–y) or standard error (SE). CL/F apparent
drug plasma clearance, i.v. intravenous, t1/2 elimination half-life, V/F apparent volume of distri-
bution, Vss volume of distribution at steady state, Vc initial volume of distribution, Vp apparent
volume of distribution of peripheral compartment, SE standard error.
a
Age is gestation age (GA, weeks).
b
Data reported using allometric model. Estimate presented for a 30kg individual estimated.
Reproduced from Jacqz-Aigrain and Anderson (2006) with permission of Elsevier, publishers of
Seminars in Fetal and Neonatal Medicine.

A kinetic analysis has shown that there was no effect of age on the pharmacoki-
netic properties of a suspension of the drug in a group of 38 patients (Kauffman and
Nelson 1992). It was found that ibuprofen was rapidly absorbed with a Cmax of
35.8  16.7 (mean  SD) at 0.7  0.5 h (mean  SD). The absorption was faster
than that found in earlier studies, and similarly the half-life of absorption was fast
(t½abs 0.3  0.3 h). The plasma elimination t½ was 1.6  0.7 (mean  SD) h,
which was within the range observed in other studies and in adults.
Brown et al. (1992) investigated the bioavailability of 5 or 10 mg/kg ibuprofen
and 12.5 mg/kg paracetamol in 153 febrile children. The Cmax occurred about 2.5 h
earlier than the maximal antipyresis with both drugs, thus being in agreement with
the study of Kauffman and Nelson (1992). The plasma AUC0–1 was lower for the
high dose of ibuprofen than the lower, an observation which is at variance with that
obtained in other studies.
Kelley et al. (1992) undertook a randomised, open-label parallel PK study of the
R(
) and S(þ) enantiomers of ibuprofen in febrile children, in which 39 patients
(aged 11 months to 11.5 years) received 6 mg/kg ibuprofen suspension or
5–10 mg/kg paracetamol. However, only values of Cmax being 33.5  14.7
(mean  SD) mg/mL and tmax being 60  19.7 min were recorded, but not the
values for the individual enantiomers.
The disposition of ibuprofen enantiomers was studied in 11 infants (6 to
18 months) who were anaesthetised for minor genitor-urinary surgery and given
7.6  0.3 mg/kg ibuprofen suspension post-operatively (Re et al. 1994). The values
of racemic S(þ) and R(
) were 24.4  6.6, 9.7  2.9 and 11.8  4.4 mg/mL at
tmax approximately 2–4 h respectively. It was apparent from these studies that the
40 2 Biodisposition in Relation to Actions

peak plasma concentrations were much longer than those observed in the previous
studies in febrile infants and children, suggesting that either the surgical–
anaesthetic procedure delayed GI absorption of the drug, or the age of the infants
influenced the PK of ibuprofen. The lower S/R ratio obtained is in contrast to that of
other investigators in infants where this was higher.

2.5.1 Juvenile Idiopathic (Rheumatoid) Arthritis

Mäkelä et al. (1979, 1981) published two studies on the PK of ibuprofen in juvenile
idiopathic arthritis (JIA): these studies determined the concentrations of racemic
drug in serum and synovial fluids in 17 patients with JIA (aged 1.5–15 years) who
received ~40 mg/kg/day ibuprofen. It was found that the proportion of ibuprofen in
the synovial fluids was relatively high compared with that in the serum (Fig. 2.14).
The absorption of oral ibuprofen was rapid, and comparable to that in adults
(Mäkelä et al. 1979, 1981). In 33 patients (1.5–15 years) that received approxi-
mately 40 mg/kg/day t.i.d., peak serum concentrations Cmax were 31 mg/mL at
1.0–2.0 h while those in the synovial fluid were approximately 1/2 those in serum
and peaked at about 5–6 h. The t½ in serum was 2.3 h, which is comparable with that
in adults.

2.5.2 Cystic Fibrosis

Ibuprofen is not specifically indicated for use in cystic fibrosis (CF), but has been
investigated and found efficacious in this disease (Rainsford 2009). Data on the PK
of ibuprofen in cystic fibrosis (CF) are both extensive and useful for indicating the
disposition of ibuprofen at high dosages, especially where there is considerable
pulmonary (often with accompanying Pseudomonas or other bacterial infections as
well as from the disease) and gastrointestinal inflammation (Rainsford 2009).
Konstan et al. (1991, 1995) were amongst those who initiated the application of
ibuprofen for treating CF. In a randomised, double-blind, placebo-controlled,
dose-escalating study in 19 children (6–12 years) in Ohio (USA), they compared
the plasma PK of the enantiomers following 300 mg of the racemic drug for first
month, followed by 400 mg in the second month and 600 mg in the third month
(Konstan et al. 1991). The dose of ibuprofen was increased if the peak plasma level
was 50 mg/mL.
The PK of ibuprofen was also investigated in 13 children who received
13.4  4.1 mg/kg (mean  SD) compared with that in four normal children who
received similar doses of the drug.
In the dose-escalation study, the values of Cmax were 38, 29 and 65 mg/mL for the
three dosages 300, 400 and 600 mg/day respectively. The tmax values were 68, 128,
2.5 Pharmacokinetics in Children 41

and 109 min, indicating that at the highest dose there was some limitation due to
gastric absorption. Indeed, there are indications of drug absorption and a wide
scattering of Cmax data in relation to dose (mg/kg) of ibuprofen, suggesting that
some of the GI effects of the disease (excess mucus secretion) may influence
absorption of the drug. Compared with PK in normal adults or those with arthritic
diseases (Tables 2.1, 2.3, 2.4 and 2.5) the values of Cmax and tmax are higher by a
twofold factor or greater. The values of AUC (5.8, 6.3 and 10.8 mg/min/mL) for the
three doses also appear higher than in adults with the rates of clearance (1.8, 2.1,
1.9 mL/min/kg) being relatively low. The t½ was approximately 68, 128 and 109
min for each dosage level, reflecting extension of residence time of the drug in the
body. Thus, these investigations show that there are marked differences in the PK of
ibuprofen in CF patients compared with young or mid-aged adults. In the second
part of this study, the plasma concentrations and the AUC values in the CF patients
(6.1  1.7; mean  SD mg/min/mL) were significantly lower than in controls
(11.3  3.4, mean  SD, mg/min/mL), with reduction in clearance being about
1/3 accompanied by an increase in Vd. The possible reasons for these substantial
alterations in PK include decreased bioavailability (from possible reduced GI
absorption), increased metabolic clearance, and increased unbound fraction in
plasma (Brocks and Jamali 1999).
Dong et al. (2000) undertook a study of 38 children of both sexes, age range
2–13 years, with CF; the enantiomer PK’s were investigated in a single-dose,
open-label investigation following 20 mg/kg racemic ibuprofen (Dong et al.
2000). The enantiomeric ratio of the plasma AUC was 2.09:1 (S:R) and the free
and conjugated ibuprofen in urine was 13.9:1 (S:R), which indicated there were no
differences in these parameters compared with those in normal children. While
there were no differences observed in other PK parameters, there was an inverse
relationship between the CI/F for R(
) ibuprofen with age in CF patients. There
was no significant difference in PK parameters with gender or formulations
(suspensions, tablets) of ibuprofen.
The dose of ibuprofen employed by Dong et al. (2000) was 20 mg/kg, and
was greater than that in the second PK study by Konstan et al. (1991) (13.4 mg/kg in
CF and 13.9 in controls), so the differences in PKs between these studies might be
explained, in part, by differences in dosages, even though the actual values for
the R(
) and S(þ) enantiomers were not clear from the study by Konstan and
co-workers.
Arranz and co-workers (2003) investigated the population PK of serum ibupro-
fen in 59 CF patients (2–18 years) in order to identify the factors accounting for
inter-individual variability. Their PK analysis revealed that the inter-individual
variability was such that the absorption constant (Ka) could not be estimated
accurately. Dose-dependent kinetics were, however, demonstrated, which affected
clearance and Vd. The fasting status and formulation (acid or lysine salt) appeared to
affect the bioavailability and clearance of ibuprofen, as would be expected. Slower
absorption of the free acid was evident compared with that of the lysine salt of
ibuprofen.
42 2 Biodisposition in Relation to Actions

2.5.3 Patent Ductus Arteriosus

The i.v. lysine or other salts of ibuprofen have been employed for closure of patent
ductus arteriosus (PDA) in preterm neonates (Aranda and Thomas 2006; Aranda
et al. 2009a). Ibuprofen and indomethacin have both been approved by the FDA and
EMEA for use in closure of PDA in the newborn (Aranda et al. 2009a). However,
only indomethacin is approved for prevention of intraventricular haemorrhage
(Aranda et al. 2009a).
Studies on the safety, efficacy, pharmacokinetics, and pharmacodynamics in
patients with PDA have shown the favourable benefits of i.v. ibuprofen, especially
the lysine salt (Aranda and Thomas 2006; Aranda et al. 2009a). In comparison with
oral ibuprofen, the i.v. administration yields higher plasma concentrations (Sharma
et al. 2003; Aranda and Thomas 2006).
Aranda et al. (1997) were the first to report the pharmacokinetics and plasma
protein of i.v. lysine salt of ibuprofen 10 mg/kg bolus given within 3 h of birth to 21
premature neonates. Unfortunately, only the racemic drug was analysed. There was
a relatively high scatter in plasma concentration profiles, although the values for
AUC and Vd (62.1 mL/kg) had reasonable error. The plasma t½ was (mean  SD)
30.5  4.2 h, which was appreciably longer than in infants, children, or adults
(approximately 1–2 h). The percentage binding to cord plasma was significantly
lower (94.98  0.39 %, mean  SD) compared with that in adult plasma
(98.73  0.31 %, mean  SD). There was no correlation between gestational age
(22–31 weeks) and plasma clearance or half-life, or elimination rate constant,
indicating that there was no effect of fetal age on the disposition of ibuprofen.
The rate of clearance was low (2.06  0.33 mL/kg/h, mean  S.D.) compared with
that in infants through to adults. It was suggested that the prolonged t½ and Cl may
reflect immaturity in the formation of cytochrome P450 and glucuronyl-transferase
enzyme systems. Van Overmeire et al. (2001) studied the PK of lysine ibuprofen in
27 patients with PDA, in 13 of whom there were complete data for PK analysis, and
incomplete (although useful) data in the remaining 14. In this study, ibuprofen was
administered on days 3, 4 and 5 by 15-min i.v. infusion of 10 and 5 mg/kg
respectively.
Chapter 3
Mechanisms of Inflammation and
Sites of Action of NSAIDs

Understanding of the mechanisms underlying acute and chronic inflammation is

central to the understanding of the actions of NSAIDs and NN analgesics (Rainsford
2004c). Moreover, the site and factors controlling the expression of inflammatory
pathways and events underlie the occurrence of inflammatory events at different
sites in the body. In relation to inflammatory pain these sites have widespread
location in the body, yet the underlying inflammatory reactions are essentially
common (Wall and Melzack 1989; Gallin et al. 1992). This is especially so in the
peripheral and central nervous system pathways that underlie pain responses.

3.1 Pathways of Inflammation

The sequence of changes in microvascular and cellular events that characterise

acute inflammation has been well-defined (Gallin et al. 1992; Rainsford 2004c).
A schematic representation of the sequence of events following a hypothetical
injurious event is shown in Fig. 3.1, along with an explanation of the major events
underling these reactions. The cellular responses and mediators produced by
leucocytes are shown in Fig. 3.2.
To illustrate how these initiating cellular events in acute inflammation, and the
transition to chronic, fit in with the pathogenesis of arthritic states, it is necessary to
consider the inter-relationships with the immune pathways involved in conditions
such as rheumatoid arthritis. Figure 3.3 shows these inter-relationships and how they
impact upon the processes of joint destruction. Since ibuprofen affects a limited array
of cellular mediators and reactions, but few if any immune pathways (e.g., T- and
B-cell functions, it is evident that the drug has limited effects involving local cellular
reactions and mediators which underlie soft-tissue inflammation and joint-destructive
enzymes. The same is true of the local joint destruction in osteoarthritis.

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 43

DOI 10.1007/978-3-0348-0496-7_3, # Springer Basel 2012
44 3 Mechanisms of Inflammation and Sites of Action of NSAIDs

Fig. 3.1 Hypothetical series of vascular and cellular events accompanying the development of
swelling (oedema) and associated production of inflammatory mediators with cellular infiltration
and activation of leucocytes during acute inflammation (based on Rainsford 2004c, Gilroy and
Lawrence 2008). The development of pain (right side scale) is associated with local tissue swelling
(left side scale). The sequence of cellular infiltration and activation is shown below the x-axis. The
initial mast cell activation releases amines (5-HT, histamine), which initiate swelling by vascular
dilatation in what is termed the “histamine phase”. Antihistamines block this reaction, and
consequently reduce swelling. After about 1–2 h there is accumulation and activation of comple-
ment components for the circulation. At about this time there is appreciable generation of
prostaglandins and bradykinin activation (from the actions of kinases on kinins in the circulation),
which characterises what has been termed the “prostaglandin (PG) phase”. The significance of this
phase is illustrated by the reduced swelling that occurs in rats that have been rendered deficient in
dietary poly-unsaturated fatty acids, which are necessary for the formation of the arachidonic acid
precursor for the oxidative production of PGs and leukotrienes (Bonta and Parnham 1981).
Vasodilatation follows which leads to a cycle of ischaemia-reperfusion and extravasation of
blood-borne proteins and inflammatory mediators, among them superoxide and hydroxyl-radicals.
During this and later phases there is a progressive vascular adhesion and transcellular migration
and activation of polymorphonuclear neutrophil leucocytes (PMN), followed by accumulation of
monocytes which adhere to microvessels, which then transgress across the endothelia and are
activated to form macrophages. Activation of macrophages and PMNs leads to (a) induction of
COX-1 and PLA-2, with subsequent amplified generation of PGs and LTs, (b) production of
oxyradicals and nitric oxide, which in turn form peroxynitrite among the most powerful tissue
oxidants known with tissue destructive activity, (c) production of pro-inflammatory cytokines, and
(d) release of lysosomal enzymes which cause autolysis of local tissues. The progress to resolution
of inflammation is regulated by lipoxins/resolvins and D/J-type prostaglandins, and the TGFb1
regulation of apoptosis and phagocytosis (Gilroy and Lawrence 2008). Should the supervening
insult or immunological reactions be so severe as to overcome the development of resolution then
this process is deemed to have “failed”, and persistent inflammatory reactions ensue, resulting in
chronic inflammation which may involve abscess formation (from persistent infectious agents),
excess scarring and auto-immunity from severe immunological reactions
3.2 Link of Pharmacokinetics to Pharmacodynamics 45

Fig. 3.2 Cells and mediators involved in the expression and development of inflammation and
their interaction with peripheral neural systems

3.2 Link of Pharmacokinetics to Pharmacodynamics

Ibuprofen has multiple modes of action through inhibition of the production of

inflammatory prostaglandins (PGs) such as PGE2 which is one of a number of the
key components of this multi-factorial property of the drug (Rainsford 1999b). Like
many conventional (or traditional) NSAIDs, ibuprofen inhibits both the constitutive
cyclo-oxygenase-1 (COX-1) which is responsible for production of prostanoids
(PGs and thromboxane A2, TxA2) that control a range of physiological or
“housekeeping” functions (vascular, blood flow, gastric, and renal functions), and
the inducible COX-2 whose synthesis is increased, leading to amplified production
of PGE2 in inflammation and pain (Cryer and Feldman 1998; Rainsford 1999b,
2004a, b; Vane and Botting 2001; Warner et al. 1999; Fig. 3.4).
COX-1 inhibition has been considered a factor underlying the possibility of
NSAIDs to cause some adverse effects (GI ulcers, bleeding, renal abnormalities),
although there are other biochemical and cellular actions of NSAIDs that contribute
to their untoward effects (Rainsford 2004a; Bjarnason et al. 2007; Fig. 3.4). The
ratio of inhibition of COX-1 to COX-2 varies considerably among different
NSAIDs and the coxibs (Table 3.1), although part of the variability may be due
to the experimental conditions under which the inhibitory effects of the drugs has
been measured (Warner et al. 1999).
46 3 Mechanisms of Inflammation and Sites of Action of NSAIDs

Pathogenesis of rheumatoid arthritis

Rheumatoid
factors Immune complexes
B Cell Bacterial products
IL-1, TNFα stimulate
Cognate and IL-1, TNFα
cytokine IL-6
interactions

Macrophage

IL-2R
IFN
TCR T cell Clonal
proliferation LT GM, CSF TNFα
MCH
IL-1 IL-6
IL-2
APC

Peptide Stimulates
growth of
pannus

Synoviocytes

leucocytes
Pannus from vessels

Fibroblasts Chondrocytes
Articular
Cartilage
Production of collagenases
neutral proteases, stromelysin Osteoclasts

Erosion of bone

Fig. 3.3 Concepts of the pathogenesis of rheumatoid arthritis showing the range of immuno-
inflammatory cells and mediators that are involved in the joints of patients with this disease.
Ibuprofen, like other NSAIDs, affects the vascular, eicosanoid, IL-1/TNFa, macrophage and
synovial/cartilage production of actions of cell- and matrix-destructive components of joint
inflammatory disease. The production and action of B- and T-cell mediators is unaffected or
limited with ibuprofen. From: Patel et al. (2010) with modifications. Reproduced with permission
of Cambridge University Press

The relative inhibitory effects of NSAIDs and coxibs on COX-1 and COX-2
have been considered to relate to the likelihood of developing upper GI and
possibly renal and other reactions by NSAIDs in relation to their anti-inflammatory
activities (Cryer and Feldman 1998; Warner et al. 1999; Vane and Botting 2001;
Huntjens et al. 2005). The newer class of highly selective COX-2 inhibitors, the
coxibs, were developed in attempts to reduce the risks of serious upper GI and other
reactions (Rainsford 2004b).
3.2 Link of Pharmacokinetics to Pharmacodynamics 47

Cell membrane Exogenous

anandamide
endocannabinoids CB Receptors
Phospholipase (increased with COX inhi-
bition)

Arachidonic acid
Analgesia

All non-selective COX-2 selective NSAIDs (e.g. celecoxib, rofecoxib)

COX 3 (a COX 1 variant) in CNS NSAIDs & only inhibit COX-2 in the therapeutic dose range
Paracetamol inhibit
COX-1 and COX-2

COX-1 COX-2
Postulated site for Constitutive expression+++
paracetamol and Induction+++
Induction+ Constitutive expression
aminopyrine Most organs Predominantly inflammatory and
Stomach, kidney, platelets, Neoplastic sites,also present in
Vasculature small intestine, kidney, ovary
“Physiological- Uterus and brain
Housekeeping” Activated in inflammation and pain. Role in
Modulation of inflammation repair, neoplasia,
Immunomodulation & tolerance

PGG2 PGH2

Cell-specific synthase
or isomerase

Products: TXA2 PGI2 PGE2 PGE2 PGI2 PGF2α PGD2 TXA2 PGJ2

Receptors: TP IP EP EP IP FP DP TP PPAR

Fig. 3.4 Pathways of arachidonic acid metabolism involving the actions of constitutive cyclo-
oxygenase-1 (COX-1) and inducible cyclo-oxygenase-2 and subsequently the respective synthase
or isomerase enzymes, leading to the formation of specific prostaglandins (PG) or thromboxane A2
(TXA2). These prostanoids act on their specific receptors. Ibuprofen, like other NSAIDs, inhibits
both COXs. Additionally, phospholipid-derived anandamide, which is an endogenous cannabi-
noid, can be stimulated by ibuprofen from the combination of inhibiting anandamide hydrolase, an
enzyme that breaks down anandamide, while the net effect of inhibiting COXs may contribute to
the increased production of anandamide. Both effects may contribute to the CNS components of
analgesia induced by ibuprofen. Modified from Rainsford (2004c)

Ibuprofen, like a number of traditional NSAIDs has been shown in a number of

in vitro and some in vivo studies to have inhibitory effects on both COX-1 and
COX-2 (Boneberg et al. 1996; Cryer and Feldman 1998; Warner et al. 1999;
Rainsford 1999b, 2004; Vane and Botting 2001; Huntjens et al. 2005), which raises
issues about why such an non-selective COX-1/2 inhibitor would have low risks of
GI and renal effects compared with other NSAIDs. It has been suggested that one of
the reasons for the low gastro-ulcerogenicity of ibuprofen may relate to the compe-
tition of the COX-1 inactive R( )-isomer with the active enantiomer for the active
site of COX-1, so effectively diminishing the potential for inhibition of PG synthe-
sis by the drug (Rainsford 1999b, 2003). The short plasma elimination half-life of
the drug may also be a feature accounting for low risks of upper GI injury from the
drug (Henry et al. 1993, 1996, 1998).
 48

Table 3.1 Relative effects of NSAIDs on cyclo-oxygenase activities in different systems

Therapeutic plasma
Therapeutic concentration Whole blood COX-1 Whole blood COX-1 Gastric mucosa COX Whole blood COX-2 Whole blood COX-2
Drug dose (mg/day) mM mg/mL IC50 (mM) IC80 (mM) IC50 (mM) IC50 (mM) IC80 (mM)
Aspirin 1,200–5,200 111 6.17* 4.45 8 0.03 13.88 >100
(high dose)
Aspirin (low dose) 81–325 15 2.7* 4.45 NA 0.03 13.88 NA
Celecoxib 100–200 0.8 0.29 10.0–20.0 28 NA 0.3 6
Diclofenac 150–200 0.8 0.25 0.26 1 0.23 0.01 0.27
Ibuprofen 1,200–3,200 111 22.9 5.9 58 0.7 9.9 67
(high dose)
Ibuprofen 800–1,200 38.8 7.8 5.9 NA 0.7 9.9 NA
(low dose)
Indomethacin 75–200 3 1.1 0.16 0.46 0.85 0.5 5
Ketoprofen 100–300 9.4 2.4 0.11 1 0.08 0.88 22
Naproxen 500–1,000 253 58.2 32.01 110 0.52 28.19 260
Piroxicam 20 16.6 5.5 2.68 15 0.87 2.11 31
Rofecoxib 25–50 1.9 0.68 13 >100 NA 0.59 6
Modified from Huntjens et al. (2005), with permission of Oxford University Press publishers of Rheumatology
*Aspirin concentrations relate to its metabolite, salicylate. It is also an irreversible inhibitor of COX-1
3 Mechanisms of Inflammation and Sites of Action of NSAIDs
3.3 Relation of Analgesic Effects to COX-1 and COX-2 Inhibition 49

3.3 Relation of Analgesic Effects to COX-1 and COX-2

Inhibition

It is well-established that the anti-inflammatory and analgesic effects of ibuprofen

are due in a large part to inhibition of the inducible pro-inflammatory cyclo-
oxygenase (COX-2), as well as the constitutive, physiologically related COX-1
(Rainsford 2009). To establish what could be regarded as “clinically-significant”
effects of NSAIDs/coxibs on COX-1 and COX-2 activities in humans requires use
of either ex-vivo whole blood or in-vivo blood or tissue-sampling techniques that
are now well-established (Rainsford et al. 1993; Warner et al. 1999; Brooks et al.
1999; Bjarnason and Rainsford 2001).
Among the studies which have addressed the issue of the PK of NSAIDs to their
in-vivo activities as COX inhibitors is the study by Blain et al. (2002). Using the
whole blood assay, these authors compared the effects of ibuprofen, diclofenac, and
meloxicam on in-vitro activities of COX isoenzymes using blood from 24 healthy
male volunteers, and the ex-vivo production of COX-1-derived TxB2 during
clotting and COX-2-derived PGE2 upon stimulation with endotoxin after the
same volunteers took single and multiple (3 days for ibuprofen and diclofenac
and 5 days for meloxicam) doses of 400 mg ibuprofen (Brufen®), 75 mg diclofenac
SR (Voltaren®), or 7.5 mg meloxicam (Mobic®). Plasma concentrations of the
drugs and in the case of ibuprofen the R/S enantiomers were determined and used to
relate these as free and unbound concentrations to in-vitro inhibition profiles.
These authors then modelled the time-course of plasma concentrations of the
drugs to the inhibition of the COX isoenzymes.
The plasma concentration of ibuprofen after a single dose of 400 mg was
24.0  8.0 mg/mL (116 mM) while that after 400 mg t.i.d. for 3 days was
14.8  5.9 mg/mL (70.4 mM). At these concentrations the ex-vivo inhibition of
COX-1 and COX-2 was 83 %, while COX-1 was 96 % after single dose of 400 mg
and 76 % and 83 % after multiple dosing, respectively.
These data in essence mean that during analgesia with 400 mg ibuprofen, the
therapeutic drug concentrations of racemic ibuprofen are 24 mg/mL (single dose)
and 14.9 mg/mL (multiple doses). These concentrations are within those required
for analgesia (Table 2.1), showing that relevant therapeutic drug concentrations for
ibuprofen are in the order of 15–25 mg/mL.
Ibuprofen, taken singly or repeatedly, inhibited production of TxB2 by COX-1
by 96 % and 90 % respectively. COX-2 production of PGE2 was inhibited by 84 %
and 76 % respectively after single and multiple doses. Almost complete inhibition
of both COX-1 and COX-2 was achieved under in-vivo conditions and this was
paralleled by the modelling of in-vitro inhibition profiles. Near complete COX-
2 inhibition in vitro was achieved at free concentrations of the racemate as well as
the S(+) enantiomer, which almost completely inhibited both COX-1 and COX-
2 in vitro. When these data were compared with the inhibition ex vivo, it was
evident that although there was wide scatter of about 10 % of the latter data most
fell within about 80 % inhibition of COX-1 and COX-2 observed in vitro.
50 3 Mechanisms of Inflammation and Sites of Action of NSAIDs

In comparison, after oral intake diclofenac inhibited COX-1 by 70 % and COX-

2 by 95 % and 97 %. COX-1 inhibition from meloxicam was 30 % and 55 %, and
COX-2 was 63 % and 83 % respectively after single and repeated doses.
The time course of inhibition by ibuprofen 400 mg of COX-1 and COX-2
activities ex vivo has been shown by Kerola et al. (2008) to extend from 1 to 6 h,
and this is within the time of analgesia with this drug (Table 2.2). Thus, in
conclusion, the therapeutically relevant concentrations of ibuprofen after 400 mg
dosage are those at which there is appreciable and significant inhibition of COX
activities.
The data obtained in these studies gives a clear basis for relating the in-vivo
effects of ibuprofen on prostanoids from COX-1 and COX-2 activities with the anti-
inflammatory and analgesic effects of the drug in various clinical models and during
therapy. Since the doses of ibuprofen used in these studies (1.2 g/day) correspond to
those used OTC, and these doses produce effective analgesic activity in various
pain models, notably also inflammatory states such as dental pain involving extrac-
tion of molars, or throat pain where there is local inflammation, it can be concluded
that inhibition of COX-2 as well as COX-1 underlies the therapeutic effects of
ibuprofen in these conditions. It could be argued that the studies of Blain et al.
(2002) were in normal volunteers, and during inflammatory pain there is likely to be
more COX-2 activity. However, the in-vitro inhibition profiles modelled against
plasma concentration profiles of R( ) and S(+) ibuprofen determined before and
after surgery make it possible to suggest that these concentrations as well as free
concentrations of the drug would be sufficient to achieve about 70–80 % inhibition.
Thus, this evidence shows that there is a direct relationship between inhibition of
the synthesis of pro-inflammatory prostanoids that is within the dose range of
ibuprofen which corresponds to that used in OTC conditions for the relief of mild
to moderate pain; a central tenet of the therapeutic actions of ibuprofen in the
context of the OTC dosage of the drug.

3.4 Multiple Modes of Anti-inflammatory Activities

Another key feature about the mode of action of ibuprofen in inflammation is that
it has multiple modes of action (Rainsford 1999b, 2009; Figs. 3.5, 3.6 and 3.7).
There are several sites of action of ibuprofen enantiomers, including (a) prevention
of the accumulation of activated leucocytes (neutrophil PMNs, monocytes–
macrophages), (b) reduced expression of leucocyte adhesion molecules which
underlies the reduction of leucocyte accumulation in inflamed tissues, (c) inhibition
of the production and actions of leucocyte-derived inflammogens (e.g., leukotriene
B4 [LTB4], nitric oxide [NO]), pro-inflammatory cytokines (e.g., interleukin-1
[IL-1], tumour necrosis factor-a [TNFa]), and (d) reduction in selected neural
afferent and efferent pathways mediating pain resulting from inhibition of PGs,
NO as well as Na+ and Ca++ fluxes (Malmberg and Yaksh 1992a, 1992b; Björkman
1995a, b; Rainsford 2009). Several studies have emphasised the differentiation of
3.4 Multiple Modes of Anti-inflammatory Activities 51

Relationship of Pharmacokinetics to
Anti-Inflammatory Activity
Covalent tissue binding

Covalent tissue binding

Acyl glucuronides
H CH3
H3C OH
Acyl glucuronide
Metabolism
O via CoA H CH3
H3C
OH
CH3
R-(-)-Ibuprofen
O Hydrolysis
CH3
S(+)-Ibuprofen

Reduced inflammation and pain from decrease in

LEUKOCYTE ACCUMULATION &
ACTIVATION
LTB4
NO, Oxyradials, NFkB
Pro-inflammatory cytokines
(IL-Iβ, TNFα) Carboxymetabolite
Adhesion molecules Hydroxy metabolite
Ca2+ in flux in nerves + acyl glucuronides
Na+ from synapses COX-2

Carboxymetabolite
Hydroxy metabolite (R)-(-)-Ibuprofen-CoA (S)-(+)-Ibuprofen-CoA
+ acyl glucuronides

Hybrid triglycerides
incorporating Ibuprofen

Fig. 3.5 The inter-relationships between the actions of R( ) and S(+)-ibuprofen and intermediary
metabolites on cyclo-oxygenases, leukotrienes, and leucocyte-derived inflammatory mediators
and functions. Modified and redrawn from Rainsford (2009) with permission of Springer,
publishers of Inflammopharmacology

Fig. 3.6 Sites of actions of the enantiomers of ibuprofen on leucocytes, endothelial cells, and
postulated localization of effects on inflamed joints of arthritic patients. Modified from Rainsford
(2004c, 2009) with permission of Springer, publishers of Inflammopharmacology
52 3 Mechanisms of Inflammation and Sites of Action of NSAIDs

Fig. 3.7 Sites of action of ibuprofen in comparison with those of salicylate and paracetamol
(as oxyradical scavengers) on (a) the receptors and receptor signalling and inter-relationships
between PGEs and the pro-inflammatory cytokines, interleukin-1 (IL-1) and tumour necrosis
factor-a (TNF-a), (b) relative effects on oxyradicals that regulate nuclear factor kappa B
(NFkB) activation and nitric oxide production from inflammatory-regulated nitric oxide synthesis
(iNOS), and (c) control of gene-regulated production of COX-1, iNOS, metalloproteinases (MMP)
and pro-inflammatory cytokines. Based on Rainsford (1999b, 2009) with permission of Springer,
publishers of Inflammopharmacology. IBU ibuprofen, PAR paracetamol, SAL salicylate

analgesic from anti-inflammatory mechanisms of NSAIDs (McCormack and Brune

1991) but there is a clear anti-inflammatory component that contributes to the relief
of pain, especially that in chronic conditions (Rainsford 1999b, 2009). In addition
to the range of actions of ibuprofen on cyclo-oxygenases, leukotrienes, oxyradicals,
nitric oxide and leucocyte adhesion and accumulation (Fig. 3.5), there is a range of
anti-inflammatory actions of ibuprofen on signalling pathways (e.g. NFkB/IkB
dissociation and activation) which underlie the activation of leucocytes and other
cells mediating inflammation (Rainsford 2009) (Figs. 3.6 and 3.7).

3.4.1 Pain Control Pathways

Control of pain by NSAIDs, including ibuprofen, involves several different but

inter-related mechanisms (Rainsford 1999b, 2004c, 2005b, 2009). The principal
components of analgesic activity relate to the anti-inflammatory actions of the drug
3.4 Multiple Modes of Anti-inflammatory Activities 53

Fig. 3.8 Sites of action of ibuprofen on the peripheral and central neural afferent pathways of pain
transmission, as well as the efferent modulating pathways. Main neural pathways based on Fields
(1987) and modified from Rainsford (2004c)

and several sites of action in peripheral and central pathways of the nervous system.
As shown in Fig. 3.8 (Rainsford 2004c; with modifications based on Rainsford
2009) there are several sites of action of ibuprofen on the afferent transmitting and
efferent modulating pain pathways in the nervous system.
Like many other NSAIDs, ibuprofen inhibits the PG and NO components of
peripheral and spino-thalamic transmission of afferent pain impulses by the inhibi-
tion of the production of these mediators (Fig. 3.8; Rainsford 2009). Moreover,
ibuprofen is one of a few NSAIDs that stimulate production in the CNS of the
endogenous cannabinoid-like analgesic, anandamide, by inhibiting the enzyme that
hydrolyses this to arachidonic acid (Fowler et al. 1997a, b; Tiger et al. 2000; Holt
et al. 2007).
The components of peripheral neurotransmission that are affected by ibuprofen
and some other NSAIDs are shown in Fig. 3.9. Here, multiple actions of the drug
occur on the mediators of the peripheral inflammogenic response, including the
unique regulation and facilitation of these pathways by prostaglandin E2 (PGE2),
which in turn acts in the periphery via its specific receptor subtypes, EP1 and EP2
(Rodger 2009). The expression of inflammatory reactions and pain mediators that
occurs in a hypothetical arthritic joint, and the actions of ibuprofen are shown in
Fig. 3.10.
In the spinal cord (Figs. 3.9 and 3.11), ibuprofen has multiple actions the
transmission of pain stimuli at the level of the dorsal horn by affecting the release
and actions of the pain mediating peptides, substance P, calcitonin gene-related
peptide (CGRP), the excitatory amino acid, glutamate, in part, via PGE2, whose
production is reduced by COX-1 and COX-2 (Fig. 3.10; Rodger 2009).
54 3 Mechanisms of Inflammation and Sites of Action of NSAIDs

Fig. 3.9 Peripheral pain pathways leading from the sites of inflammation wherein there is
(a) production of various pain-evoking mediators in the “inflammatory soup”, (b) the subsequent
actions of these various mediators on their specific receptors on peripheral nerves, and (c) actions
at the level of the dorsal horn with activation of local COX-2 and iNOS, so amplifying the pain
responses. Regulation of these afferent pathways is achieved at the dorsal horn via negative “gate
control” of afferent nerves by downward projecting efferent pathways originating from central
activation of serotonergic (5-hydroxytryptamine producing) and noradrenergic pathways. Based
on Rainsford (1999b, 2009) and Rodger (2009)

Fig. 3.10 Actions of ibuprofen on peripheral pathways involved in the mediation of pain in a
typically inflamed joint, emphasising the variety of inflammatory mediators, including prostaglan-
din E-mediated regulation of pain transmission. Abbreviations: ATP adenosine triphosphate; 5-HT
5-hydroxytryptamine; CGRP calcitonin gene related peptide; DRG dorsal root ganglion
3.4 Multiple Modes of Anti-inflammatory Activities 55

Fig. 3.11 Actions of ibuprofen on pain transmission at the dorsal horn mediated via substance P,
calcitonin gene-related peptide (CGRP), and glutamate, each of which acts on their own specific
receptors. Based on Rodger (2009)

The induction of COX-2 activity is a feature of inflammatory pathways and those in

the spinal cord, so that inhibition of this enzymic activity by ibuprofen and other
NSAIDs and coxibs has a profound effect on the production of PGE2, since its
production is amplified via inflammogenic and pain responses; the impact quanti-
tatively of inhibiting COX-2 is, therefore, greater than that of the inhibition of
COX-1, even though the latter enzyme exists in a variety of pathways of pain
transmission and modulation in the CNS. Gene-knockout experiments (k/o) in mice
have shown that compensation for the absence of COX-1 in the spinal cord may not
involve increased expression of COX-2, whereas up-regulation of COX-1 in the
spinal cord may compensate for the absence of COX-2 (Ballou et al. 2000). This
shows there is evidence of cross-talk in the control of COX-1 and COX-2. These
observations are to some extent paralleled by responses to painful stimuli in mice.
Thus, in male and female COX-1 +/ mice, the reaction times are increased
compared with those in COX-1 and COX-2 k/o or wild type mice in the hot plate
test, a model of central or spinal algesia. In contrast in the writhing test, a model of
peripheral pain, COX-1 /+ or k/o mice and female COX-2 /+ mice had remark-
ably lower pain response (numbers of writhes) (Ballou et al. 2000). From the point
of view of analgesic actions by ibuprofen it is possible that this drug inhibits COX-1
somewhat more than COX-2.
56 3 Mechanisms of Inflammation and Sites of Action of NSAIDs

With COX-1/COX-2 ratios being approximately 2.6 (compared with rofecoxib

with ratios of ~0.05–0.0049, and celecoxib with ratios of 0.11–0.3; Warner et al.
1999) this would suggest that COX-1 inhibition by ibuprofen might have the effect
of decreasing peripheral COX-1, and thus produce peripheral analgesia, whereas in
the central analgesia this may be less pronounced.
The pioneering studies by Malmberg and Yaksh (1992a, b) highlighted the
central actions of some NSAIDs, including notably S(+), but not R( )-ibuprofen.
Thus, intrathecal administration of S(+) ibuprofen inhibited the 2nd phase of
flinching induced by hindpaw administration of formalin in rats. Other NSAIDs
and paracetamol also inhibited the nociceptive reactions in approximate order of
potency as PG synthesis inhibitors ranging from the more potent, flurbiprofen (IC50
2.1 nmol), S(+) ibuprofen (IC50 16 nmol) to paracetamol (IC50 250 nmol)
(Malmberg and Yaksh 1992a). These authors inferred that the central analgesic
actions of NSAIDs and paracetamol relate to their effects as PG synthesis
inhibitors. Another study by the same group focussing on the role of NMDA and
substance P receptors showed that spinal administration of S(+)-ibuprofen (like
aspirin or ketorolac) inhibited the hyperalgesia induced in rats by the excitatory
amino acid, glutamate, and the pain-mediating peptide, substance P (Malmberg and
Yaksh 1992a). Studies by Björkman (1995a, b) showed that the “scratching–bitin-
g–licking” response during thermal hyperalgesia in rats was markedly reduced by
spinal administration of S(+) but not by R( ) ibuprofen. This author also showed
(Björkman 1995a, b; Björkman et al. 1996) that the analgesic response from the
spinal administration to rats of NMDA agonist was observed following S(+)-
ibuprofen, but not R( )-ibuprofen. The pain response was also reduced by L-, but
not, D-arginine, suggesting that the nitric oxide (NO) generated from the L-arginine
overcame the excitatory effect of NMDA, invoking a NO mechanism in the
analgesic actions of ibuprofen. No responses to these NSAIDs were observed to
spinal application of substance P (Björkman et al. 1996).
Spinal serotonergic pathways have been shown to be involved in the analgesia
induced by NSAIDs (Björkman 1995a, b; Rainsford 2004c).

3.4.2 Antipyretic Activity

Another well-established anti-inflammatory action of ibuprofen and other NSAIDs

is the ability to control fever. This antipyretic response to ibuprofen and some other
NSAIDs has two components: (a) the control of the production of leucocyte-derived
interleukin-1 and other peptide components of endogenous pyrogen, and (b) the
direct inhibition of the production of endogenous pyrogens (or IL-1) induced PGE2
by the hypothalamus (Rainsford 1999b, 2004c, 2005b; Fig. 3.12).
3.4 Multiple Modes of Anti-inflammatory Activities 57

Fig. 3.12 Sites of antipyretic activity of ibuprofen involving the control of leucocyte production
of interleukin-1b (IL-1b) and IL-6, their subsequent actions at the level of the hypothalamus on
their respective receptors and the principal CNS actions of S(+)-ibuprofen on PGE2 production.
With modifications from Rainsford (2004a, b, c) based on Rainsford (1999b, 2004b, c, 2009)
Chapter 4
Clinical Efficacy

It is well-established that ibuprofen at both OTC and prescription level dosages

is effective in controlling pain and inflammation in a variety of inflammatory
and painful conditions. Among these are rheumatic and other musculo-skeletal
conditions, dental pain and surgery, dysmenorrhoea, upper respiratory tract condi-
tions (colds, influenza), headaches, accidental sports injuries, and surgical conditions
(Dionne 1998; Nørholt et al. 1998; Kean et al. 1999; Dionne and Cooper 1999;
Rainsford 1999c; Hersh et al. 1993, 2000a, b; Steen Law et al. 2000; Doyle et al.
2002; Beaver 2003; Dalton and Schweinle 2006; Sachs 2005; McQuay et al. 1986,
1989, 1992, 1993, 1996; McQuay and Moore 1998, 2006; Eccles 2006; Verhagen
et al. 2006; Huber and Terezhalmi 2006; Tables 4.1, 4.2 and 4.3). It is not the purpose
of this report to review the evidence in extenso about the clinical efficacy in various
painful states, since this is well-established from over 40 years of research and
applications of ibuprofen in the treatment of these conditions (Kean et al. 1999;
Rainsford 1999c).

4.1 Dental Pain

The dental pain model, involving the measurement of acute pain following extrac-
tion of one or more impacted third molars, is probably the most-widely accepted
robust and reliable method of determining relief from pain and swelling in humans
(Cooper 1984; Dionne and Cooper 1999). As shown in Table 4.1 ibuprofen has
comparable analgesic effects to other NSAIDs in the model of dental pain elicited
following surgical removal of third molars. Indeed, the relative efficacy of ibuprofen
as measured by the Number Needed to Treat (NNT) for determining the efficacy
from ibuprofen is either comparable or superior to other NSAIDs or analgesics
(Table 4.1). The adverse reactions from ibuprofen are often lower than with other
drugs (Table 4.1).
Another significant clinico-experimental fact is that ibuprofen has frequently
been used as a comparator drug in clinical trials with other NSAIDs, including those

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 59

DOI 10.1007/978-3-0348-0496-7_4, # Springer Basel 2012
 60

Table 4.1 Relative efficacy and adverse events from single doses of analgesics or NSAIDs used for relief of pain following dental (third molar extraction)
surgery
Adverse events (%)c
a b
NNT No. of Relative efficacy Relative risk
Drug (dose) (95 % CI) patients (RR 95 % CI) Active Placebo (95 %) CI
Ibuprofen (400 mg) 2.4(2.3–2.6) 4,703 6.3(4.2–2.9) 34 41 0.8(0.7–1.0)
Aspirin (600/650 mg) 4.4(4.0–4.9) 5,061
Celecoxib (200 mg) 4.2(3.4–5.6) 497
400 mg 2.5(2.2–2.9) 412
Diclofenac (50 mg) 2.3(2.0–2.7) 734 2.1(1.2–4.2) 60 41 1.2(0.9–1.6)
Morphine (10 mg IM) 2.9(2.6–3.6) 946
Naproxen (550 mg) 2.1(1.6–2.7) 88 5.7(3.0–1.1) 31 29 1.1(0.7–1.7)
Paracetamol (1,000 mg) 3.8(3.4–4.4) 2,759
Paracetamol (600/650 mg) 4.2(3.4–5.3) 1,123 41 39 1.0(0.7–1.4)
þ codeine (60 mg)
Rofecoxib (50 mg) 2.3(2.0–2.7) 738 5.9(3.0–1.1)
Data compiled from meta-analysis or Cochrane Collaborative review studies undertaken by the Oxford University Pain Research & Nuffield Division of
Anaesthesia (Barden et al. 2002, 2004; Derry et al. 2008; Edwards et al. 2004)
a
NNT Number need to treat to obtain 50 % pain relief at 6 h (approx).
b
Relative efficacy is determined as a relative risk (RR) value.
4

c
Adverse events—mostly minor and include nausea, dizziness in about 1–2 % of patients. Some patients had alveolitis from the surgery, but this was mostly
unaffected by treatment with the drugs.
Rofecoxib is now discontinued, but data included as this was investigated in original comparative studies
Clinical Efficacy
Table 4.2 Effects of ibuprofen compared with placebo or other analgesics in headache/migraine
Author (year) Treatment drug dosage (mg) Outcome pain relief Adverse effects
Tension headache
Diamond (1983) Ibu (400), Ibu (800), Asp (650), Pla All drugs ¼ > Pla
Noyelle et al. (1987) Ibu (400), Asp (650, 1,000), Par (1,000)
4.1 Dental Pain

Nebe et al. (1995) Ibu (200), Asp (500), Pla Ibu ¼ Asp; both > Pla
Schachtel et al. (1996) Ibu (400), Par (1,000), Pla Ibu > Par Both > Pla 1 pt Pla, nausea
Lange and Lentz (1995) Ibu (200), Ket(12.5, 25), Nab (275) Ibu ¼ all other drugs
High-altitude headache
Broome et al. (1994) Ibu (400), Pla Ibu > Pla 1 Ibu and 1 Pla pt vomited
Packman et al. (2000) Ibu (400; solubilised), Par (1,000), Pla Ibu > Par, both > Pla None
Diamond et al. (2000) Ibu (400), Ibu (400) þ Caffeine (200), Ibu þ Caffeine > Ibu > Caffeine > Pla Nervousness, nausea and dizziness
Caffeine (200), Pla (greater effect of Ibu þ Caffeine most frequent in Ibu þ Caffeine
and Ibu at 3–6 h)
Harris et al. (2003) Ibu (400), Par (1,000) Ibu ¼ Par Reduced nausea in both, no
headache or pulmonary oedema
Kubitzek et al. (2003) Ibu (400), Dic (12.5), Dic (25), Pla All drugs equivalent effects > Pla AEs equal, less digestive AEs in
Dic group (1 %) than Ibu (3 %)
Migraine
Havanka-Kanniainen (1989) Ibu (800), Ibu (1,200), Pla Ibu (800) Ibu (1,200) > Pla None
Kloster et al. (1992) Ibu (400), Pla Ibu > Pla (reduced migraine index) 12 % Ibu had stomach discomfort
(non-serious)
Kellstein et al. (2000) Ibu (400, 600 soluble), Pla Ibu (400 ¼ 600) > Pla
EMSASI study group Ibu (400), Asp (1,000), Sumatriptan (50), All drugs equiactive > Pla AEs: Asp (16 %), Ibu (12 %),
Diener et al. (2004) Pla Sumatriptan (20 %), Pla (14 %).
1 pt dizziness
Goldstein et al. (2006) Ibu (200), Par (250) þ Asp PAC > Ibu; both > Pla AEs all non serious: 9.7 %
(250) þ caffeine (65) (¼PAC) Pla PAC > 5.1 % Ibu < 5.5 % Pla
PAC nervousness
(1.9 %) þ nausea
(1.6 %) > Ibu þ Pla dizziness
Pla > Ibu
Based on data in Dotzel (2002)
61
Table 4.3 Comparison of Ibuprofen with other analgesics (given as single doses) in acute post-operative pain in adults
62

At least 50 % maximum pain relief over 4–6 h

Number with outcome/
Number of: total Percent with outcome Relative benefit
Drug Dose (mg) Studies Participants Active Placebo Active Placebo (95 % CI) NNT (95 % CI)
A. Painful dental conditions
Ibuprofen 200 18 2,470 680/1,462 100/1,008 47 10 4.5(3.7–5.4) 2.7(2.5–3.0)
Ibuprofen 400 49 5,428 1,746/3,148 271/2,280 55 12 4.3(3.8–4.9) 2.3(2.2–2.4)
Ibuprofen 200 solublea 7 828 270/478 34/350 56 10 5.7(4.2–7.9) 2.1(1.9–2.4)
Ibuprofen 200 standarda 15 1,883 406/984 62/899 41 7 5.9(4.7–7.6) 2.9(2.6–3.2)
Ibuprofen 400 solubleb 9 959 361/550 41/409 66 10 6.5(4.8–8.9) 1.8(1.7–2.0)
Ibuprofen 400 standardb 46 4,772 1,385/2,598 230/2,174 53 11 5.2(4.6–5.9) 2.3(2.2–2.5)
Aspirin 600/650 45 3,581 634/1,763 251/1,818 36 14 2.6(2.3–2.9) 4.5(4.0–5.2)
Aspirin 1,000 4 436 87/250 20/186 35 11 2.8(1.9–4.3) 4.2(3.2–6.0)
Celecoxib 200 3 423 94/282 01/02/41 41 1 16(5.1–49) 3.2(2.7–3.9)
Celecoxib 400 4 620 184/415 01/09/05 34 4 11(5.9–22) 2.5(2.2–2.9)
Codeine 60 15 1,146 79/573 52/573 14 9 1.5(1.1–2.1) 21(12–96)
Dexketoprofen 10/12.5 3 251 61/131 17/120 47 14 3.3(2.0–5.3) 3.1(2.3–4.6)
Dexketoprofen 20/25 4 322 82/176 17/146 47 12 4.5(2.8–7.2) 2.9(2.3–3.9)
Dextropropoxyphene 65+650 3 353 61/173 23/280 35 13 2.8(1.8–4.2) 4.6(3.2–7.2)
(a)+ paracetamol
Diclofenac (b) 25 3 398 99/196 22/202 51 11 4.7(3.1–7.1) 2.5(2.1–3.2)
Diclofenac 50 9 1,119 378/678 82/441 56 19 3.0(2.4–3.7) 2.7(2.4–3.1)
4

Diclofenac 100 4 413 151/228 19/185 66 10 6.6(4.3–10) 1.8(1.6–2.1)

Diflunisal 500 3 220 61/112 19/108 55 18 3.1(2.0–4.8) 2.7(2.0–3.8)
Etodolac 100 4 418 80/211 34/207 38 16 2.3(1.6–3.3) 4.7(3.4–7.6)
Etodolac 200 7 670 145/333 44/337 44 13 3.3(2.5–4.5) 3.3(2.7–4.2)
Etodolac 400 2 149 43/85 01/03/64 51 5 11(3.5–18) 2.2(1.7–2.9)
Etoricoxib 120 4 500 233/326 16/174 71 9 8.0(5.0–13.0) 1.6(1.5–1.8)
Clinical Efficacy
Etoricoxib 180/240 2 199 129/150 01/06/49 79 12 6.4(3.1–14) 1.5(1.3–1.7)
Flurbiprofen 50 7 473 161/245 74/228 66 32 2.1(1.7–2.5) 3.0(2.0–4.0)
Flurbiprofen 100 6 354 119/184 48/170 65 29 2.4(1.9–3.1) 2.8(2.2–3.7)
Ketoprofen 12.5 3 274 77/138 18/136 56 13 4.2(2.7–6.6) 2.4(1.9–3.1)
Ketoprofen 25 6 452 153/239 26/213 64 12 5.2(3.6–7.5) 1.9(1.7–2.3)
4.1 Dental Pain

Ketoprofen 50 3 190 61/98 01/06/92 62 6 9.0(4.2–19) 1.8(1.5–2.2)

Ketoprofen 100 3 195 79/97 01/10/98 72 10 7.3(4.0–13) 1.6(1.4–2.0)
Lornoxicam 8 3 273 71/155 13/118 46 11 4.7(2.7–8.1) 2.9(2.3–4.0)
Lumiracoxib 400 3 460 163/307 01/07/53 53 2 9.7(4.3–2.2) 2.1(1.8–2.7)
Naproxen 500/550 5 402 122/199 14/203 61 7 8.7(5.2–14) 1.8(1.6–2.1)
Oxycodone 10/650 6 673 252/496 01/11/77 51 6 6.8(3.9–12) 2.3(2.0–2.6)
+paracetamol
Paracetamol 500 3 305 84/150 46/155 56 30 1.9(1.4–2.5) 3.8(2.7–6.4)
Paracetamol 600/650 10 1,276 225/638 74/638 35 12 3.1(2.4–3.8) 4.2(3.6–5.2)
Paracetamol 975/1,000 19 2,157 545/1,335 82/822 41 10 4.1(3.3–5.2) 3.2(2.9–3.6)
Rofecoxib 50 22 3,060 1,332/2,173 73/887 61 8 7.3(5.9–9.2) 1.9(1.8–2.0)
B. Other painful conditions
Ibuprofen 200 2 220 42/110 01/05/10 38 5 7.7(3.2–18) 3.0(2.3–4.2)
Ibuprofen 400 12 1,047 277/580 103/467 48 22 2.2(1.8–2.6) 3.9(3.2–5.0)
Ibuprofen 200 solublec 7 828 270/478 34/350 56 10 5.7(4.2–7.9) 2.1(1.9–2.4)
Ibuprofen 200 standardc 15 1,883 406/984 62/899 41 7 5.9(4.7–7.6) 2.9(2.6–3.2)
Ibuprofen 400 solubled 9 959 361/550 41/409 66 10 6.5(4.8–8.9) 1.8(1.7–2.0)
Ibuprofen 400 standardd 46 4,772 1,385/2,598 230/2,174 53 11 5.2(4.6–5.9) 2.3(2.2–2.5)
Aspirin 600/650 19 1,384 349/733 128/651 48 20 2.4(2.0–2.8) 3.6(3.1–4.3)
Aspirin 1,000 4 334 91/166 35/168 55 21 2.6(1.9–3.6) 2.9(2.3–4.1)
Dextropropoxyphene 65+650 3 610 123/305 51/305 40 15 2.4(1.8–3.2) 4.2(3.3–6.0)
(a)+paracetamol
Diclofenac 50 2 206 63/102 20/104 62 19 3.2(2.1–4.9) 2.4(1.8–3.3)
(continued)
63
Table 4.3 (continued)
64

At least 50 % maximum pain relief over 4–6 h

Number with outcome/
Number of: total Percent with outcome Relative benefit
Drug Dose (mg) Studies Participants Active Placebo Active Placebo (95 % CI) NNT (95 % CI)
Diclofenac 100 3 374 79/188 24/186 42 13 3.3(2.2–4.9) 3.4(2.7–4.9)
Diflunisal 500 3 171 42/86 01/08/85 49 9 5.3(2.7–10) 2.5(1.9–3.7)
Dipyrone 500 4 210 78/104 29/106 75 27 2.7(2.0–3.8) 2.1(1.7–2.8)
Flurbiprofen 50 3 219 84/108 34/111 78 31 2.5(1.9–3.3) 2.1(1.7–2.8)
Oxycodone 01/10/50 4 370 93/184 37/186 51 20 2.5(1.9–3.4) 3.3(2.5–4.7)
+paracetamol
Reproduced from Moore et al. (2011) with permission of John Wiley and Sons, publishers of the Cochrane Database of Systematic Reviews
Data from Cochrane Collaboration® Review by Moore et al. (2011) see http://www.thecochranelibrary.com. Reproduced in part, with permission of John
Wiley & Sons Ltd.
(a) Dextropropoxyphene now withdrawn.
(b) Data from sodium or potassium formulations of diclofenac not shown, but all these have comparable relative benefit or NNT to data in this table of
diclofenac.
(c) Data judged by authors (Moore et al. 2011) to be of good standard.
(d) a,b,c,d These data are from direct comparisons of soluble and standard formulations.
4
Clinical Efficacy
4.2 Pain Relief at OTC Dosages 65

with celecoxib (Derry et al. 2008), rofecoxib (Barden et al. 2002, 2004), diclofenac,
and paracetamol combinations (Table 4.1). In general, these studies have shown
that ibuprofen is either equivalent to or better than the comparator drugs (Tables 4.1
and 4.2).

4.2 Pain Relief at OTC Dosages

Ibuprofen is often a preferred drug among the OTC analgesics for treatment of
tension-type headache and migraine (Verhagen et al. 2006; Table 4.2). A recent
evidence-based consensus report (Haag et al. 2011) based on recommendations of
the Deutsche Migräne und Kopfschmerzgesellschaft (DMKG), the Deutsche
Gesellschaft für Neurologie (DGN), the Österreichische Kopfschmerzgesellschaft
(ÖKSG) and the Schweizerische Kopfwehgesellschaft (SKG) rated ibuprofen
400 mg as a drug of first choice for self-treatment of tension-type headache and
migraine attacks with or without aura, along with acetylsalicylic acid (aspirin)
(900–1,000 mg), diclofenac (25 mg for headache alone), naratriptan (2.5 mg),
paracetamol (1,000 mg), and phenazone (1,000 mg), as well as various fixed
combinations of some of these drugs. As also shown in Table 4.3, there has been
a large number of studies in which ibuprofen has clearly shown dose-related
analgesia.
Ibuprofen is very effective in controlling fever both in adults and in children
(Hersh et al. 2000b; Eccles 2006). It also has wide applications in the treatment of
viral respiratory infections where there is an appreciable inflammatory component
(Winter and Mygynd 2003). There are, however, some key points about the efficacy
of ibuprofen which need to be emphasized in the context of the OTC use of this drug
and comparisons with other analgesics.
Ibuprofen has rapid onset of analgesia, and this is maintained in parallel with the
plasma elimination half-life of ibuprofen, which for both the active (S+) and
inactive (R) enantiomers is approximately 2 h (Graham and Williams 2004);
the analgesia extends to approximately 6 h as evidenced by a number of analgesia
models (e.g., third molar dental extraction pain model; Dionne and Cooper 1999;
Table 4.1).
It has been observed that in acute pain there are alterations in the PKs of
ibuprofen, resulting in decreased serum levels of the enantiomers after dental
surgery (Jamali and Kunz-Dober 1999). Gender differences have been observed
in response to acute pain in the dental pain model, with ibuprofen being more
effective in men than in women (Walker and Carmody 1998). Other studies using a
similar third molar extraction dental pain model have not revealed any gender
differences in response to analgesia with ibuprofen (Averbuch and Katzper 2000).
Aside from these factors, it appears therefore that variability in response to
66 4 Clinical Efficacy

analgesia with ibuprofen may relate to acute pain and altering the pharmacokinetics
of the drug, and possibly to gender differences.
The relationship between plasma or serum concentrations of ibuprofen to the onset
of analgesia has been the subject of much interest. Aside from knowledge that is of
significance pharmacologically (i.e., relating PK of the drug to its PD properties) this
is of significance in determining doses at which plasma/serum concentrations are
achieved during therapy of different pain states (Rainsford 2009).
In order to derive values of the therapeutically relevant plasma concentrations
(TRPC) of ibuprofen, data have been extracted from published studies in various
acute and chronic (arthritis) studies and acute experimental pain models in humans
in which plasma concentrations of the racemic or enantiomeric forms of the drug
were compared with therapeutic response, comprising the relief of pain symptoms
or the pharmacological actions as attributed to the S(+) and R() forms, as well as
those components of ibuprofen required for reducing circulating levels of the
cyclo-oxygenase products.
Therapeutically-relevant drug concentrations vary according to (a) the selection
of pharmacokinetic (PK) parameters at which pain responses are evident, (b) the
effects of the individual enantiomers concentrations to their pharmacodynamic
(PD) activity with the S(+) isomer the active form for inhibiting both pain relief
and prostaglandin synthesis inhibitory actions, and (c) the impact of different
painful conditions on both the PK of ibuprofen and the analgesic responses.
In modelling of the data on PK in relation to PD from published studies, it is
possible to take two approaches: (1) select data at the earliest period when there is
significant increase in plasma concentrations, and relate this to the development of
the analgesic response, or (2) to select data on the plasma concentrations of the
drug, Cp, at the lowest effective dose of the drug (400 mg), and relate this to
analgesic activity; the latter occurs mostly after the peak concentrations of the drug.
Using data derived from the third molar dental surgery pain model, it has been
possible to identify the earliest significant analgesic activity from ibuprofen 400 mg
at 0.5 h, associated with serum concentrations of 17.5 mg/mL of racemic ibuprofen.
In less severe inflammatory conditions than observed in dental surgery, it is
established that the lowest dose of 200 mg ibuprofen can be effective in relieving
symptoms of mild pain (headache, colds, and acute injuries). Under these
circumstances, lower TRPC is anticipated. Thus, in considering the TRPC of
ibuprofen it is important to identify the degree of pain and inflammation
accompanying the respective painful conditions.
From these and other data, it is proposed that the TRPC of racemic ibuprofen are
within the range of 11–25 mg/mL and 10–15 mg/mL of S(+) ibuprofen following
intake of 400–600 mg ibuprofen. These values are obtained from data on the
optimal or lowest dose of the drug for acute pain relief, and the same or slightly
higher concentrations required for relief of symptoms in arthritic pain. The values
for the TRPC of ibuprofen correspond with those at which there is ex-vivo inhibi-
tion of COX-1 and COX-2 derived prostaglandin production in whole blood
preparations. Fast-absorbing salts or other formulations enhance the onset of
4.2 Pain Relief at OTC Dosages 67

analgesia, and the range of concentrations required for the early stages of onset is
lower than observed above.
Recently, Li et al. (2012) have examined the onset and offset of dental pain relief
by standard ibuprofen 400 mg (Nurofen) and an effervescent ibuprofen 400 mg
tablet preparation in patients undergoing third molar extraction. They employed
linear “hazard” models to determine the time of first perceptible pain relief (TFPR),
the time to meaningful pain relief (TMPR), and the time to remedication (REMD),
from ibuprofen in relation to placebo, and correlated these values with PK profiles.
Maximum pain relief was obtained at drug concentrations of 10.2 mg/mL. This is
within the same order as the TRPC concentrations calculated above. As expected,
effervescent ibuprofen was more rapidly absorbed, and surprisingly was complete
by 15 min. This rapid absorption resulted in earlier values of TMPR and lower
REMD than standard ibuprofen. The authors have developed a series of nomograms
which can be used to estimate pain responses in relation to plasma concentrations of
ibuprofen for different immediate response (IR) formulations of ibuprofen.
Ibuprofen has been found to be effective in chronic arthritic pain, with
associated improvement in joint inflammatory symptoms even at low
(800–1,200 mg/day) doses (Grennan et al. 1983; Kean et al. 1999). Under these
conditions paracetamol is less effective, and indeed, several studies have shown
that it has no effects at all in controlling chronic inflammatory pain in rheumatic
diseases at the recommended OTC dosages of 1,000 mg/day (Kean et al. 1999).
There is now unequivocal evidence for a dose–response effect with ibuprofen in
acute pain conditions (McQuay and Moore 2006; Li Wan Po 2007; Fig. 2.10),
although the meta-analysis of McQuay and Moore (2006) only showed that 400 mg/
day ibuprofen was superior to 200 mg. The studies by Schou et al. (1998) showed
that there was a much greater range of dose–response that extended from 100 to
400 mg (Fig. 2.10). The NNT for ibuprofen was in the range of 6–23 for the low
high-dose comparisons, compared with that of paracetamol 1,000 mg compared
with 500 mg which was 6–20; the inference is that there is no difference in the NNT
between these two treatments. However, a consensus view is that in certain
inflammatory pain conditions (e.g., dental surgery) ibuprofen is superior at its
recommended OTC dosage of 200–400 mg per single treatment compared with
that of paracetamol 500–1,000 mg (McQuay and Moore 1998; Dionne and Cooper
1999; Hargreaves and Keiser 2002).
In comparison with other NSAIDs, including the newer coxibs, ibuprofen has
been shown in a variety of studies to be at least as effective as these drugs [with the
possible exception that longer half-life drugs such as rofecoxib exhibit a longer
duration of action (Dionne and Cooper 1999; Huber and Terezhalmi 2006;
Hargreaves and Keiser 2002; Edwards et al. 2004)] as well as having been shown
to be effective in a variety of acute pain conditions (Sachs 2005).
A key pharmacokinetic feature about the analgesic actions of ibuprofen is that
the drug has the ability to penetrate the CNS, and is present in free concentrations in
the CSF (Brocks and Jamali 1999; Graham and Williams 2004). In addition,
ibuprofen accumulates and is retained in inflamed joints of arthritic patients
(Brocks and Jamali 1999; Graham and Williams 2004). Thus, the drug is present
in sites where analgesic and anti-inflammatory effects are required.
68 4 Clinical Efficacy

Recent reviews of the choice of analgesics for pain management have

highlighted the fact that, although paracetamol may be useful and perhaps a choice
initially for pain control, the safest and most effective of all NSAIDs is ibuprofen at
doses of 400 mg for acute non-specific pain (Sachs 2005), and it is highly effective
in tension-type headache (Verhagen et al. 2006). A particularly challenging view
provided by a recent analytical review by Arora et al. (2007) suggested that oral
ibuprofen is as effective in analgesia as parenteral ketolorac, a drug which is used in
postoperative surgical pain control as well as in acute traumatic muscular–skeletal
pain conditions. Since ketolorac is amongst those NSAIDs the highest risks for
causing upper gastrointestinal bleeding ulcers, it appears that substitution of oral
ibuprofen in acute surgery and traumatic conditions may represent a valid alterna-
tive, with much lower risk that parenteral ketolorac.

4.3 Treatment of Pain in Osteoarthritis and Related Conditions

There are indications that ibuprofen is used quite extensively in some countries
where it is available for OTC use for occasional treatment of osteoarthritis (OA)
and other musculoskeletal conditions. Here, ibuprofen finds particular value in
being more effective than paracetamol and having less GI symptoms than aspirin.
Evidence in support of ibuprofen being effective in relieving pain and joint
symptoms at OTC dosage in OA has come from various clinical trials; the earlier
studies showing effectiveness in this condition were reviewed by Kean et al. (1999).
Among the more recent studies, Bradley et al. (1991) found that 1 month’s
treatment with ibuprofen 1,200 mg/day (referred to as an analgesic dose) had
superior rest and walking pain scores and comparable Health Assessment Ques-
tionnaire (HAQ—Stanford University) pain and walking scores with paracetamol
(acetaminophen) 4,000 mg/day in patients (>70 % females; total number of 182
subjects) with OA of the knee. Adverse events were minor symptomatic and of
comparable. The higher prescription level dose of 2,400 mg/day ibuprofen (referred
to as an anti-inflammatory dose) resulted in increased pain and walking scores. A
later re-analysis of this study by the same group (Bradley et al. 1992) attempted to
resolve the issue of whether drug effects on joint tenderness and swelling, reflecting
synovitis, were affected by “anti-inflammatory” doses of ibuprofen without any
indications of these actions. A second re-evaluation of the earlier study by the same
group (Bradley et al. 2001) showed that baseline pain could influence the anti-
inflammatory/analgesic effects of ibuprofen, with better response being observed
when there were higher levels of baseline pain. This is relevant, since there were
indications that the original study population (Bradley et al. 1991) comprised
patients with mild to moderate joint conditions. Thus, the effectiveness of ibuprofen
is greater in patients with more pronounced joint symptoms.
The semantic definition of analgesic effects at OTC dosage of ibuprofen
(1,200 mg) being separate from anti-inflammatory effects of the drug is probably
not justified, since there are several studies in chronic arthritic conditions showing
4.3 Treatment of Pain in Osteoarthritis and Related Conditions 69

that joint symptoms are significantly improved with 800–1,200 mg/day ibuprofen
(Kean et al. 1999). Moreover, there is an important study performed by Deodhar
et al. (1973) on the effects of ibuprofen 1,200 mg/day for 1 week on joint inflam-
mation in RA patients, in which they investigated knee inflammation following i.v.
injection of radioactive pertechnate (99mTc). The uptake of 99mTc uptake into knee
joints was significantly reduced by ibuprofen compared with placebo. A correlation
was observed between inflammatory indices of knee functions and 99mTc uptake.
This is direct evidence for local anti-inflammatory effects of ibuprofen under
conditions where there is effective relief of joint inflammatory symptoms and
pain in arthritic diseases. Such relief of joint inflammatory pain is not evident
with high doses of paracetamol.
In a short-term study designed to measure pain relief (measured using a 100 mm
visual analogue scale, VAS) over the 8-h period following the first and sixth dose
(total 1,200 mg/day) of ibuprofen 200 mg compared with placebo or ibuprofen +
codeine (30 mg) to 29 patients with knee OA, Quiding et al. (1992) found that
relatively rapid pain relief was evident with ibuprofen (as well as ibuprofen +
codeine), and this was sustained throughout the 8-h period of evaluation. These
results attest to the specific time-course effects of ibuprofen in relief of pain in OA.
Schiff and Minic (2004) compared the effects of 1,200 mg/day ibuprofen with
naproxen sodium 660 mg/day at an OTC dose (another NSAID that is available
OTC in some countries) and placebo for 7 days in two multicentre parallel group
studies in 440 patients with knee OA. They found that both NSAIDs relieved joint
symptoms, with naproxen being slightly more effective than ibuprofen, ibuprofen
being, however, more effective in relief of day pain.
In another large multi-centre study (known as ‘ibuprofen, paracetamol study in
osteoarthritis’ or IPSO) by Boureau et al. (2004) in 222 patients with OA of the hip
(30 % patients) or knee (70 % patients), ibuprofen 400 mg taken as single or
multiple (1,200 mg/day) doses was compared with paracetamol 1,000 mg single
dose or 4,000 mg/day for relief of and pain joint symptoms, WOMAC (Western
Ontario McMaster University) scores over 2 weeks. Significant reduction was
observed in Pain Intensity Scores over the first 6-h period and then progressive
reduction continued over the 2-week period with ibuprofen as compared with
paracetamol. This study shows that ibuprofen is superior to paracetamol at OTC
doses in relief of joint symptoms in both knee and hip OA. This conclusion is
supported by a more general Cochrane Review of randomised and placebo-
controlled trials in which NSAIDs (including ibuprofen) were superior to paraceta-
mol in achieving reduction in pain, global efficacy assessments, and improvements
in functional status (Towheed et al. 2006).
Thus, of the available OTC treatments, ibuprofen would appear to have particu-
lar advantage for self-treatment of joint pain and symptoms in OA in being superior
in efficacy to paracetamol and preferable to aspirin because of a lower incidence of
GI symptoms (see later section).
70 4 Clinical Efficacy

4.4 Paediatric Uses

The effectiveness of ibuprofen in headache and migraine has been demonstrated in

a number of studies in children. Less is known about the mechanisms of action in
these conditions, but it is probably due in part to S(+) ibuprofen affecting platelet
activation and thromboxane A2 production, and local vascular effects in the
affected regions of brain vessels. It is significant that ibuprofen can penetrate into
the CNS, so that this may contribute to the central analgesic effects including those
in headache and migraine as a consequence of local accumulation of the drug.
Several experimental studies suggest that S(+) ibuprofen administered intrathecally
(i.a.) into the CNS has direct analgesic effects which are greater than the R() form.

4.4.1 Acute Fever in Children

Ibuprofen is widely used in the treatment of fever, and in the treatment of this
condition carers can have a considerable involvement. Likewise, paediatricians and
general physicians as well as pharmacists have a role in the administration or
prescription of ibuprofen for the treatment of fever. While ibuprofen has had
apparently a second place in the treatment of fever over the past three to four
decades, paracetamol has found wide popular application, and is considered to be a
safe and effective treatment for most febrile conditions. However, there is evidence
from clinical trials that ibuprofen may be more effective than paracetamol
(Table 4.4). There are also indications that alternating treatments with paracetamol
and then ibuprofen or combinations of these two are becoming increasingly popu-
lar, especially amongst paediatricians and those involved in the treatment of
children under emergency or outpatient conditions. The administration of
combinations or alternating treatments with paracetamol and ibuprofen is highly
controversial, and is regarded by most as having potential risks. Indeed this author
believes that there is a major issue concerning potential toxicity in certain organs,
for example in the liver and kidney, which may place paediatric patients who have
very high febrile states that may lead to cytokine activation and precipitation of
liver reactions. Monotherapy is generally preferred, and ibuprofen has a key place
in treatment of fever in infants and children.
Amongst the most frequent indications for use of ibuprofen in children is for the
treatment of fever. Since febrile conditions lead to elevation of febrile-inducing
pro-inflammatory cytokines (especially IL-1b, TNFa, IL-6), and these can lead to
alterations in the activities of drug-metabolizing enzymes, it is important to under-
stand if the pharmacokinetics of antipyretic agents is altered in febrile conditions
in children. Earlier reviews (e.g., Walson and Mortensen 1989) emphasized the lack
of PK data in children, a situation that has been addressed more extensively
in recent years, although there are still some gaps in knowledge of PKs of
antipyretic/analgesic drugs, especially in infants.
4.4 Paediatric Uses 71

Table 4.4 Comparative studies of ibuprofen and paracetamol in the treatment of acute fever
Dose of Dose of
Dose Age No of ibuprofen paracetamol
frequency (years) children (mg/kg) (mg/kg) Outcome
Sidler et al. Multiple 1.25–13 90 7 or 10 10 Ibu 7 > Para
(1990) Ibu
10 > Para
Wilson et al. Single 0.25–12 178 5 or 10 12.5 Ibu
(1991) 10 > Para
Autret et al. Multiple 0.5–5 154 7.5 10 Ibu ¼ Para
(1994) 3 days
Van Esch et al. Multiple 0.25–4 70 7.5 10 Ibu > Para
(1995) 3 days
Vauzelle- Single 4  0.6 116 10 10 Ibu ¼ Para
Kervroedan
et al. (1997)
Autret et al. Single 0.5–2 351 7.5 10 Ibu > Para
(1997)
Reproduced with permission of the publishers from Rainsford (2009). Ibu Ibuprofen; Para
Paracetamol

Nahata et al. (1991) studied the PK of ibuprofen in 17 patients (aged 3–10 years)
with fever from streptococcal pharyngitis and otitis media, who received 5 mg/kg
and 10 mg/kg liquid formulation of the drug (mean ages  SD for this group being
6.7  2.5 and 6.2  2.1 years) The peak (mean  SD) serum concentrations of the
racemate in these two groups were 28.4  7.5 and 43.6  18.6 mg/mL, which were
evident at 1.1 and 1.2 h respectively. The t½s were 1.6 h in both groups and the rates
of oral clearance 1.2  0.4 1.4  0.5 mL/min/kg respectively, showing that the
serum PK are unaffected by the doses employed. An earlier study by Walson et al.
(1989) using liquid ibuprofen in febrile children showed that the values for Cmax
were slightly lower at the 5 mg/kg dose than observed in the study by Nahata et al.
(1991), but were within the same range.
A later study by the same group performed a randomized, double-blind,
parallel-group placebo-controlled study in 56 infants and children (0.5–12 years)
who were primarily investigated for antipyretic effects (Nahata et al. 1992). They
were given 5 and 10 mg/kg ibuprofen suspension or placebo in separate groups but
blood samples for PK assay of the plasma concentrations of the racemate in only
17 patients who received the drug alone. The mean maximal plasma concentration
was 28.4 mg/mL and 43.6 mg/mL at 1.0 and 1.5 h for the 5 and 10 mg/kg dosage
groups respectively. These plasma values (Nahata et al. 1992) correspond closely
with those in serum which were obtained in the earlier study (Nahata et al. 1991),
showing consistency both in plasma cf serum and between the studies.
Another study in febrile patients was performed by Kauffman and Nelson (1992)
in 49 infants and children aged 3 months to 10.4 years, the primary purpose being to
investigate the relationship between plasma concentration of the racemic form of
the drug and antipyretic effects. Fever was diagnosed as arising from a variety of
conditions including pneumonia, otitis media, upper respiratory tract infection,
tonsillo-pharyngitis, and various other conditions. The dose of ibuprofen was
72 4 Clinical Efficacy

8 mg/kg, which is between that of 5–10 mg/kg used in the earlier studies. Further
discussion about the therapeutic effects of this and other studies reported in this
section will be considered in the next section. However, it was found that there was
a delay in peak concentration of ibuprofen and maximal decrease in temperature,
highlighting that the therapeutic benefit follows the peak or optimal plasma
concentrations of the drug as shown in Chapter 3.
Despite these apparent benefits, the administration of antipyretic agents to treat
fever in infants and children has not been without its critics; furthermore, parents
and carers have been considered to have numerous misconceptions about what
fever is and how it should be treated (Crocetti et al. 2001). Schmitt (1980) found
that parents had many misconceptions about what fever really is in terms of
temperature, and he coined the term “fever-phobia”. In a survey of 340 carers in
two urban-based paediatric clinics in the Baltimore region, MD, USA, Crocetti
et al. (2001) found that care-givers varied considerably in their belief of potential
harm of fever to their children, of what temperature range actually constitutes fever,
and in the use of sponging and other treatments to control fever.
Hay and co-workers (2006) reviewed some of the recent studies on single and
combination antipyretic therapies, and highlighted that the combination
preparation’s safety is limited. These authors also highlighted the occurrence of
renal failure or renal tubular necrosis from ibuprofen, and the potential for nephro-
toxic metabolite formation from paracetamol (quinine-imine paracetamol) in pro-
ducing both nephrotoxicity and hepatic reactions. These authors also pointed out
that the definition of clinically useful difference in temperature after treatment is
still debatable. To achieve better understanding, continuous thermometry should be
employed. Knapp-Długosz and co-authors (2006) have reviewed the appropriate
use of non-prescription antipyretics in paediatric patients. They referred to the
ongoing debate about whether and when to treat fever, but pointed out that
clinicians agree that antipyretic therapy is important for febrile children who have
(a) chronic cardio-pulmonary disease, metabolic disorders or neurological
conditions, and (b) are at risk of febrile seizures. They point to the lack of guidelines
on the use of antipyretic agents in other categories of fever in children. Thus, patient
comfort is cited most often as the deciding factor. Moreover, there is little support
for administering antipyretic agents when the temperature is less that at 101  F
unless the child is uncomfortable. None-the-less, they regard paracetamol and
ibuprofen as effective agents for reducing fever, and this is supported by evidence
from meta-analyses and other studies.
They point to risks of paracetamol hepatotoxicity, especially in children with
diabetes, those with concomitant viral infections, patients with a family history of
hepatotoxic reactions, obese children and chronically malnourished individuals.
Dlugosz et al. (2006) also emphasized the precise dosing of paediatric patients with
either ibuprofen or paracetamol, and in the case of a patient less than 6 months
recommended consultation of physician.
The application of ibuprofen and other antipyretics to prevent the development
of febrile seizures is now well-established treatment for this condition
(van Stuijvenberg et al. 1998).
4.4 Paediatric Uses 73

The question of precise dosage of antipyretics for treatment of fever and pain has
been addressed by a number of experts and professional organisations. Among
these, the Royal College of Paediatrics and Child Health with the Neonatal and
Paediatric Pharmacists Group in their monograph “Medicines for Children” (2003)
recommend for pyrexia and mild-to-moderate pain, where ibuprofen is given by the
oral route, that the dosage should be by body weight (5 mg/kg) 3–4 times daily
when treating infants or children from 1 month to 12 years of age. Dosage by age is
recommended above 1 year: for 1–2 years 50 mg, 3–7 years 100 mg, and 8–12 years
200 mg of ibuprofen. In the 12–18 year age group, 200–600 mg ibuprofen is
recommended 3–4 times daily.
In juvenile rheumatoid arthritis or juvenile arthritis, application of ibuprofen
is recommended at the dose of 10 mg/kg for the 1-month- to 18-year-old group
3–4 times daily, or up to 6 times daily in systemic juvenile arthritis.
In Martindale’s “The Complete Drug Reference” (Reynolds 2003), ibuprofen is
not recommended for children below 7 kg bodyweight; in the same way as with the
previous authors, dosage on a bodyweight basis is recommended in the range of
20–30 mg/kg/day in divided doses or alternatively in the 6–12 month age group
150 mg/day, 1–2 year 150–200 mg/day, 3–7 year 300–400 mg/day and 8–12 years
of age 600–800 mg/day. These two authorities clearly differ in the precision in
which they make recommendations for treating fever and pain in children on a
dosage basis. Arguably, however, dose recommendations are probably rather simi-
lar, and it is a question of the application of information that is given to the carers.
The UK National Institute for Health and Clinical Excellence (NICE) has
prepared recommendations for the assessment and management of children
younger than 5 years in their report “Feverish Illness in Children” (National
Institute for Health and Clinical Excellence 2007). In these guidelines, there is
emphasis given on the detection of fever and the clinical assessment of the child
with fever, as well as the relative roles of the non-paediatric practitioner and
paediatric specialist. Surprisingly, the NICE recommendations state that
antipyretics do not prevent febrile convulsions, and should not be used specifically
for this purpose. This view is supported to some extent by a recent Cochrane
analysis and review in which antipyretic - analgesic drugs, along with anti
convulsants, appear to have limited benefit in treating febrile siezures in children
(Offringa and Newton, 2012). Their recommendations also give a considerable
number of clinical diagnostic indices for fever of various origins. Some of these
recommendations are complex in themselves: “A Traffic-light System” for
identifying risks of serious illness involving colour-coding of green for low risk,
amber for intermediate risk, and red for high risk, with appropriate diagnostic and
investigative procedures for identifying the origin of fevers.
The NICE recommendation for antipyretic interventions state that tepid spong-
ing is not recommended for the treatment of fever. This is in contrast with
recommendations of other authorities. On the question of the administration of
antipyretic agents, these should be considered in children with fever who appear
distressed or unwell. Antipyretic agents should not routinely be used with the sole
aim for reducing temperature in children with fever who are otherwise well.
74 4 Clinical Efficacy

The views and wishes of parents and carers should be taken into consideration; this
would in any physician’s eyes be regarded as a statement of the obvious.
NICE recommendations are that either paracetamol or ibuprofen can be used to
reduce temperature in children with fever, but that they should not be given at the
same time or alternating the drugs. The only case for alternating of drug treatment
would be considered for a child that does not respond to the first agent.
The guideline development group (GDG) of NICE has made a number of
recommendations for research, based on the review of evidence to improve NICE
guidance for patient care in the future, for example predictive values of heart rate,
remote assessment, and a number of issues concerning diagnosis. They also recom-
mend investigation of the administration of antipyretics in primary and secondary
settings in relationship to the degree of illness.
Amdekar and Desai (1985) compared the antipyretic effects of ibuprofen with
that of paracetamol in 25 children suffering from fever due to upper respiratory tract
infection or systemic viral infections. There was a difference in the initial
temperatures of patients that were treated for upper respiratory tract infection, in
that the mean initial temperature was 39.9  in the ibuprofen group and 40.81  in
the paracetamol group. Despite this variation, both ibuprofen and paracetamol
produced statistically significant reductions in rectal temperatures following admin-
istration of 7 mg/kg of ibuprofen or 8 mg/kg of paracetamol in a random order. The
initial reduction in temperatures of patients with upper respiratory tract infections
incurred at about 0.5 h, with the maximum at 4 h after administration of both drugs.
The level of antipyretic activity was evident up to 8 h, with patients having
temperatures in the range of 37.5  . In the group of children with fever due to
viral infections, both the mean temperatures were comparable (40.51  –40.75  ),
and similar results were observed to those in patients with upper respiratory tract
infections, with the exception that by 8 h the temperatures had risen to
38.34  –38.77  , which is somewhat higher than those observed in the patients
with upper respiratory tract infections and probably reflects ongoing viral activities.
A single blind, parallel group investigation comparing the antipyretic properties
of ibuprofen syrup versus aspirin syrup in 78 febrile children aged 6 months to
10 years was undertaken in two centres in Belgium by Heremans et al. (1988). At
doses of ibuprofen syrup (6 mg/kg body weight) or aspirin (10 mg/kg bodyweight),
significant reductions in rectal temperature were observed with both treatments,
there being no statistically significant difference between the two. These patients
had a greater variation of clinical history, although most were being treated
for upper respiratory tract infections, in some cases with antibiotics being
co-administered.
Significant reductions in temperatures were observed by 0.5–1 h with both
treatments, with maximum reduction in rectal temperature being observed with
both drugs at 4 h, and being maintained 6 h after administration.
A summary of more recent data from various studies reviewed by Autret-Leca
(2003) is shown in Table 4.4. These studies were performed with modern
methodologies, and in some cases Good Clinical Practice (GCP) conditions.
4.4 Paediatric Uses 75

They show that ibuprofen is equal to or in some cases slightly more effective than
paracetamol in relief of febrile symptoms in a variety of age groups in children.
There are three paediatric groups where ibuprofen has been investigated for
therapeutic benefits in relation to pharmacokinetic properties. These are for relief of
pain and joint symptoms in juvenile idiopathic (chronic) or juvenile rheumatoid
arthritis (JIA, JRA respectively), the i.v. administration in patent ductus arteriosus
(PDA), and in high doses in cystic fibrosis (CF). While both these treatments may
be considered outside the norm, none-the-less they are potentially important uses of
the drug in therapy. Moreover, they provide important therapeutic data on the
pharmacokinetic properties of ibuprofen in extremes of dosage and administration
which, with safety data, are important for giving outside values for indications for
the drug.

4.4.2 Juvenile Idiopathic (Rheumatoid) Arthritis

This condition presents with a varying spectrum of clinical manifestations that

include differing joint involvement including pauciarticular (4 joints) and
polyarticular (5 joints), with juvenile rheumatoid arthritis (JRA; Still’s Disease)
as a subgroup of the latter resembling the adult disease (Dieppe et al. 1985; Klippel
1997). Pyrexia is common (50 %) along with lymphadenopathy, splenomegaly,
pericarditis, and rashes (Dieppe et al. 1985). High doses of the NSAIDs, especially
aspirin and other salicylates, have been widely used in the treatment of juvenile
arthritis and more recently the coxibs (Ansell 1983; Hollingworth 1993; Klippel
1997; Eustace and O’Hare 2007).
Amongst the earlier studies on the effects of ibuprofen in JRA was that by Ansell
(1973). She undertook an open-label investigation in 8 patients (aged 7–14 years;
5 female, 3 male), most of whom were treated because they were unable to tolerate
aspirin and had a prior history of dyspepsia (5) or GI bleeding (2) or in one case
where there was poor control. These patients received various doses of ibuprofen
(13–32 mg/kg). Initially, they received 200–300 mg/day in those with body weight
of 20–30 kg and 400 mg for those <30 kg. Later, all but one received 600 mg/day
and one 1,200 mg/day for what appears to have been long periods of time (12–24
months). Satisfactory control of pain and stiffness was observed in 6/8 cases,
although in 2 of these the dose had to be increased before this was achieved. Occult
blood which had been observed in those patients who were on aspirin was negative
with ibuprofen. In 6 patients, liver function tests were performed, and none showed
increased SGOT, SGPT or alkaline phosphatase; some showed decrease in these
values. This is important, since plasma/serum levels of elevated liver enzymes have
been frequently observed in patients with JRA or JIA that have received aspirin, and
ADRs in the GI tract and other systems are frequently observed with the salicylates
and other NSAIDs in these conditions (Hollingworth 1993; Buchanan et al. 2004).
Giannini et al., with the Pediatric Rheumatology Collaborative Study
Group (1990), undertook two studies—one being a multi-centre, randomized,
76 4 Clinical Efficacy

double-blind study in 92 children (76 girls, 16 boys), mean age 7.7 years (range
1.8–15.1 years), mean body weight 26.4 (range 11.5–58.7) kg with JRA. Of these,
45 received ibuprofen suspension 30 mg/kg/day and 47 aspirin (200 mg tablets or
300 mg caplets) according to body weight (60 mg/kg/day) for 12 weeks. This was
followed by an open-label study in 84 patients [aged 1–15 years, mean 5.3 years;
average body weight 19.9 kg (range 10.0–58.0 kg)]. Ten patients failed to complete
the double-blind study, 9 of whom had received aspirin and ibuprofen, while a
further 6 patients were excluded from the aspirin group due to variations in
diagnosis or disease condition. All the patients on ibuprofen showed reduction in
all five joint parameters, while those that received aspirin showed significantly and
clinically fewer reductions in joint inflammation and pain on motion, although the
reduction in morning stiffness was the same in both groups.
In the open-label study, 3 dropped out and 16/84 failed to complete the 24 weeks
of the study. Time dependent improvement in overall scores was observed in all
71 patients that completed the study, who received 30–50 mg/kg/day ibuprofen.
One or more ADRs were observed in 55 % of patients, which were classified as
possibly, probably, or definitely related to the drug. Upper GI disturbances were
recorded in 31 % and 27 % in the lower tract, with dose-related effects in the former
group. Of these, 3 patients had GI bleeding which resolved after discontinuing the
drug. Increased serum alkaline phosphatase and bilirubin occurred in 2 patients who
had 40 mg/kg/day ibuprofen.
Steans et al. (1990) examined the safety, efficacy, and acceptability of 10
(initially) to 40 mg (maximum)/kg/day ibuprofen syrup in 46 children with JIA
(aged 18 months–13 years; mean 6.8 years) in a multicentre, open-label study that
extended on average for 8 months (range 8 weeks to 2+ years). Six patients failed to
complete the study, 2 of whom had suspected side-effects. Assessments of active
joints and disease activity at monthly intervals over the first 3 months showed
statistically significant reduction in numbers of swollen and/or tender joints at
2 months of therapy which progressed to 6 months, while the physician’s VAS
was reduced by 1 month and showed significant improvement thereafter, which was
sustained at 4–6 months. Side-effects included gastritis (1 patient), abdominal pain
(1 patient) and taste complaint and nausea (1 patient). Of the 39 children that
completed the trial, 28 showed improvement on therapy, 7 were worse, and 4
remained unchanged.
The PK of ibuprofen in patients with juvenile idiopathic (or chronic) arthritis
(JIA), aka juvenile rheumatoid arthritis (JRA), might be expected to be affected by
production of pro-inflammatory cytokines, and other inflammatory reactions would
be expected to have profound consequences for drug metabolism, biodisposition, or
toxicological actions in these patients (Skeith and Jamali 1991; Furst 1992; Litalien
and Jacqz-Aigrain 2001).
The dose of ibuprofen in JIA (30–40 mg/kg/day) is much higher than generally
employed in infants and children for the treatment of fever and painful conditions
(5–10 mg/kg/day), and is more in line with that employed in cystic fibrosis.
Reference to the extensively studied PK properties of ibuprofen in CF may,
therefore, be useful for relating to those in JIA.
Chapter 5
Drug Derivatives and Formulations

It is a special feature of ibuprofen that it is possible for it to be prepared as many

derivatives and formulations, both for oral and parenteral administration. This is
due to its unique physicochemical properties. As an organic acid with a pKa of
4.4–5.2 (Boggara and Krishnamoorti 2010; Boggara et al. 2010), it is soluble in a
wide variety of solvents and aqueous–organic solvent systems. Like many NSAIDs,
ibuprofen is amphiphilic, and this leads to unique interactions with lipid membranes
(Boggara and Krishnamoorti 2010; Boggara et al. 2010). Although ibuprofen
partitions into the liposoluble layer in organic solvent (e.g. n-octanol)-aqueous (or
buffer) systems, it has detergent-like characteristics. These physicochemical
properties of ibuprofen lend themselves to the development of a wide range of
salts, complexes, and carboxylate or other chemical derivatives (Nichol 1999;
Higton 1999).

5.1 Dexibuprofen

The development of dexibuprofen (i.e. S(+) ibuprofen) arose from the observations
of Adams et al, (1976), subsequently verified and confirmed by others (Boneberg
et al 1996; Evans 1996, 2001), that the S(+) isomer of ibuprofen was more active as
a prostaglandin synthesis inhibitor, and could inhibit COX-1 and COX-2 with
greater potency than the R(
) enantiomer. Based on these observations that S(+)
ibuprofen was a more potent anti-inflammatory and analgesic than the R(
)
enantiomer or rac-ibuprofen (Björkman et al. 1996; Rainsford 1999b; Evans
2001), it was suggested that S(+) ibuprofen was the pharmacologically active
form (Evans 1996, 2001; Kaehler et al. 2003). Possibly, this statement needs
modifying to say that S(+) ibuprofen, or dexibuprofen, is the PG synthesis
inhibiting component of rac-ibuprofen, since it is known that R(
) ibuprofen has
distinct non-prostaglandin-dependent mechanisms which may contribute to the
overall anti-inflammatory properties of the racemate (Evans 1996, 2001; Rainsford
2009). Whatever the definition, dexibuprofen is more potent clinically in the

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 77

DOI 10.1007/978-3-0348-0496-7_5, # Springer Basel 2012
78 5 Drug Derivatives and Formulations

treatment of acute pain or osteoarthritis than rac-ibuprofen on a weight for weight

basis (Phleps 2001; Kaehler et al. 2003).
The physico-chemical properties of dexibuprofen differ considerably from those
of rac-ibuprofen (Leising et al. 1996; Kaehler et al. 2003). Thus, the crystal
structure, powder X-ray diffraction; thermodynamic, solubility, UV and photolumi-
nescence emission spectra of dexibuprofen differ considerably from rac-ibuprofen.
These differences in physico-chemical properties of dexibuprofen and
rac-ibuprofen translate into differences in their pharmacokinetics, principally their
kinetics of oral absorption, plasma elimination half-lives, and also their metabolic
(chiral inversion) profiles (Evans 1996; Kaehler et al. 2003). While dexibuprofen has
almost complete bioavailability and is absorbed with a peak Cp in about 2 h (Evans
1996), this is somewhat longer than many formulations of racemic ibuprofen. The
absence of the R(
) isomer in dexibuprofen means that this drug is not metabolised
via hepatic fatty acyl CoA metabolism, but proportionately greater metabolism
occurs via cytochrome P450 oxidation and glucuronidation mechanisms. S(+) ibupro-
fen is extensively bound to plasma proteins, with the fraction unbound (0.006) being
greater than that of R(
) ibuprofen (Evans 1996). The half life of elimination of
dexibuprofen is about 2 h, and contrasts with that of 1–2 h for rac-ibuprofen (or its R-
enantiomer which is about 2 h) (Evans 1996).
Extensive clinical studies have shown the clinical effectiveness of dexibuprofen
in acute oral surgery in a dose-related manner (Dionne and McCullagh 1998; Moore
et al. 2011a, b), in several studies in patients with osteoarthritis of the hip or knee,
rheumatoid arthritis, ankylosing spondilitis, lumbar vertebral pain, ankle joint
injury, and dysmenorrhoea (Kaehler et al. 2003), and in febrile children with
upper respiratory tract infections (Yoon et al. 2008a, b). It is approved (as Seractil®)
for use in the treatment of pain and inflammation associated with OA and other
musculoskeletal disorders, and in mild-to-moderate pain including dysmenorrhoea
and dental pain in the UK (British National Formulary 2009), as well as in Austria
and other countries of the EU.
An interesting property of dexibuprofen is that it has about twice the potency
of rac-ibuprofen as a platelet aggregation inhibitor, and while reversible this is
comparable with that of the irreversible inhibitor, aspirin (de la Cruz et al. 2010).
Since extensive use of low-dose aspirin to control thrombo-embolic and CV
conditions is associated with increased incidence of upper GI ADRs (see Chap. 7),
especially when this drug is used in combination with other NSAIDs or coxibs
for therapy of arthritis conditions, it might be preferable to consider the rever-
sible anti-platelet–anti-thrombotic actions of dexibuprofen with its analgesic and
anti-inflammatory properties as cognate and coincident therapeutic properties, rather
than using the combination of aspirin with other NSAIDs or the coxibs for treatment
of arthritic patients at risk for developing CV disease.
There has been interest recently in the development of various oral formulations
of dexibuprofen, among these an enhanced oral bioavailability/absorption
self-emulsifying drug delivery system (Balakrishnan et al. 2009), extended-release
tablets (Cox et al. 1999; Yi et al. 2008; Kim et al. 2011; Xu et al. 2011), and
microencapsulation systems (Manjanna et al. 2010). These formulations open up
5.2 Combinations with Caffeine 79

the possibility of modifying or optimising pain control using dexibuprofen for

different acute and chronic painful states. The extended-release and microencapsu-
lation systems may be useful for long-term therapy of rheumatic conditions, with
the benefit of once or twice daily therapy coincident with less fluctuation in
peak–trough plasma concentrations, and, therefore, less variation in pain responses.
An L-arginine complex with dexibuprofen has been found to be absorbed at a faster
rate than the acid alone (Fornasini et al. 1997) and so may have utility as a rapidly
acting analgesic for short-term use. The L-arginine may also have other actions
relating to its stimulation of nitric oxide production.

5.2 Combinations with Caffeine

The rationale for addition of caffeine to ibuprofen and other analgesics has been
based on the premise of raising the “analgesic ceiling” of the analgesic. The
addition of caffeine to NSAIDs and paracetamol has been investigated for over
three decades as an adjuvant to enhance pain relief (Aronoff and Evans 1982;
Sunshine and Olson 1989; Zhang 2011). Combinations of caffeine and sodium
salicylate and aspirin have been available in the UK since 1949, and have been
mentioned in several pharmacopoeias (Martindale The Extra Pharmacopoeia 1958;
Reynolds 1993). Caffeine is mentioned in the British National Formulary (2009) as
a weak stimulant to enhance analgesia, but the alerting effect, mild habit-forming
properties, and possible provocation of headache may not always be desirable.
Earlier studies of the efficacy due to the addition of caffeine were largely negative,
except the combination with paracetamol (Laska et al. 1983, 1984).
Ibuprofen–caffeine combinations have been investigated by several workers for
efficacy compared with that of ibuprofen (Stewart and Lipton 1989; Dionne and
Cooper 1999). Combinations of ibuprofen with caffeine have been shown to be
more effective than ibuprofen alone in the dental pain model (Forbes et al. 1990,
1991; McQuay et al. 1996). In particular, enhanced pain relief has been observed
with doses of 100 mg caffeine and 200–400 mg ibuprofen (Forbes et al. 1990, 1991;
McQuay et al. 1996; Dionne and Cooper 1999). Ibuprofen 400 mg with caffeine
200 mg has been found to give greater pain relief in the treatment of migraine than
ibuprofen 400 mg alone (Stewart and Lipton 1989). Caffeine has also been found to
enhance the pain relief with ibuprofen in tension headache (Diamond et al. 2000;
Sparano 2001) and in children’s headache (Dooley et al. 2007).
There are, however, several issues that are raised about the use of combinations
of caffeine with ibuprofen, as well as with other non-narcotic analgesics/non-
steroidal anti-inflammatory drugs (NSAIDs) which include:
(a) The pharmacological rationale for including caffeine; what is the pharmaco-
logical basis or mechanism for the enhanced analgesic activity?
(b) The confounding effects from the intake of caffeine-containing beverages,
estimated to be of the order of 100–400 mg daily (Rall 1990; Reynolds,
Martindale, The Extra Pharmacopoeia; Nawrot et al. 2003; Rainsford 2004a).
80 5 Drug Derivatives and Formulations

(c) The possibility of increased incidence of gastric adverse effects, especially in

the stomach from stimulation of gastric acid secretion leading to gastric distress
(Rainsford 2004a) or CNS toxicity (Thayer and Palm 1975; Christian and Brent
2001; Nawrot et al. 2003).
As a nervous system stimulant, caffeine acts by inhibiting phosphodiesterase,
a well-known property which leads to an increase in the second messenger
cyclic-30 ,50 -adenosine monophosphate (cAMP), as well as acting as an antagonist
of central adenosine receptors. Studies in laboratory animal models of analgesia
show that caffeine, like that of some selective adenosine antagonists produces
analgesic effects principally via central adenosine A1 receptors (Ahlijanian and
Takemori 1985; Poon and Sawynok 1998), and this is the generally accepted mode
of clinical analgesia (Dunwiddie and Masino 2001). Thus, from the viewpoint of
contribution to the action of caffeine in the combination with ibuprofen, the focus
would seem to be on the central actions as an A1 receptor agonist.
Cronstein and co-workers (1999) provided evidence from studies in mice, in
which the genes for inflammatory cyclo-oxygenase-2 (COX-2) or transcription
factor, nuclear kappa B (NFĸB) proteins were selectively “knocked out”, that the
mode of acute anti-inflammatory actions of aspirin or salicylic acid was due to the
anti-inflammatory effects of adenosine acting on the NFĸB signal transduction
pathway. Using mice lacking the gene for the adenosine A2A-receptor, Cadieux
et al. (2005) have shown that their polymorphonuclear neutrophil leucocytes
(PMNs) have diminished capacity to induce expression of COX-2, but not that
in monocytes. This would suggest that adenosine receptor activation leads to
increased COX-2-derived prostaglandins (PGs) from PMNs, so producing an
increase in acute inflammatory reactions. A2A-receptor agonists reduce expression
of adhesion molecules and a range of pro-inflammatory mediators [e.g., reactive
oxygen species, tumour necrosis factor-a (TNFa)] (Sullivan 2003). It is also known
that adenosine A1-receptors mediate plasma exudation in a non-prostaglandin,
non-nitric oxide mediated fashion (Rubenstein et al. 2001). These effects are
different from the effects of caffeine mediating analgesia in the central nervous
system. However, as peripheral anti-inflammatory effects of NSAIDs are central to
their analgesic actions (Rainsford 1999b, 2004c), it is possible that caffeine
contributes to analgesic effects of NSAIDs or paracetamol indirectly via activation
of adenosine A2 receptors in both the peripheral and central nervous systems.
As far as adverse reactions are concerned, it appears that in the randomised
controlled trials in acute pain models there are no appreciable adverse reactions
from the ibuprofen–caffeine combination compared with that of ibuprofen alone
(McQuay et al. 1996). Some mild CNS effects have been reported, ranging from
excitatory reactions and irritability; this may be especially evident in individuals
who are genetically predisposed to these reactions (Ellinwood and Lee 1996).
A condition known as “caffeinism”, which is a acute and chronic effect from
intake of 500–600 mg caffeine per day (equal to approximately 7–9 cups of tea or
4–7 cups of coffee), is probably a health risk (Ellinwood and Lee 1996). Caffeine
preparations in analgesics have 50–65 mg caffeine (Zhang 2001). At these doses
5.3 Ibuprofen–Codeine Combinations 81

taken 4–6 times daily, the amount of caffeine taken would be within the intake of
caffeine-containing beverages.
The common adverse events attributed to caffeine are: (1) associations with
increased myocardial infarction, tachycardia, and increased blood pressure, (2)
insomnia, anxiety, tremor, tenseness, and irritability, (3) increased free fatty acids
and hyperglycaemia, (4) nausea, vomiting, and stimulation of gastric acid secretion,
(5) increased diuresis, and (6) urticaria (Ellinwood and Lee 1996), gastro-
oesophagal reflux, symptoms of anxiety and tachycardia in infants and children
(Ellinwood and Lee 1996). With long-term intake of caffeine-containing
analgesics, addiction may develop coincident with the analgesic abuse syndrome
(Ellinwood and Lee 1996; Rainsford 2004c). There has been concern that drinking
>7–8 cups of coffee per day may be associated with an increased incidence of
stillbirths, pre-term deliveries, low birth weights of infants and spontaneous
abortions, but other factors including intake of analgesics per se may contribute
to these states (Beers and Berkow 1999). Concerns about the possibility of the risks
of mutagenicity, genotoxicity, and carcinogenicity led to an assessment of these
risks by the US Food and Drug Administration and several reviews (Thayer
and Palm 1975). A variety of in-vitro and in-vivo experiments and studies had
been reported since 1948 from which both positive and negative observations
were recorded (Thayer and Palm 1975). A considerable number of animal studies
of genetic changes, enhancement of dominant lethal changes, and teratogenic
potential in rodents as well as in-vitro studies in cell lines, in relation to the
pharmacokinetics and tissue/organ distribution of caffeine, were analysed and
assessed by Thayer and Palm (1975) in their comprehensive review.
In conclusion, it appears that caffeine may have some moderate potentiating
effects on analgesia from NSAIDs or paracetamol, but where these combinations
are taken in large quantities for long periods of time there are risks of CNS adverse
reactions, and at extremes analgesic abuse syndrome. Considering the availability
of other combinations with ibuprofen (e.g., paracetamol, codeine) which are
probably more effective than the ibuprofen–caffeine combination, it would not
seem of appreciable therapeutic benefit to use ibuprofen–caffeine mixtures. It
would appear just as simple and more pleasurable to take ibuprofen alone with
coffee, tea or other caffeine-containing beverages.

5.3 Ibuprofen–Codeine Combinations

The combination of codeine with aspirin or paracetamol has been a popular and
effective analgesic in moderate to severe pain for over 30–40 years (Reynolds 1993;
Martindale; Cooper 1984). Combination of ibuprofen with codeine has been found
to be more efficacious than either the drug alone, placebo or other NSAIDs in pain
following episiotomy or gynaecological surgery (Norman et al. 1985; Cater et al.
1985; Sunshine et al. 1987), tonsillectomy (Pickering et al. 2002), post-operative
dental pain (Mitchell et al. 1985; Giles et al. 1986; McQuay et al. 1989, 1992,
82 5 Drug Derivatives and Formulations

Walton and Rood 1990; Peterson et al. 1993), or in the treatment of OA pain
(Quiding et al. 1992). Additionally, combinations of ibuprofen and hydrocodone
have been shown to have greater pain relief than ibuprofen alone (Barkin 2001). In
post-arthroplasty pain, ibuprofen 800 mg/codeine 60 mg was more effective than
800 mg ibuprofen alone (Dahl et al. 1995). A meta-analysis of the efficacy of
adding codeine to ibuprofen for relief of surgical pain showed that addition of
60 mg codeine to 400 mg ibuprofen enhanced its analgesic effect by only 8 %, but
also increased its side-effects (Li Wan Po and Zhang 1998). The possibility of
pharmacokinetic interactions between ibuprofen and codeine has been investigated
in 24 healthy human subjects, and no such interactions were observed (Kaltenbach
et al. 1994).
Recently, there have been concerns about morbidity associated with codeine–
ibuprofen abuse in Victoria, Australia (Frei et al. 2010). Of 27 patients reviewed,
most had no history of substance abuse. They had GI haemorrhage and opioid
dependence associated with massive daily doses of 435–602 mg codeine and
6,800–9,000 mg ibuprofen. A study from New Zealand reported excess intake of
codeine þ ibuprofen in 7 patients, 6 of whom had a history of alcohol dependency.
GI ulcers and bleeding and hepatotoxic reactions were reported (Robinson et al.
2010). There is a case report of 2 patients who had taken excessive amounts of
codeine þ ibuprofen associated with gastric ulcers (Dutch 2008). Another case was
reported from Victoria, Australia where excess intake of ibuprofen þ codeine
together with a high caffeine-containing beverage (Red Bull®) was associated
with hypokalaemia (Ernest et al. 2010). it was suggested that the mechanism of
this reaction was due to ibuprofen causing type 2 renal acidosis and antagonism by
caffeine of adenosine receptors or shift of K+ into the extracellular space. Little
evidence has been obtained for these proposed actions, the effects of codeine not
being considered in this appraisal.
The mechanisms of analgesic effects of ibuprofen–codeine combinations have
been investigated in acetic acid-induced abdominal writhing in mice (Janovsky and
Krsiak 2011). Codeine with ibuprofen showed a marked antinociceptive interaction
which was not evident when the codeine was added to the COX-2 inhibitors,
etoricoxib or celecoxib. This suggests that additional COX-1 and other cellular
effects of ibuprofen contribute to the combined action of these two drugs.
Overall, it appears that although analgesic combinations have relatively accept-
able safety profiles (Friedman et al. 1990a, b; Hersh et al. 2007), it is clear that in
some societies this combination may, albeit rarely, be open to abuse potential with
adverse consequences for GI and renal system.
In conclusion, of the available combination analgesics, the ibuprofen–caffeine
combination probably has little significant advantage. Ibuprofen–codeine has some
limited advantages, while ibuprofen–paracetamol has potential for raising the
analgesic ceiling while at the same time reducing ADRs that may occur with higher
doses of these drugs alone which would be sufficient required to achieve the same
degree of analgesia as the combination.
5.4 Ibuprofen–Paracetamol Combination 83

5.4 Ibuprofen–Paracetamol Combination

The combination of ibuprofen with paracetamol probably represents the most

acceptable and useful of all combinations. There have been considerable number
of attempts at examining the efficacy of combinations of the two drugs especially in
children with fever (Cranswick and Coglan 2000; Erlewyn-Lajeunesse et al. 2006;
Hay et al. 2008, 2009; Hollinghurst et al. 2008; Lal et al. 2000; Ong et al. 2010) or
peri- or post-operative pain (Hyllested et al. 2002; Pickering et al. 2002; Kokki
2003; Gazal and Mackie 2007; Mehlisch et al. 2010a, b; Daniels et al. 2011). Some
studies have also considered the efficacy of alternating ibuprofen and paracetamol
for control of fever in children (Nabulsi et al. 2006), this regime being quite popular
amongst paediatricians. In the study by Nabulsi et al. (2006), the ibuprofen treat-
ment (10 mg/kg) followed 4 h later by paracetamol (15 mg/kg) was superior to
ibuprofen/placebo in reducing rectal temperature after 6–8 h treatment. Unfortu-
nately, the design of this study may have deviated from logic and accepted practice,
since most would employ ibuprofen after paracetamol when there was poor reduc-
tion in temperature from paracetamol. The logic would be to employ the more
potent antipyretic, i.e., ibuprofen, after first trying paracetamol.
The pharmacological basis for fixed combinations of ibuprofen and paracetamol
was established by Miranda and co-workers (2006) in their investigations in the
acetic acid induced constriction, or writhing assay in mice. The authors compared
the effects of i.p. administration of various doses of paracetamol combinations with
varying doses of NSAIDs, including ibuprofen; the anti-writhing results were
compared with the effects of the drugs alone. To establish whether there were
synergistic or additive effects with the drug combinations, the ED50 data of various
ratios was subjected to isobolographic analysis. With this procedure, the ED50 data
for the individual NSAID alone are plotted against the ED50s of paracetamol being
plotted separately. Where there is deviation from the linear relationship between the
ED50s for the respective NSAID and paracetamol, with the combination notably
towards the origins, then this is evidence for synergistic interactions. Miranda and
co-workers established a synergistic interaction between paracetamol and ibupro-
fen. The ED50 value for ibuprofen alone was 0.8 (0.12–6.1, 95 % CI) mg/kg, and
that with paracetamol was 49.4 (33.4–59.1. 95 % CI) mg/kg, while the combination
had an ED50 of 9.6 (8.3–11.1, 95 % CI) mg/kg, giving a ratio of 1:58.1 of ibuprofen
to paracetamol, this ratio being the largest amongst the combinations of
NSAIDs/paracetamol that were determined by these authors.
The mechanisms of this interaction in relation to effects of the drug
combinations on the pain pathways has not been established, but it is considered
that several sites of action in the nervous system and periphery may be affected
differently by paracetamol and the individual NSAIDs. Thus, although paracetamol
is relatively weak as a direct inhibitor of PG production and COX activities (Flower
and Vane 1972, 1974; Tolman et al. 1983; Graham et al. 1999; Graham and Scott
2003), it exhibits inhibitory effects under differing oxidant conditions, which is
effective in some tissues in vivo (Tolman et al. 1983; Graham et al. 1999;
84 5 Drug Derivatives and Formulations

Graham and Scott 2003; Hinz and Brune 2011). Another part of the effects of this
drug is that it inhibits the peroxidative reactions in cyclo-oxygenases and PMN
myeloperoxidases (Graham and Scott 2005; Lucas et al. 2005); the latter reactions
are only affected by phenolic compounds, among them the salicylates (Rainsford
2004c). Ibuprofen would not appear to affect these peroxidative reactions.
It has been found that paracetamol selectively affects PG production in the brain
and not in the spleen, suggesting that there may be selective effects of this drug in
the CNS (Flower and Vane 1972). Paracetamol also inhibits COX-1 in the brain (or
its splice variant, COX-3—note however that the latter not been found in humans),
and PGE2 concentrations have been shown to be reduced in the brains of mice in
parallel with the reduction in writhing (Cashman 1996; Ayoub et al. 2004, 2006;
Botting and Ayoub 2005; Ayoub and Botting 2010). Furthermore, activation
of efferent opioid-pathways with increased activity of serotonergic (5-hydroxy-
tryptamine) pathways and activation of 5-HT1B and 5-HT3 receptors which inhibit
nociceptor signalling in the spinal cord (Alloui et al. 2002; Raffa et al. 2000, 2004;
Bonnefont et al. 2003, 2005; Sandrini et al. 2003) may contribute to the analgesic
effects of paracetamol. The central analgesic effects of paracetamol mediated
through these pathways appear to be independent of any anti-oedemic activities
of the drug (Alloui et al. 2002).
In contrast, ibuprofen has been postulated to affect COX-1, COX-2, nNOS or
iNOS NFĸB in the CNS as well as the serotinergic pathway activation (Rainsford
2007). The most potent effects of the racemic drug mediated centrally are due to the
S(+)enantiomer, although R(
) ibuprofen also has demonstrable analgesic activity
in laboratory models of analgesia (Wang et al. 1994; Björkman 1995a, b; Björkman
et al. 1996). Both ibuprofen and paracetamol affect glutaminergic activation via
effects on nitric oxide production (Björkman 1995a, b; Björkman et al. 1996). Most
significantly, ibuprofen has been shown to inhibit the breakdown of the endogenous
cannabinoid, anandamide (Fowler et al. 1997a, b, 2005; Tiger et al. 2000; Guindon
et al. 2006) as well as interacting synergistically with this endocannabinoid
(Guindon et al. 2006). These combined effects on CB1 receptor activation in the
spinal cord, dorsal root ganglia, and higher centres of the CNS, though not entirely
unique to ibuprofen, may set this drug aside from paracetamol in relation to its
analgesic actions. Furthermore, actions of ibuprofen on purinergic P2X3 receptors
in the dorsal root ganglia that are inhibited by ibuprofen (Wang et al. 2010), effects
which like those on the anandamide pathway, have not been identified to be
appreciably affected by paracetamol, which gives another possible basis for the
differential actions of these two drugs. Thus, the combination of ibuprofen and
paracetamol may lead to differential actions of these drugs, underlying their
interactions on various pain pathways in the CNS that underlie the apparent synergy
between these two drugs. There is a possibility that there may be local pharmaco-
kinetic interactions between ibuprofen and paracetamol, bearing in mind that these
drugs have differing localisation in the inflamed areas and the CNS (Graham and
Hicks 2004; Graham and Williams 2004). In particular, the lack of accumulation of
paracetamol in experimentally induced inflammatory sites, compared with that of
acidic NSAIDs, differentiates paracetamol from NSAIDs (Graham and Hicks 2004;
Graham et al. 2004).
5.4 Ibuprofen–Paracetamol Combination 85

In terms of total body PK, the serum kinetics and bioavailability of ibuprofen
and paracetamol taken concurrently were not found to be different from the drugs
taken alone in 20 normal healthy volunteers (Wright et al. 1983). A more detailed
PK investigation of the potential effects on PK of combining these two drugs was
recently undertaken by Tanner and co-workers (2010). They compared the effects
of a standard OTC combination of 200 mg ibuprofen with that of 500 mg of
paracetamol in 26 healthy human volunteers, 25 of whom were enrolled in a single
dose study (study 1), and 26 in a two-way crossover repeat dose study (study 2).
Subjects were either fed or fasted overnight before beginning of the study; the
effects of food intake predictably reduced both the Cmax and tmax of the drugs in
combination. The results of this investigation showed that the fixed combination of
ibuprofen and paracetamol did not show any significant differences in the PK
parameters, tmax, Cmax, t½, AUC or kel in study 1 and tmax, Cmax and AUC in
study 2, compared with that of the individual drugs.
To evaluate the analgesic efficacy of the fixed-dose combinations of ibuprofen
and paracetamol that was employed in the abovementioned PK study (Tanner et al.
2010), two separate trials were undertaken by Mehlisch et al. (2010a, b), the first in
two clinical research centres in Austin and San Marcos, TX, USA (Mehlisch et al.
2010a) and the second in the same cities but different locations as the first, and with
an additional centre in Salt Lake City, UT, USA (Mehlisch et al. 2010b). The pain
responses following surgical removal of 3 or 4 impacted molars (2 of which were
mandibular) were initially graded and the subjects then randomised (n ¼ 234 in the
first study and 735 in the second) to ibuprofen 200 mg, ibuprofen 100 mg þ para-
cetamol 250 mg, paracetamol 500 mg, or placebo; or in a separate comparison,
ibuprofen 400 mg, ibuprofen 200 mg þ paracetamol 500 mg, ibuprofen 400 mg þ
paracetamol 1,000 mg, paracetamol 1,000 mg (all at stage 1 for 8 h) followed by
a second stage of treatment for 72 h with ibuprofen 100 mg/paracetamol 250 mg,
ibuprofen 200 mg/paracetamol 500 mg or ibuprofen 400 mg/paracetamol 1,000 mg
for those subjects that received either the respective doses of the individual
or combination drugs in stage 1. The placebo group also received placebo in
the second stage (Mehlisch et al. 2010b). The first proof of concept study
(Mehlisch et al. 2010a) involved a 5-arm treatment with ibuprofen 400 mg, ibuprofen
200 mg/paracetamol 500 mg, ibuprofen 400 mg/paracetamol 1,000 mg, paracetamol
1,000 mg, or placebo. In both studies, the populations were predominantly female
and in the first study were white. Overall, both studies showed that the fixed drug
combinations (FDC) produced superior pain relief than when the drugs were given
alone; this was particularly apparent in the second study which extended over 80 h,
where the different FDCs had marked superiority over placebo. Therapy with the
FDC of ibuprofen 200 mg/paracetamol 500 mg or ibuprofen 400 mg/paracetamol
1,000 mg was significantly more effective than with comparable doses of with
either drug alone (Mehlisch et al. 2010b). The overall pain relief profiles in each of
the studies showed slight differences in the ibuprofen 400 mg/paracetamol
1,000 mg or ibuprofen 200 mg/paracetamol 500 mg groups; in the first study, the
differences between these two groups appeared greater than in the second. The
responses to paracetamol alone were lower than those with ibuprofen alone.
86 5 Drug Derivatives and Formulations

A recent study examined the safety and efficacy of 10 days and 13 weeks daily
treatment with ibuprofen 1,200 mg, paracetamol 3,000 mg, the FDC of ibuprofen
600 mg + paracetamol 1,500 mg in patients, and the FDC of ibuprofen 1,200 mg +
paracetamol 3,000 mg in patients with osteoarthritis of the knee (Doherty et al.
2011). By 10 days the WOMAC scores for pain relief with the high dose combina-
tion exceed those for paracetamol. However, there were increases in the plasma
levels of liver enzymes, ALT and γ-glutamyl transpeptidase, in patients that
received paracetamol or the combinations, reflecting hepato-cellular injury. At 13
weeks treatment, there was a marked loss of haemoglobin (≥1 g/dL) in over one-
third of patients that received the high dose combination of paracetamol and
ibuprofen: this exceeding the loss in patients that had the other treatments. No
investigations were undertaken to understand the basis to the marked loss of blood
in these patients. It appeared that the effect of ibuprofen in the FDC was to enhance
the analgesia by paracetamol.
In terms of achieving a maximal “analgesic ceiling”, it appears that FDC of
ibuprofen 400 mg/paracetamol 1,000 mg has higher and longer duration of analge-
sia than the other FDCs. The FDC had fewer adverse events, possibly as a result of
slightly reduced facial swelling and GI symptoms (nausea, vomiting). Overall,
these investigations suggest that the higher dose FDC is preferable therapeutically.
Another study compared the efficacy of one or two tablets of the FDC ibuprofen
200 mg/paracetamol 500 mg, two tablets of ibuprofen 200 mg/codeine 12.8 mg,
two tablets of paracetamol 500 mg/codeine 15 mg, or placebo in the dental surgical
pain model (Daniels et al. 2011). Treatment with two tablets of ibuprofen
200 mg/paracetamol 500 mg produced superior pain relief (measured as SPID, or
pain relief scores) which lasted over a longer period (up to 8–12 h) than any of the
other treatments or placebo.
A review by Ong and co-workers (2010) of paracetamol FDC involving ibupro-
fen in various surgical conditions showed that this combination produced superior
pain relief over that of the individual drugs alone. A similar finding was obtained
with other NSAIDs in combination with paracetamol over the individual drugs. A
retrospective safety evaluation of ibuprofen and paracetamol taken concomitantly
with that of the drugs alone was undertaken by de Vries and co-workers (2010),
using 1.2 million patients from the UK General Practice Research Database
(GPRD). The safety evaluations included gastrointestinal events, myocardial
infarction, stroke, acute renal failure, congestive heart failure, intentional or
accidental overdose, suicidal behaviours, and mortality, these being evaluated in
relation to dose, duration, and exposure.
Of the patients analysed, 1.0 million had not been prescribed other NSAIDs
including aspirin in the preceding 6 months. The patient population and frequency
of prescribing ibuprofen and/or paracetamol were different between the groups.
Ibuprofen was prescribed to a younger population (mean age 57.0 years) and less
frequently than paracetamol alone (mean age 71.6 years), or concomitant ibuprofen
and paracetamol (mean age 64.6 years).
The overall occurrence of upper GI events (RR ¼ 1.18, 95 % CI 1.13, 1.24) was
lower with ibuprofen than with paracetamol (RR ¼ 1.36, 95 % CI 1.31, 1.41) or the
5.5 Amino Acid and Salt Formulations 87

FDC (RR ¼ 1.70, 95 % CI 1.32, 2.19). The rates of myocardial infarction, stroke,
heart failure, and renal failure did not differ between the groups, and tended to be
RR-1.1. The RR of suicidal behaviour or overdose was about 1.3, and did not differ
between the groups. Mortality was notably higher with the FDC ibuprofen/
paracetamol group (RR ¼ 1.5, 95 % CI 1.34, 1.68) and paracetamol alone
(RR ¼ 1.28, 95 % CI 1.26, 1.68) compared with that of ibuprofen alone
(RR ¼ 1.12, 95 % CI 1.10, 1.15).
An interesting outcome from the time-course of these observations was that the
crude hazard rates for all major adverse events (except overdose) appeared notably
lower with ibuprofen alone or FDC ibuprofen than with paracetamol. It must be
emphasised, however, that these data do not quantify the amount of drug taken,
even though they highlight the apparent higher toxicity of paracetamol.

5.5 Amino Acid and Salt Formulations

A variety of salts of ibuprofen have been developed, among them salts of sodium
or potassium, or combinations with aluminium, aminoethanol, meglumine,
guaiacol, pyridoxine, and the amino acids arginine and lysine (Reynolds 1993).
The lysine combination with ibuprofen (lysinate) is a (DL) lysine salt of ibuprofen
[chemically 2-(4-isobutyl-phenyl) propionate (DL) lysine]. After oral ingestion, this
complex dissociates into ibuprofen (acid) and DL-lysine. The gastric absorption of
ibuprofen proceeds at a faster rate from the complex, due to rapid solubilisation
and dissociation that is more than that of ibuprofen (acid) in tablets or caplets
(Geisslinger et al. 1989). Once absorbed, ibuprofen assumes the pharmacokinetic
properties of the conventional ibuprofen. It is unlikely that the DL-lysine influences
any other pharmacokinetic processes.
DL-lysine is a 50:50 mix of the metabolisable, essential amino acid, L-lysine with
the non-metabolisable D-isomer. The latter is not metabolised or incorporated into
newly synthesised proteins in mammalian cells but may be oxidised by D-amino
acid oxidases. It is presumably excreted unchanged after oral intake, and would be
expected to have no metabolic or biochemical impact at the doses ingested with
ibuprofen.
The L-enantiomer of lysine would be expected to be metabolised in the same
way as that from dietary sources, and would be incorporated into newly synthesised
proteins de novo. It is unlikely that the L-lysine component in the doses ingested
would be expected to have any substantive effects on metabolic processes, as
the relative amounts in the diet far exceed those in the ibuprofen lysine tablets.
DL-lysine, like that of some other amino acids (e.g., arginine, glutamine) is widely
used as a salt or pharmaceutical additive or excipient.
The rationale for development of the lysine salt of ibuprofen is to enable
increased disintegration and solubilisation of the complex in GI tract following
ingestion of the tablets, with consequent more rapid gastro-intestinal absorption
than observed with ibuprofen acid. The pH-dissolution studies of Geisslinger et al.
88 5 Drug Derivatives and Formulations

(1989) show that there is appreciably greater dissolution of ibuprofen from ibupro-
fen lysine tablets (90 % after 90 min) at pH 4.0, compared with 15 % from
conventional ibuprofen (acid) tablets under the same conditions.
The comparative pharmacokinetic properties of ibuprofen lysine studied by
Klüglich et al (2005) showed bioequivalence of ibuprofen lysine formulations
with that of ibuprofen acid. There appear to have been two formulations of
ibuprofen lysine investigated, one known as Dolormin® (McNeil) and the other
which is the Reckitt–Benckiser/Boots formulation known as Nurofen® Express.
The pharmaceutical properties of Dolormin® are described in the pharmacopoeal
literature (e.g., “Martindale”, Reynolds 1993) and it appears that Nurofen® Express
is an improved formulation, more as a consequence of manufacture, stability, and
dissociation characteristics.
Intravenous ibuprofen lysinate has been employed in the treatment of patent
ductus arteriosus, where it has proven effective and safe (Poon 2007; Hirt et al.
2008; Aranda et al. 2009a, b).
The clinical PKs of the arginine salt of ibuprofen has been extensively
investigated (Cattaneo and Clementi 2010). In human volunteers the arginine salt
shows more rapid gastric absorption than the acid (Cattaneo and Clementi 2010). At
a dose of 400 mg, it has been shown to produce effective pre-emptive or post-
operative analgesia in the third molar dental pain model (Lau et al. 2009). The
potential for arginine to generate nitric oxide (NO) has been found to be related to its
enhanced acute and chronic anti-inflammatory effects in animal models compared
with that of ibuprofen alone (De Palma et al. 2009). This suggests that the arginine–
ibuprofen combination may have greater anti-inflammatory effects compared with
ibuprofen acid. A functional (or pharmacological) magnetic resonance imaging
(MRI) double-blind, placebo-controlled study in healthy human volunteers in
whom pain was elicited from right medial nerve stimulation indicated that blood
oxygen level-dependent signalling was modified in relation to somatosensory pain
evoked potentials by ibuprofen compared with placebo (Delli Pizzi et al. 2010). The
authors considered this effect was due to arginine. However, since the effects of
ibuprofen alone were not investigated in this study, it is not possible to conclude that
the analgesic mechanism was related to the NO-donor effect of arginine.

5.6 Topical Formulations

Topical formulations of ibuprofen have found extensive application as OTC

treatments of musculo-skeletal pain (Cross et al. 2005; Tiso et al. 2010). These
treatments are particularly helpful for the elderly with knee or back pain, where
they are likely to have fewer GI adverse reactions than with the oral drug (Cross
et al. 2005; Carnes et al. 2008; Underwood et al. 2008a, b; McCarberg 2010). In
Cochrane assessments, ibuprofen gel and other topical formulations are clearly
superior to placebo, and are about comparable to some other effective NSAIDs
(e.g., diclofenac) (Massey et al. 2010). Evidenced-based evaluation of pain relief
5.6 Topical Formulations 89

Fig. 5.1 Comparison of ibuprofen with some topical NSAIDs in placebo-controlled trials in
chronic pain conditions of 2 weeks duration. From: McQuay and Moore (1998). Reproduced
with permission of one of the authors, Dr. Andrew Moore

from different formulations of NSAIDs has shown that ibuprofen has similar
efficacy to other NSAIDs (Fig. 5.1; McQuay and Moore 1998).
Variation in the formulations and uptake of NSAIDs through different layers of
skin and adjacent muscle determines the relative efficacy of these formulations
(Rainsford et al. 2008a, b; Massey et al. 2010). Muscle pain appears well-controlled
in mild–moderate pain by ibuprofen, notably in elderly compared with younger
subjects (Hyldahl et al. 2010). The issue of cost-effectiveness of topical versus oral
ibuprofen has been examined (Castelnuova et al. 2008), and the cost–benefits (at
least within the UK National Health System) and results are equivocal and depend
on the length of time of treatment. Long-term topical treatments (e.g., over a year or
more) may not be as practical as taking the drug orally, since the repeated applica-
tion may be accompanied by skin irritation and lack of compliance. It is clear,
90 5 Drug Derivatives and Formulations

however, that the more frequent occurrence of adverse events with the orally
administered drug compared with the topically-applied formulation favours the
latter, especially in the elderly who are most likely to have greater benefits in
relation to adverse reactions from use of topical preparations (Carnes et al. 2008;
Underwood et al. 2008a, b). The benefits to the elderly in whom topical ibuprofen
appears as effective as the oral drug may depend on attention to close monitoring by
health carers (Carnes et al. 2008).
Thus, topical ibuprofen has a place in therapy of mild–moderate musculo-
skeletal pain, with the possibility of fewer GI and other adverse reactions than
that with the oral drug. Recent development of novel dressings (Sibbald et al. 2007;
Cigna et al. 2009; Arapoglou et al. 2011) or formulations, e.g., nanoscale emulsions
(Abdullah et al. 2011), offer prospects for future development of more effective
topical preparations.
Chapter 6
General Safety Profile

There were indications of a favourable safety profile for ibuprofen from the
post-marketing data during the 15-year period after approval in the USA (Royer
et al. 1984). This information was important in decisions made by the FDA in
granting approval for OTC use in the USA (Rainsford 1999c).
Since then, the safety profile of ibuprofen has been compared with a range of
other new and established NSAIDs on the basis of being a recognised “bench
mark” for safety and efficacy comparisons (Kean et al. 1999). In particular,
ibuprofen has been used as a comparator drug in several trials with the newer
coxib class of NSAIDs; an aspect that will be considered later in this section
and subsequent sections on the adverse events and toxicity in individual organ
systems.

6.1 Introduction

6.2 Pharmacokinetic Aspects of Importance in the Safety

of Ibuprofen

During the development of ibuprofen, pharmacokinetic issues were of partic-

ular importance, especially in the pre-clinical evaluation of the toxicity of the
drug (Adams 1987; Rainsford 1999a). The Boots Company had already
experienced problems with ibufenac in causing hepatic reactions in patients
with rheumatoid arthritis during early-stage clinical trials. Furthermore, there
was a major objective in the pre-clinical programme to discover a drug which
was safer to the gastrointestinal tract than was evident with aspirin and
some other NSAIDs at the time. Thus, to obviate the possibility of a new
NSAID that was in discovery causing hepatic reactions, evidence for a lower
rate of accumulation in the liver than was evident with ibufenac was obtained
with ibuprofen.

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 91

DOI 10.1007/978-3-0348-0496-7_6, # Springer Basel 2012
92 6 General Safety Profile

Fig. 6.1 Postulated competition between the R(
) and S(+) enantiomers of ibuprofen and the
cyclo-oxygenase (COX) isoenzymes in the upper gastrointestinal mucosa. There is no intestinal
metabolism of R(
)-ibuprofen to its S(+) antipode and possibly also in the stomach, this occurring
principally in the liver. Thus, at least half of the racemic form of the drug, i.e., R(
), is available
for competing with the inhibitory S(+) from active sites on COX isoenzymes in the stomach and
intestinal mucosa. This masking of the COX active sites by R(
)-ibuprofen effectively prevents
appreciable inhibition of prostaglandin production in the gastrointestinal mucosa. This may
account for the relatively low ulcerogenic activity and bleeding that is observed in
clinico-epidemiological and experimental studies (from Rainsford et al. 1997, 1999b, 2003).
Reproduced with permission of Springer, publishers of Inflammopharmacology

What has emerged since ibuprofen was initially discovered is that (a) the
drug undergoes metabolism of inactive R(
)-ibuprofen enantiomer (present as
half the mass of ingested drug) to the prostaglandin synthesis inhibitory or
active S(+) isomer, and (b) these isomers each have pharmacological effects
of importance to the therapeutic actions of the drug, thus highlighting the inter-
relationships between its metabolism and pharmacodynamic effects (Fig. 3.5)
(Rainsford 1999b).
The presence of the R(
)-ibuprofen in the ingested drug may account for the low
gastric irritancy of ibuprofen, by masking the interaction of the S(+)-isomer with
the active site of COX-1 in the stomach and platelets circulating through the gastric
circulation, so reducing the inhibitory potential of the latter isomer on production of
gastric prostaglandins (Rainsford 1999b, 2003; Fig. 6.1).
In considering the pharmacokinetic profile of ibuprofen (Tables 2.1 and 6.1),
there are several important features that should be noted:
1. The drug has a relatively short plasma elimination half-life (t½) a feature which
has been identified in comparative studies of gastrointestinal gastro-ulcerogenicity
(Henry et al. 1996, 1998) which is probably a key safety feature. The plasma
half-life of the drug averages between 2 and 3 h, with some inter-subject and
intra-subject variability but not such that this vastly influences half-life values
(Brocks and Jamali 1999; Graham and Williams 2004). Differences have also
been observed in the bioconversion of the inactive (R
) enantiomers to (S+)
enantiomers and in their clearance under conditions of acute surgical pain.
2. There is no evidence of increased accumulation in elderly or retention in
specific body compartments. There is no evidence of formation of bio-reactive
metabolites sufficient to cause covalent modification of liver, or other proteins
that might contribute to toxicity of the kind seen in the case of paracetamol-
induced irreversible hepatic injury (Graham and Hicks 2004). Glucuronide
conjugates of ibuprofen represent the major metabolites of the drug, and it has
6.2 Pharmacokinetic Aspects of Importance in the Safety of Ibuprofen 93

Table 6.1 Pharmacokinetic aspects affecting the safety of ibuprofen

General pharmacokinetic properties:
• Near complete bioavailability
• Low variability of PK parameters
• R(
) isomer protects against effects of S(+) in stomach
• Clearance not dependent on dose
• Little if any effects of food on gastric absorption
• Negligible excretion in milk
• Metabolised to pharmacologically inactive metabolites
• No evidence of appreciable systemic retention
• Little if any effects of gender
• Age: the elderly have increased unbound (albumin) fraction, clearance and Vd so overall may
have higher exposure to drug than young adults
• Short plasma elimination half-life (T1/2)
In healthy subjects:
R ¼ 1.6–4.2 h
S ¼ 1.9–3.4 h
In osteoarthritis patients:
R ¼ 1.7–2.9 h
S ¼ 2.0–3.0 h
In rheumatoid arthritis patients: more variable PK; AUC increased
• Hepato-renal impairment:
In liver disease: T1/2 decreased, AUC increased, glucuronides decreased
Renal clearance: variably affected by arthritic state
and increased by 50 % at >70 years
In renal insufficiency increase in AUC of S(+) with age and hypertension
In painful states; delayed gastric absorption and increase renal clearance
Based on Jamali and Brocks (1999), Rainsford (2009). Reproduced with permission of Springer,
publishers of Inflammopharmacology

been speculated that these conjugates might lead to formation of adducts such as
are seen with other phenyl propionic and benzoic acid NSAIDs (Castillo et al.
1995). Whether these conjugates contribute to covalent modification of proteins
that leads to toxicity is not known. There does not appear to be any indication of
appreciable accumulation of ibuprofen in the liver and other organs, such as
might result from such covalent modification. It is very likely that there is a
considerable degree of spontaneous hydrolysis both of the glucuronides and the
ibuprofenyl-derivatives of proteins.
Mild/moderate renal impairment does not appear to cause any elongation of the
plasma elimination half-life, and there is little evidence of alterations in plasma
pharmacokinetics in patients with mild hepatic disease. Clearly, patients with
considerable renal impairment or liver malfunctions should not be taking ibuprofen
as there would be an expected increase in risk of systemic accumulation, although
this risk is probably of a low order in comparison with the short plasma half-life of
the drug.
94 6 General Safety Profile

6.3 Pharmacokinetic Variations

The pharmacokinetic parameters obtained in studies with ibuprofen in normal

subjects show relatively low variability (Table 6.2). This is illustrated in the
mean values (SD) or median and ranges of the various parameters obtained
from a wide range of studies (Table 6.2).
As shown in Table 6.2, there is relatively little difference between the PKs in
Western (or non-Chinese) populations compared with that from two studies
performed in Chinese subjects (see also later section).
A major source of variability in the metabolism of ibuprofen, like that of other
NSAIDs, is determined by the genetic variations in the cytochromes P450, espe-
cially the CYP2C9 and CYP2C8 isoforms (Agundez et al. 2009).
The oxidative pathway of ibuprofen metabolism catalysed by the cytochrome
P450s constitutes a major Phase 1 pathway for the liver and intestinal detoxification
of the drug (Brocks and Jamali 1999; Fig. 2.2). In recent years, it has become
evident that there are genetic variants of those isoforms of cytochrome P450 that
underlie the variation in catalytic activity, and consequently the metabolic clear-
ance of ibuprofen as well as that of other NSAIDs and paracetamol (Garcı́a-Martı́n
et al. 2004; Agundez et al. 2009). These variations in cytochrome metabolism of
NSAIDs and analgesics may be expected to have appreciable consequences for the
safety and efficacy of these drugs (Agundez et al. 2009; Ali et al. 2009). Indeed,
there is also evidence that there are marked differences in the frequency of alleles of
those cytochromes involved in metabolism of these drugs in different ethnic
populations worldwide (Garcı́a-Martı́n et al. 2004; Agundez et al. 2009). Thus,
the CYP2C9 and CYP2C8 isoforms are considered to have predominant roles in the
metabolism of ibuprofen (as well as some other NSAIDs) (Agundez et al. 2009).
CYP2C9 has particular prominence in variations in oxidative metabolism of ibu-
profen, as it is the predominant isoform in the liver (Agundez et al. 2009). Allelic
variants of both these isoforms may cause decreased, or rarely increased, enzyme
activity, with consequent effects on the pharmacokinetics of ibuprofen or other
NSAIDs metabolised by these isoforms (Agundez et al. 2009). Indeed, the dose-
contributions of mutated heterozygous or homozygous CYP2C9 and CYP2C8
isoforms can have major consequences for the clearance of ibuprofen as well as
some other NSAIDs.
The relative allelic frequencies of some of the principal CYP isoforms (i.e.,
CYP2C9*2, CYP2C9*3 and CYP2C8*3) vary considerably in different ethnic
populations (Agundez et al. 2009). Although data in Chinese populations are sparse
the allelic frequency of CYP2C9*3 is relatively low compared with that in some
other populations (e.g., South and North Europeans, Caucasian Americans, and
Asian Indians) (Agundez et al. 2009). This CYP variant which involves a single
amino acid substitution of I359L is known to have decreased enzyme activity.
Table 6.2 Comparative pharmacokinetics of ibuprofen in normal Western subjects compared with those in Chinese [Data for Western subjects from Brocks
and Jamali (1999)]
Cmax (mg/mL) tmax (h) AUC (mg/mL/h) t½ (h) CL/F (L/h) VD/F (L)
Author (year)—conditions No. of subjects S R S R S R S R S R S R
Caucasians
Jamali et al. (1988) 80 30 27.5 1.44 107 74.2 2.6 2.7 – 4.04 – 15.7
Levine et al. (1992) 11 38 25 1.3 1.2 127 74 2.1 1.7 – 4.05 – 9.64
With food 29 19 1.6 1.5 116 59 2.1 1.7 – 5.08 – 12.7
6.3 Pharmacokinetic Variations

Jamali et al. (1992) solution 33 70.6 61.1 2.2 2.6 – 4.91 – 18.4
Tablets 2.17 70.8 52.7 2 2.1 – 5.69 – 17.3
Smith et al. (1994) solution 12 29 29.6 0.63 0.6 98.6 78.8 2.4 1.7 – 3.81 – 9.3
Oliary et al. (1992) 12 16.2 14 2.1 1.7 78.9 50.5 3.1 3.2 – 6.8 – 33
Li et al. (1993) 8 23.3 23.4 1.8 1.8 94.5 73.5 1.8 1.7 – 4.08 – 10
Geisslinger et al. (1990) 11 16.4 14.3 1.8 1.5 91.7 54.3 2.3 2.3 – 5.66 – 18.7
Geisslinger et al. (1989) 8 16.8 14.8 1.9 1.7 89.8 57 2.4 2.3 – 5.37 – 17.8
Mean 24.8 20.95 1.6 1.4 94.49 63.51 2.3 2.2 – 4.94 – 16.25
Median 26.15 21.2 1.8 1.5 93.1 60.05 2.25 2.2 – 4.99 – 16.5
SD 7.99 6.25 0.47 0.41 18.55 10.52 0.36 0.52 – 0.96 – 6.98
N 8 8 9 7 10 10 10 10 10 10
Min 16.2 14 0.63 0.6 70.6 50.5 1.8 1.7 3.81 9.3
Max 38 29.6 2.17 1.8 127 78.8 3.1 3.2 6.8 33
_75th % case 1–10 29.5 26.25 1.9 1.7 107 74 2.4 2.6 5.66 18.4
Chinese
Chen and Chen (1995) 5 Male 239.5 239.5 3.3 3.1 2.6 11
5 Female
Ding et al. (2007) 12 Male 23.5 20.8 3 2.95 65.9 65.9 3.4 5.02 4.57 6.45
95
96 6 General Safety Profile

That the frequency of this variant is relatively low in Chinese populations suggests
that ibuprofen metabolism is possibly less subject to impaired clearance. However,
although more extensive data should be sought on other CYP2C9 and CYP2C8
variants in the Chinese before firm conclusions can be obtained.
The potential impact of variations in the CYP2C9*2 (as well as CYP2C9*3)
variants on the risks of acute gastrointestinal (GI) bleeding is seen in data from
meta-analyses (Agundez et al. 2009). Thus, for CYP2C9*2 associations it appears
that the presence of this allelic variation confers about a 1.58-fold increase in the
risk of GI bleeding with all NSAIDs, and 1.96 (CI 1.18–3.24) for NSAIDs that are
CYP2C8 or CYP2C9 substrates; this would include ibuprofen. CYP2C9*2 and *3
polymorphisms are also related to excess of coagulation reactions due to warfarin
(Lindh et al. 2005), and this may represent an added serious risk factor for bleeding
if NSAIDs are taken with this drug.
Taking these data on GI risk together with data on allelic frequencies for
CYP2C9*2, it would appear that although there is a risk of GI bleeding from
individuals having this variant, the low frequency of this allelic variant in Chinese
populations suggests that the likelihood of this genetic factor in determining risk of
GI bleeding amongst the Chinese might be lower than that in Europeans, American
Caucasians, or Asian Indians.
The most profound reduction in PK of both ibuprofen and other drugs in relation
to allelic variations in CYP isoforms occurs in subjects with the CYP2C9*3 allele
(López-Rodrı́guez et al. 2008; Vormfelde et al. 2009). With ibuprofen in Spanish
populations, this variant leads to decreased metabolism of the R to S enantiomers,
a 30 % increased AUC and 30 % reduced clearance of the drug compared with the
most prevalent allelic variant CYP2C9*1. Subjects with CYP2C8*3 have reduced
clearance and increased AUC and t½ of R(
) ibuprofen, coincident with reduced
ADRs. It must be cautioned, however, that the number of subjects was rather small
in the CYP2C8*3 groups and so the statistical significance of data is limited.
The implications of allelic variations in CYPs for pharmacodynamics (PD) of
ibuprofen were investigated in human volunteers by Kirchheiner et al. (2002),
Lee et al. (2006), and López-Rodrı́guez et al. (2008). Since the PG synthesis
inhibitory effects of ibuprofen are largely dependent upon the concentration of
the active S(+)-isomer, and this is believed to affect both COX-1 and COX-
2 (Rainsford 1999b, 2003, 2009), the variations in the R(
) to S(+) conversion
would be expected to influence the total production of PGs and thromboxane B2
(TXB2). Kirchheiner et al. (2002) found that ex vivo production of TXB2 via
COX-1 in healthy volunteers that received a single dose of 600 mg racemic
ibuprofen was significantly dependent on CYP2C9 polymorphisms. Greater
inhibition of TXB2 formation was evident in subjects with slow CYP2C9
phenotype metabolisers compared with the “wild” type CYP2C9*1; a similar
trend was observed in COX-2 PGE2 production ex vivo, but the wide variation
in patterns of inhibition amongst subjects with CYP2CP variants meant that
the results were less clear-cut.
6.4 Pharmacokinetics in Oriental Compared with Caucasian Populations 97

6.4 Pharmacokinetics in Oriental Compared with Caucasian

Populations

The possibility that there may be ethnic or environmental (e.g., dietary) differences
in the PK of ibuprofen has been considered. The data considered here is from a few
published investigations that have been reported in which the PK was determined of
single OTC range dosage of racemic ibuprofen in normal volunteers. The PK data
from these studies have been compared with pooled data (with statistical means,
medians and errors or ranges of values) from studies in Western populations
(Table 6.2; data from Brocks and Jamali 1999). These populations are presumed
to comprise principally Caucasians, but also may include some Afro-Caribbean or
Indo-Iranian populations.
Among these studies was an investigation by Chen and Chen (1995) in
Taiwanese patients with varying hepato-renal conditions, cardiovascular, hyper-
lipidaemic, hyperuricaemic and diabetic conditions compared with 10 age-and sex-
matched healthy volunteers. For the purpose of comparison with the studies in
non-Chinese, predominantly Caucasian populations, only data from the normal
volunteers is considered. The PKs of ibuprofen in patients with diseases or
conditions that would be expected to confound the PKs of ibuprofen are considered
separately later.
The main PK data from investigations by Chen and Chen (1995) are shown in
Table 6.3. The values obtained in normal subjects are shown in Table 6.2 for
comparison with data in non-Chinese populations. It appears that with the exception
of the values for AUC (which were calculated to infinity values from linear
extrapolation), the values of Vd, Cl, and t½ for both enantiomers were within
the ranges observed in non-Chinese populations (Table 6.3). The values for AUC
in the Taiwanese all seem rather high in comparison with that in non-Chinese. An
explanation for this is not obvious, except that in this study an 800 mg dose of
ibuprofen was employed, whereas the other comparative data have been obtained
from subjects that received 600 mg of the drug.
Ding and co-workers (2007) performed a study comparing the effects of
an immediate release (IR) formulation of racemic ibuprofen with that of
a sustained-release (SR) preparation in 12 healthy Han Chinese (Table 6.4). Both
the racemic and the R(
) and S(+) enantiomers of ibuprofen, were determined by
HPLC. The volunteers were fasted overnight, and then took 600 mg of one of the
tablet formulations with water. No other foods or liquids were permitted for the next
4 h. Thereafter, hospital meals were allowed.
The serum concentrations of R(
) and S(+) ibuprofen following administration
of 600 mg of the IR ibuprofen and the pharmacokinetic parameters are shown in
Table 6.4. The time-dependent increase in the proportion of S(+) to R(
) ibuprofen
reflects the well-known metabolic conversion of the R(
) form of the drug, and this
appears to be in a similar proportion to that seen in Western populations (Ding et al.
2007).
 98

Table 6.3 Pharmacokinetic parameters of ibuprofen enantiomers in Oriental patients admitted to National Taiwan University Hospital (1992–1994) with
various cardiovascular and renal disorders compared with age-matched controls
Condition/age (years) Cr (mg/dl) t½(S) (h) t½(R) (h) AUC(S) (mg/mL/h) AUC(R) (mg/mL/h) Vd/F(R) (L) CL/F(R) (L/h)
Diabetes mellitus
63.8  2.1 1.4  0.2* 7.7  1.4** 3.2  0.5 715.8  148.8* 338.1  6.1 11.1  2.1 1.7  0.3
Hypertension
59.6  3.2 1.3  0.1** 6.3  1.2* 3.1  0.5 800.6  150.4** 396.3  64.1 7.8  1.4 1.4  0.2
Hyperlipidaemia
64.6  4.7 2.1  0.4* 3.3  1.5 3.5  0.8 780.5  394.1* 374.9  100.8 8.8  3.3 1.4  0.4
Hyperuricaemia
67.3  3.4 2.0  0.5* 2.6  0.4 4.3  1.5 433.5  123.4 490.1  107.2 6.3  2.8 1.0  0.2*
Coronary artery disease
63.2  2.5 1.3  0.1** 5.8  1.6 3.9  0.5 796.1  203.0* 377.6  64.0 9.2  1.9 1.3  0.2
Cerebral vascular disease
60.5  0.5 1.4  0.1* 4.4  0.5 3.6  2.5 320.4  171.3 212.4  53.8 15.2  9.2** 2.0  0.5
Congestive heart failure
68.5  3.9 1.4  0.1** 4.3  1.1 3.9  1.1 529.1  86.3* 423.0  114.0* 9.3  3.4 1.1  0.3
Coronary renal failure
6

60.1  3.7 2.0  0.2** 4.5  0.9 3.5  0.7 768.3  189.5* 436.1  81.5* 8.8  2.1 1.3  0.3
Control
57.9  3.0 0.8  0.1 3.3  0.5 3.1  0.6 286.8  54.9 239.5  45.4 11.0  1.3 2.6  0.7
V/F fractional volume of distribution calculated for (R)-ibuprofen, with dose calculated to one-half of administered racemate (800 mg)
From Chen and Chen (1995) with permission of the publishers
General Safety Profile
6.4 Pharmacokinetics in Oriental Compared with Caucasian Populations 99

Table 6.4 Pharmacokinetic parameters of racemic and R-(
)- and S-(+)-ibuprofen following oral
administration of 600 mg immediate-release (IR) preparation to 12 Han Chinese healthy male
volunteers
Enantiomer proportions
Racemate R
S+
Cmax (mg/mL) 46.21  8.20*** 20.82  5.90** 23.46  7.30**
tmax (h) 2.83  1.03* 2.96  1.18 3.00  1.35*
AUC (mg/mL) 195.90  31.69 65.94  20.06 100.81  32.28##
MRT (h) 4.34  0.89*** 3.43  0.64*** 4.51  0.79***##
K0 (h
1) – – –
ka (h
1) 1.37  2.12 1.32  2.00 1.62  2.06
VdG/FG (L) – – –
VdT/FT (L) 6.46  2.13 6.45  1.73 4.57  2.47
Kel (h
1) 0.54  0.16 0.58  0.14 0.41  0.12##
Tau (h) – – –
Lag timeG (h) – – –
Lag timeT (h) 0.95  0.97 0.90  0.82 1.10  1.08#
CL/(FG or FT) (L/h) 3.14  0.55 5.02  1.81 3.40  1.68
S/R AUC ratio 1.57  0.45
Cmax the maximum serum concentration, tmax the time to reach Cmax, AUC area under the plasma
concentration–time curve, MRT mean residence time, k0 zero order absorption rate constant, ka
first-order absorption rate constant, VdG/FG volume of distribution/fraction absorbed of SR
preparation; VdT/FT volume of distribution/fraction absorbed of IR preparation, kel elimination
rate constant, Tau drug release time of SR preparation, LagtimeG absorption lagtime of
SR preparation, LagtimeT absorption lag time of IR preparation, CL/(FG, or FT) total body
clearance/fraction absorbed IR preparation
Each value is the mean  SD of results from 12 volunteers. From Ding et al. (2007) with
permission of the publishers

Overall, it appears that the PK of racemic ibuprofen does not differ appreciably
from that in other western populations.
Supporting evidence for the similarity of the PK properties of ibuprofen in
Chinese compared with that in Western or Caucasian populations comes from
another study by Zheng et al. (2008), as well as bioavailability studies in Chinese
subjects in which various tablet formulations or suspensions of ibuprofen were
compared (Table 6.5). Thus, Luan and co-workers compared the dissolution
characteristics of three different ibuprofen formulations with that of a standard
Boots preparation as a reference standard. They compared the bioequivalence of
these preparations in volunteers using gas chromatography analysis of the racemic
drug. The values for Cmax for the 200 mg dose varied from 14.94 to 25.79 mg/mL for
the three preparations under investigation compared with 20.96 to 24.46 mg/mL for
three test preparations in comparison with the Boots product. Apart from one
preparation (A) with a low value, the results were not significantly different from
one another. The values for tmax ranged from 1.694 to 2.605 h for the three test
preparations, and 1.737 to 2.126 h for the Boots preparation. The preparation
(A) with the lowest Cmax had the longest tmax, and this was statistically significant
compared with the Boots preparation.
Table 6.5 Pharmacokinetics of various ibuprofen formulations in Chinese Subjects
100

Author’s Ibuprofen Cmax

name (year) preparation Dose (mg) (mg/mL) Tmax (h) Ka (h
1) AUC (mg/h/mL) Vd (L) Cl (L/h) t½ (h) Other comments
Li and Chen Sustained-release 22.7 3.5 150 Correlation between
(2001) in vitro dissolution
and PK
Wu et al. Tablets multiple 28.74 2.05 271.26(S.S.)
(2001) dose (q 6. 6d)
Sustained-release 18.42 7.47 263.31(S.S)
Wang et al. Tablets 400 42.43 2.68 0.7 237 1.92 Biovail. Susp/tabs.
(2002) 102.8 %
Suspension 400 52.62 1.55 1.65 242 1.89 No diff. PKs.
Wu and Kong Tablets 600 13.56 1.76 44.13 Biovail. Susp/tabs.
(2004) Suspension 600 14.46 1.21 46.76 104.3 %
Zhao et al. Ibu–arginine tabs 400 42.43 2.68 0.7 237 1.92 Biovail. Susp/tabs.
(2004) Suspension 400 52.62 1.55 1.65 242 1.89 102.8 %
Bao et al. Hard capsules 400 32.77 2.83 147.57 (0-1) 2.39 Biovaol. Soft/hard
(2006) Soft capsules 400 34.94 2.78 157.43(0-00) 2.49 capsules 103.5 %
Wang et al. Tablets 28 2.7 148.49 (0-1)
(2006) Ibu–arginine syrup 47 0.6 157.28 (0-00)
Xue (2006) Sustained-release 300 (S.D) 19.21 5 136 (0-10) 2.45 Biovail test/ref 101.74
(Ref) 300 (M.D) 17.58 4.68 150 (0-10) 3.01
6

Sustained-release 300 (S.D) 16.86 4.85 3.42

300 (M.D) 14.46 4.68 3.6
Wen et al. Suspension ref test 400 34.6 2 125.4 (0-10) 2.1 Biovail test/ref
(2007) 400 37.78 1.7 130.38 (0-10) 2.19 (98.2 %)
Xu et al. Ibu–arginine tabs 400 50.6 0.51 118.63 (0-1) Preparations
(2009a, b) 121.18 (0-00) bioequivalent
Ibu–arginine 400 50.53 0.34 115.75 (0-1)
granules 118.55
General Safety Profile
6.5 Influence of Disease States on PK of Ibuprofen 101

The AUC values for the three test products varied from 58.37 to 122.8 mg/h/mL,
compared with 78.41 to 109.8 mg/h/mL for the Boots preparation. These kinetic
parameters have been related to mean dissolution times for the four preparations, with
the preparation A being bio-inequivalent to the Boots preparation. It is significant that
the values are, in general, within the range of racemic ibuprofen in other studies.
A study by Benjie and co-workers (2002) compared the bioequivalence of
ibuprofen tablets (400 mg) with that of a suspension of the drug (400 mg) in
Chinese volunteers. Serum levels of racemic ibuprofen were determined by
HPLC. Values for Cmax were 52.62 (14.21 SEM) mg/mL for the suspension and
42.43 (10.62 SEM) mg/mL for the tablets. The Tmax was 1.55 (0.70 SEM) h for
the suspension and 2.68 (0.86 SEM) h for the tablets. The values for AUC were
242.03 (35.70 SEM) mg/h/mL for the suspension and 237.04 (39.63 SEM)
mg/h/mL for the tablets. The bioequivalence of the suspension was the same as
that for the tablets, and was 102.8 (11.45 SEM) %.
Overall, these data show that the PK parameters of various IR formulations and
suspensions of ibuprofen are similar in Chinese subjects to those from a variety of
studies in Western/Caucasian or other populations. However, other data from
studies of bioavailability of different ibuprofen formulations available in China
reported in Chinese journals shows there is a high degree of variability on the PK of
preparations available in China (Rainsford 2011).

6.5 Influence of Disease States on PK of Ibuprofen

It is well-known that impaired hepatic and renal function can reduce the metabo-
lism and clearance of ibuprofen (Brocks and Jamali 1999). In order to establish the
influence of these and other diseases in Oriental populations and their impact on the
rates of conversion of the R(
) to S(+) enantiomers of ibuprofen, Chen and Chen
(1995) undertook a pharmacokinetic investigation in 32 Chinese patients in Taiwan
compared with ten age-matched volunteers (Table 6.3). The patients had a variety
of cardiovascular disorders: hypertension (46.9 %), hyperlipidaemia (15.6 %),
hypercuricaemia (12.5 %), and diabetes mellitus (50 %), with or without
complications including coronary artery disease (31.3 %), congestive heart failure
(18.8 %), cerebrovascular disease (6.3 %) and chronic renal failure (37.5 %) with
associated impaired renal function.
All the subjects received 2  400 mg of Boots racemic ibuprofen as a single dose
(800 mg), without any dietary restriction but without regular medications. The PK
data from this study are shown in Table 6.3. The most marked changes were evident
in patients with compromised renal haemodynamics and especially patients with
hyperuricaemia who showed reduced clearance of R(
) ibuprofen. Patients with
most of the conditions showed increased AUC for S(+) and to some extent R(
)
ibuprofen, this being most marked in patients with coronary vascular conditions.
The fractional volume of distribution (Vd/F) for R(
) ibuprofen was very high in
patients with cerebral vascular disease, but was somewhat lower, though not
statistically significant from controls, in patients with hyperuricaemia. There was
102 6 General Safety Profile

Fig. 6.2 Patterns of adverse reactions from the NSAIDs (Bjarnason et al. 2005). Adverse
Reactions shown in red are most frequent.

a trend towards higher S/R AUC ratios in patients with renal insufficiency, diabetes
mellitus, hypertension, hyperlipidaemia, and coronary artery disease, reflecting
alterations in the renal and hepatic reactions in the disposition of the respective
enantiomers. The exact nature of these altered functions in hepato-renal metabolism
and elimination was not clear from these studies.

6.6 ADRs and Safety in Prescription-Level Doses

The overall pattern of adverse events from ibuprofen at prescription-level (Rainsford

1999b) probably conforms to that of all NSAIDs; a diagrammatic representation of
the spectrum of adverse reactions from NSAIDs is shown in Fig. 6.2.
This has given rise to the concept that most NSAID adverse events can be
considered as class-related. Within this concept, it is clear that NSAIDs vary
considerably in their frequency or occurrence of individual side-effects. Some of
these are mechanism-related, that is to say related to the effects on prostaglandin
production via COX-1 inhibition for example in the GI tract and kidneys. However,
it has been argued that in relation to some of these effects, there are important
interactions between inhibition of COX-1 and COX-2, nitric oxide synthase and
physico-chemical factors which are of significance in the development of these
effects, so that they cannot all be considered to be mechanism-related.

6.7 Epidemiological Studies

A considerable number of studies have been performed since the introduction of

ibuprofen examining the relative safety and adverse events attributed to ibuprofen
compared with other NSAIDs. Many of these studies have involved examination of
6.7 Epidemiological Studies 103

the occurrence of adverse events e.g., in specific system organ classes (SOC) or
individual reactions in organ systems (e.g., gastro-intestinal ulcers and bleeding).
These studies are reviewed in subsequent sections of this report. There are
relatively few studies where overall “toxicity” of NSAIDs has been examined in
studies with any credibility that meet standards of epidemiological investigations
(e.g., sufficient numbers of study subjects or validity of databases).
Among the earlier studies investigating the overall occurrence of serious adverse
reactions was a study by Freis and co-workers (1991). They determined what they
described as the relative toxicity of a range of NSAIDs used in the treatment of RA
(rheumatoid arthritis) in the USA with data recorded in the Arthritis, Rheumatism,
and Aging Medical Information System (ARAMIS). This is an extensive database
developed by Fries and colleagues at Stanford University (Palo Alto, CA, USA),
and has been extensively used as a research system, including for prospective
comparative studies of drug toxicity factors accounting for the development of
ADRs in rheumatic patients (Fries 1996, 1998; Fries et al. 1991, 2004; Singh
et al. 1991; Fries and Bruce 2003).
It should be noted that at the beginning, these studies, patients (Fries 1996, 1998;
Fries et al. 1991; Singh et al. 1991) were undertaken in what can be described as the
“pre-coxib” era, i.e., before the introduction of the coxibs in 1999. This has
significance, since the coxibs had an appreciable if variable share of the NSAID
market world-wide, and thus influenced the overall patterns of use of the NSAIDs
in rheumatic and other musculo-skeletal conditions.
A summary is shown in Table 6.6 of the Standardised Toxicity Index from 11
most-frequently prescribed NSAIDs including ibuprofen in RA patients adjusted
for weightings, demographic factors etc., as part of a sensitivity analysis.
These data comprise toxicities from all patients in the database and those that
are considered “drug starts”. The results obtained with these differing periods of
drug exposure were essentially similar. Ibuprofen was in a group with the two
other salicylates, aspirin and salsalate, in having the lowest toxicity ratings. Other
reports from the same group have confirmed the low relative toxicity of ibuprofen
(Fries 1996, 1998).
An epidemiological safety investigation known as the Safety Profile of
Antirheumatics in Long-term Administration (SPALA) was undertaken during
the late 1980s to 1990 involving 30,000 rheumatic patients in participating centres
in West Germany (N ¼ 9), Switzerland (N ¼ 3) and Austria (N ¼ 4) (Brune et al.
1992). Of the ten most-frequently prescribed NSAIDs (N ¼ 36,147 prescriptions),
ibuprofen was the second most-frequently prescribed drug after diclofenac, and it
ranked fourth in the overall total number of ADRs among the ten drugs. As shown
in Table 6.7, ibuprofen was associated with the least number of reactions in the GI,
liver and biliary, and body as a whole systems.
These two studies show that ibuprofen at prescription-level doses given to
rheumatic patients has amongst the lowest toxicity ratings of frequently prescribed
NSAIDs.
104 6 General Safety Profile

Table 6.6 Toxicity Indices of 11 most-frequently prescribed NSAIDs, including ibuprofen in

patients with rheumatoid arthritis in data derived from five centres in USA and Canada analysed
from the ARAMIS database (Fries et al. 1991)
No. of Standardised toxicity index No. of Standardised toxicity index
Drug courses score, SEM (rank) courses score, SEM (rank)
Aspirin 1,669 1.19  0.10 (1) 410 1.37  0.35 (1)
Salsalate 121 1.28  0.34 (2) 107 1.30  0.30 (2)
Ibuprofen 503 1.94  0.43 (3) 238 2.34  0.55 (3)
Naproxen 939 2.17  0.23 (4) 327 3.43  0.58 (4)
Sulindac 511 2.24  0.39 (5) 220 2.89  0.45 (5)
Piroxicam 790 2.52  0.23 (6) 291 3.33  0.46 (6)
Fenoprofen 161 2.95  0.77 (7) 71 3.09  0.65 (7)
Ketoprofen 190 3.45  1.07 (8) 147 3.44  0.78 (8)
Meclofenamate 157 3.86  0.66 (9) 84 4.43  0.84 (9)
Tolmetin 215 3.96  0.74 (10) 120 4.83  0.78 (10)
Indomethacin 386 3.99  058 (11) 159 4.32  0.60 (11)
Reproduced with permission of Springer, publishers of Inflammopharmacology

Table 6.7 Adverse Reactions from 3 most commonly preseneted NSAIDS in major organ
systems in the safety profile of Antirhiumatics in Long-Term Administration (SPALA) study
Organ system classes Diclofenac Ibuprofen Indomethacin
No. of prescriptions 14,447 4,037 3,896
Gastrointestinal system 14.1 % 11.2 % 15.9 %
Skin and appendages 3.5 % 3.3 % 3.5 %
Central and peripheral NS 2.5 % 3.0 % 7.9 %
Liver and biliary system 2.2 % 0.7 % 1.8 %
Body as a whole—general 2.7 % 2.2 % 3.1 %
Data from Brune et al. (1992); from Rainsford (2009). Reproduced with permission of Springer,
publishers of Inflammopharmacology

6.8 Outcomes from Large-scale Clinical Trials

The studies with the coxibs conducted during the past decade were undertaken with
large numbers of patients under modern standards of clinical investigation and with
demanding requirements to establish safety in the GI, CV, and other organ systems
where serious adverse events with the NSAIDs often occur at low frequencies.
Ibuprofen was used in a number of these studies as a “bench standard” in recogni-
tion of it being accepted as amongst the safest of all NSAIDs that is still widely used
in rheumatic and other musculo-skeletal conditions. These studies have afforded
useful and high quality data for assessment of the adverse reaction and general
safety profile of ibuprofen in a setting where the drug is critically evaluated against
its competitors.
The individual adverse reactions in GI, CV, and other organ systems are
reviewed in detail in later sections. Here, the adverse reaction profiles for ibuprofen
and comparator drugs are viewed in a global sense, employing outcome measures
6.8 Outcomes from Large-scale Clinical Trials 105

that are considered good indicators of overall patient and physician acceptability for
safety and efficacy. It is important to note that withdrawal of an NSAID from use
can be the moult of serious adverse events as well as lack of efficacy.
In an evaluation of the tolerability of adverse events in clinical trials conducted
with the objective of assessing celecoxib (Celebrex®; Pfizer) in osteoarthritis and
rheumatoid arthritis, Moore et al. (2005) used data from the manufacturer’s data-
base (Pfizer) of clinical trials for comparing the occurrence of responses and
discontinuations in treatment in arthritis because of lack of efficacy or side-effects
of celecoxib with those of ibuprofen, diclofenac, naproxen, paracetamol, and
rofecoxib. Although there are limited data available on ibuprofen, the data reveals
that adverse event discontinuation with ibuprofen following 12 or 24 plus weeks of
treatment were similar to those from diclofenac or celecoxib when either the
number of events or the percentage of discontinuations is compared (Table 6.8).
These data should be evaluated in relation to the 95 % confidence interval ranges,
which notably overlap. The lack of efficacy was lowest with rofecoxib and
diclofenac and then ibuprofen, which had a low rate of discontinuation at what is
effectively a prescription level of the drug, then followed by celecoxib at doses of
100–400 mg/day when all of these drugs have been taken for 12 weeks. There was
a high rate of discontinuation when the drugs had been taken for 24 plus weeks
(Table 6.8). These results suggest that ibuprofen has a relatively low rate of adverse
event discontinuation compared with the other NSAIDs or coxibs, and that this is
not impacted assessments off lack of efficacy.
Similar data available from a large-scale randomised trial of the efficacy and
tolerability of rofecoxib versus ibuprofen in patients with osteoarthritis by Day and
co-workers (2000) showed that patients who received ibuprofen 2,400 mg/day for
6 weeks had rates of discontinuation through adverse events of approximately 12 %,
and through lack of efficacy of approximately 3 %, compared with those of
rofecoxib where the discontinuations from adverse events were approximately
half these values from ibuprofen whereas the lack of efficacy was comparable.
This is an important observation, since it has often been argued that the lower rates
of ADRs and toxicity of ibuprofen, including that in the GI tract, may be a
consequence of the drug being less potent, or that it may have differing patterns
of prescribing compared with that of other NSAIDs. The evidence is, however, that
the anti-inflammatory and analgesic effects of ibuprofen are comparable to that of
other NSAIDs when given at recommended prescription levels (Kean et al. 1999). It
is true that drugs such as diclofenac and ketoprofen are more potent prostaglandin
synthesis inhibitors than ibuprofen, and that the selective COX-2 activities of the
coxibs such as celecoxib and etoricoxib may moult in greater efficacy of these
drugs. However, it is more likely that the longer plasma half-lives of drugs such as
naproxen and celecoxib may contribute to these drugs having more sustained
analgesic and anti-inflammatory activity compared with that of ibuprofen, thus
indicating that it may be a question of the duration in circulation of these drugs
that accounts for any differences in their therapeutic effects. There is little available
evidence to support these concepts, and therefore they can only be considered
theoretical.
106 6 General Safety Profile

Table 6.8 Rates of discontinuation of NSAIDs during time of therapy of arthritis due to lack of
efficacy or from adverse eventsa
Percent Percent
discontinuations discontinuations
Treatment/dose due to lack of due to adverse
Duration (weeks) (mg/day) efficacy (95 % CI) events (95 % CI)
2,6,11 Placebo 17.6 (15.8–19.4) 5.0(4.0–6.0)
Celecoxib 400 7.7 (3.6–11.8) 3.2(0.5–5.9)
Diclofenac 100/150 2.4 (1.0–3.8) 9.4(6.9–11.9)
Naproxen 1,000 1.3 (0.1–2.5) 7.8(5.3–10.3)
Paracetamol 4,000 11.0(8.3–13.7) 5.4(3.4–7.4)
Rofecoxib 25b 1.6(0.8–2.4) 6.5(5.1–7.9)
12 Placebo 45.9(43.0–48.8) 6.2(4.8–7.6)
Celecoxib 400 8.0(7.4–8.6) 9.6(8.8–10.4)
Diclofenac 100/150 2.8(2.2–3.4) 7.8(7.0–8.6)
Ibuprofen 2,400 4.1(1.9–6.3) 10.7(7.4–14.0)
Naproxen 1,000 15.6(14.2–17.0) 13.2(11.8–14.6)
Rofecoxib 25b 0.8(0.0–2.4) 9.8(4.7–14.9)
24 Placebo – –
Celecoxib 400 8.0(5.1–10.9) 10.4(7.1–13.7)
Diclofenac 100/150 14.2(12.8–15.6) 25.5(23.7–27.3)
Ibuprofen 2,400 23.0(21.2–24.8) 23.0(21.2–24.8)
From: Moore et al. (2005). Reproduced with permission of the publishers from Rainsford (2009)
a
Data from Manufacturer’s (Pfizer) database by Moore et al. (2005).
b
Rofecoxib withdrawn in 2004.

In a large scale study the coxib, lumiracoxib 400 mg (Prexige®, Novartis) was
compared with ibuprofen 2,400 mg and naproxen 1,000 mg taken for 52 weeks in
18,325 patients randomised for the treatment of osteoarthritis (Farkouh et al. 2004;
Schnitzer et al. 2004). There were two major studies performed, one addressing the
CV events (Farkouh et al. 2004) and the other GI safety (Schnitzer et al. 2004), with
each of these having two sub-studies, one a comparison of lumiracoxib with
ibuprofen and the other comparing the former with naproxen. Only the data from
the ibuprofen sub-study is reviewed here, although it is interesting that aside from
CV events ibuprofen had safety lower than or comparable with naproxen in the
occurrence of other ADRs.
Here, the numbers of discontinuations and the reasons for withdrawal are
considered (Table 6.9).
It is apparent from this data that there were similar rates of discontinuation from
ibuprofen compared with that from lumiracoxib; the same was also evident with
naproxen. The losses were mainly due to adverse events, these being relatively low
compared with what might be expected in a study lasting 1 year. Likewise, the
losses due to unsatisfactory therapeutic effects were low and comparable with one
another.
These studies from large-scale clinical trials attest to the comparable rates for
withdrawals from trials with ibuprofen and the coxibs. They show that the newer
6.9 Adverse Events Attributed to Ibuprofen at Non-prescription (OTC) Dosages 107

Table 6.9 Percent discontinuations in the TARGET study: comparisons of ibuprofen with
lumiracoxib
Lumiracoxib vs ibuprofen sub-study
Lumiracoxib Ibuprofen
(n ¼ 4,399) (n ¼ 4,415)
Discontinued 40 % 44 %
Reason for discontinuation
Adverse events 16 % 18 %
Abnormal laboratory values 1% 1%
Abnormal test procedure results <1 % <1 %
Unsatisfactory therapeutic effect 9% 10 %
Patient’s condition no longer requires study drug <1 % <1 %
Protocol violation 4% 4%
Patient withdraw consent 8% 9%
Administrative problems <1 % 1%
Lost to follow-up <1 % <1 %
Death <1 % <1 %
From Schnitzer et al. (2004). Reproduced with permission of the publishers from Rainsford (2009)

coxibs are neither more effective nor less likely to produce adverse reactions
leading to withdrawals from studies comparing them with ibuprofen.

6.9 Adverse Events Attributed to Ibuprofen at Non-prescription

(OTC) Dosages

A considerable number of studies have been reported comparing the adverse

reactions from non-prescription (OTC) doses of ibuprofen with placebo, paraceta-
mol (acetaminophen) or other analgesics. These studies have been performed using
a variety of methodologies and study designs.
Earlier reviews of published literature have reported OTC ibuprofen causes
adverse events (AEs) comparable with paracetamol or placebo (Furey et al. 1993;
DeArmond et al. 1995; Moore et al. 1996).
A systematic data analytical review of published studies compared OTC ibupro-
fen with paracetamol where the drugs were taken as single doses or daily dosages
up to 10 days (Rainsford et al. 1997; Table 6.10; Fig. 6.3). The subjects in these
studies were either healthy volunteers, or those who experienced various types of
acute pain or chronic inflammatory conditions. Some studies involved comparisons
with other analgesics/NSAIDs or placebo. Thus, there was a wide range of
conditions in which the treatments were compared. The results showed that there
were no significant differences between ibuprofen and paracetamol in occurrence of
AEs after single or multiple daily doses taken for up to 10 days (Fig. 6.3) although
there was a trend to increased GI AEs in both groups with increased duration of
drug intake. There did not appear to be any discernible differences in AEs in
108 6 General Safety Profile

Table 6.10 Overall adverse event rates and exposure grouped by duration of dosing
Overall Total Total
Total percent with number with number of
Days No. of number of adverse adverse adverse
dosed Drug groups Exposurea patients events eventsb eventsc
1 Paracetamol 27 0 4,644 10 444 479
1 Ibuprofen 25 0 2,312 6 148 172
1 Paracetamol 11 420 420 10 43 49
1 Ibuprofen 5 215 215 8 18 22
2–7 Paracetamol 15 2,882 687 8 57 64
2–7 Ibuprofen 9 1,015 227 9 20 29
8–30 Paracetamol 6 5,496 207 19 39 39
8–30 Ibuprofen 9 5,960 272 19 52 52
31–90 Ibuprofen 5 6,504 85 29 25 29
Total Paracetamol 59 8,798 5,958 10 583 631
Total Ibuprofen 53 13,694 3,111 8 263 304
a
Number of patient days.
b
Adverse events grouped as the total number of patients having these events.
c
Adverse events grouped as the total of all recorded adverse events.
From: Rainsford et al. (1997). Reproduced with permission of Springer, publishers of
Inflammopharmacology

Fig. 6.3 Percent of ADRs reported in studies where OTC doses of ibuprofen were compared with
aspirin and paracetamol (Rainsford 2011, unpublished)

different patient groups, although the number of patients in each of the groups was
probably not sufficient to meet statistical requirements for being assessable. As
paracetamol may be considered a “benchmark” drug for low propensity to cause
serious GI events, this study suggests that as there was no differences in GI AEs
between ibuprofen and paracetamol at OTC dosages, ibuprofen can be considered
to have low risk of GI reactions comparable that are with paracetamol.
6.9 Adverse Events Attributed to Ibuprofen at Non-prescription (OTC) Dosages 109

Table 6.11 Number (N) and percentage (%) of subjects experiencing a severe adverse reaction
over all body systems, the digestive system, and the body-as-a-whole system
All body systems Digestive system Body-as-a-whole system
Placebo Ibuprofen Placebo Ibuprofen Placebo Ibuprofen
Pool studies N (%) N (%) N (%) N (%) N (%) N (%)
Single-day studies 7/318 (2.2) 1/319 (0.3) 2/318 (0.6) 1/319 (0.3) 5/318 (1.6) 0/319 (0.0)
Multiple-day studies 59/775 (7.6) 38/775 (4.9) 21/775 (2.7) 14/775 (1.8) 36/775 (4.6) 21/775 (2.7)
All studies 66/1,093 (6.0) 39/1,094 (3.6) 23/1,093 (2.1) 15/1,094 (1.4) 41/1,093 (3.8) 21/1,094 (1.9)
From Kellstein et al. (1999). Reproduced with permission of the publishers from Rainsford (2009)

Using a similar analytical approach to data derived from various trials, these data
have been updated and extended to include studies of comparisons of ibuprofen
with aspirin as well as paracetamol (Rainsford 2011; unpublished studies).
Kellstein and co-workers (1999) performed a meta-analysis of reports of
randomised, double-blind, placebo-controlled parallel-group studies, having
initially reviewed published literature and established that only eight studies, all
of which were unpublished but claimed as independent studies performed under the
auspices of Whitehall–Robbins Healthcare, met the criteria as specified above
according to GCP conditions (Table 6.11). AEs were codified according to the
conventional Coding Symbol Thesaurus for Adverse Reaction Terms (COSTART),
with the exception of abdominal pain, which was “conservatively” assigned to
“body as a whole” digestive system. This may in fact have disguised the importance
of this AE, since it is a relatively frequent event in trials with NSAIDs and
paracetamol.
The eight selected studies were in mixed patient groups comprising three in OA
pain, two in delayed onset muscle soreness (DOMS), and one each in sore throat
pain, dental pain, and a study of maximal use safety and tolerability (MUST) of
non-prescription ibuprofen. The dosages ranged from 400 mg b.i.d. (800 mg/day;
two studies) and 400 mg t.i.d. (1,200 mg/day; six studies) with a duration of intake
between 1 and 10 days; the primary purpose was to compare the effects of single-
dose with multiple daily doses of ibuprofen with placebo. The subjects covered a
wide range of ages (12–97 years) and racial groups of both genders in a total of
1,094 ibuprofen and 1,093 placebo-treated subjects.
Table 6.11 summarises the serious AEs from this study. The principle outcomes
can be summarised thus:
(a) The overall number of AEs, those in body-as-a-whole, and those in the diges-
tive system were greater after multiple compared with single doses of ibuprofen
and placebo.
(b) There were no differences in AEs in all body systems and in the digestive
system after single doses of ibuprofen compared with placebo, or in the
digestive system and body-as-a-whole after multiple doses.
(c) In an analysis of individual AEs by COSTART, dizziness was identified among
the central nervous system reactions to be significantly increased after multiple
doses in the ibuprofen (2.5 %) compared with placebo groups (1.4 %), there
being no differences after single doses of the treatments.
110 6 General Safety Profile

(d) Overall tests for homogeneity among the study groups using the Breslow–Day
statistical test showed no significant differences between the occurrences of all
individual AEs over all the study groups.
(e) Serious AEs over all categories were fewer in the ibuprofen compared with
placebo groups in both the single and multiple dosage categories. Urinary tract
infections, while rare, were more frequent in ibuprofen than placebo groups.
The reason for higher rates of AEs from placebo in “all body systems” and
“body-as-a-whole” compared with ibuprofen is attributed to a larger number of
patients in the placebo group reporting headaches, neck pain and malaise. The
lower rates of these reactions in the ibuprofen groups are consistent with its
analgesic activity.
While the studies employed in this meta-analysis are from unpublished
investigations that have not been subjected to peer-review, they are none-the-less
from investigations that were performed according to GCP requirements, and
would have been in the company database that is subject to scrutiny by the US FDA.
Another study from the same company involved a prospective investigation of
GI tolerability of the maximum daily OTC dose of 1,200 mg ibuprofen compared
with placebo taken for 10 days in 1,246 healthy volunteers (Doyle et al. 1999).
A total of 19 % of ibuprofen-treated subjects (67 of 413) and 16 % of placebo-
treated individuals (161 of 833) experienced GI AEs, there being no significant
differences between the two groups. The GI adverse reactions were dyspepsia,
abdominal pain, nausea, diarrhoea, flatulence, and constipation. Occult blood tests
were positive in 1.4 % of all subjects, there being no differences between the two
treatments in the occurrence of these reactions. The results in this prospective study
confirmed the data from previous retrospective studies, and showed that ibuprofen
at OTC dosages has comparable GI reactions to placebo.
In a large-scale general practice based investigation (known as the PAIN Study)
in 4,291 patients in France, Le Parc et al. (2002; Moore et al. 2002) compared the
tolerability of 7 days treatment of ibuprofen (up to 1.2 g/day) with aspirin (up to 3 g/
day) for relief of musculoskeletal conditions. So-called “significant” AEs were
reported in 15.0 % of patients who took ibuprofen, 17 % on paracetamol and
20.5 % on aspirin; the difference between the ibuprofen and paracetamol groups
being not statistically significant but significantly different from the aspirin
group (Tables 6.12 and 6.13). GI AEs were fewer in the ibuprofen group (4.4 %)
than in the paracetamol (6.5 %) or aspirin (8.6 %) groups, the differences in all
groups being statistically significant from one another. In the non-musculoskeletal
group there were similar trends, although there was no occurrence of serious
digestive AEs.
Using the data acquired in the abovementioned PAIN Study, Moore and co-
workers (2003) performed an assessment of risk factors that accounted for the
development of, or association with AEs. By employing multivariant logistic
regression analysis of 8,633 patients, they identified the following risk factors: (a)
indication (e.g., musculo-skeletal pain, sore throat, colds and flu, menstrual pain,
headache), (b) concomitant medications, (c) history of previous GI disorders, and
6.9 Adverse Events Attributed to Ibuprofen at Non-prescription (OTC) Dosages 111

Table 6.12 Most frequent significant adverse events by COSTART body systems and terms
Systems/terms Ibuprofen (%) Aspirin (%) Paracetamol (%)
Body as a whole 5.8 7.4 5.7
Digestive system 3.6 4.7 4.3
Nervous system 1.0 2.2 1.1
Respiratory system 1.2 1.5 1.3
Abdominal pain 2.4 5.1 2.7
Nausea 1.6 1.8 1.3
Dyspepsia 0.9 1.9 1.3
Headache 1.2 1.1 1.6
From Le Parc et al. (2002), Moore et al. (2002)

Table 6.13 Rates of adverse events by intensity

P-value Confidence limit*
Ibuprofen Aspirin Paracetamol (ibuprofen vs (ibuprofen vs
(%) (%) (%) aspirin) paracetamol)
SGAE 12.0 15.7 12.3 0.02 2.4
All AE 16.0 22.3 19.0 <0.001 0.1
Severe AE 3.6 3.7 2.9 NS 2.2
Moderate AE 6.9 10.3 8.5 <0.01 0.7
AE leading to 4.3 6.5 5.1 0.033 0.9
discontinuation
Data from the PAIN studies by Moore et al. (2002) and Le Parc et al. (2002)
AE adverse event, SGAE significant adverse event
*One-sided 96.5 % confidence limit for difference between ibuprofen and paracetamol;
equivalence is concluded if the upper limit of the confidence interval of the difference is <2.7 %
Reproduced with permission of the publishers from Rainsford (2009).

(d) female sex. Age was not a risk factor. There were fewer clinically significant
risk factors for GI AEs in the ibuprofen compared with paracetamol groups. The
overall conclusion was that the main risk factor was concomitant medications.
A meta-analysis was undertaken by Ashraf and co-workers (2001) in elderly
(>65 years) osteoarthritic patients in which the incidence of adverse events
(COSTART-coded) from ibuprofen 1,200 mg daily with those that received pla-
cebo. Following an initial assessment of the quality of papers, three independent
clinical trials that had been performed by Whitehall–Robbins (USA) were selected
in which the drug treatments were for 10 days. The pooled overall incidence of
adverse events was 29.4 % with the ibuprofen group (N ¼ 197 patients) and 29.0 %
in the placebo group (N ¼ 210 patients), with the three studies individually
showing no statistically-significant differences. The percentages of adverse events
in the organ systems were for: (a) “body as a whole”—12.7 % ibuprofen vs 9.5 %
placebo, (b) digestive system—12.2 % ibuprofen vs 13.3 % placebo, and (c)
nervous system—10.2 % ibuprofen vs 8.1 % placebo, the differences being not
statistically significant. This study is important in showing that ibuprofen at OTC
doses has a relatively low incidence of adverse events in elderly OA patients, a
group who frequently self-administer the drug.
112 6 General Safety Profile

Several investigations have been performed in what could be regarded as “at

risk” patients; either those admitted to hospitals for clinical investigation (and who
could be regarded as being at “suspect” risk because of indicative symptoms
requiring investigation), or patients with rheumatic diseases. The focus of these
studies has been to identify the risks of serious AEs in the GI tract from intake of
OTC analgesics. The rheumatic patients may have increased susceptibility to GI
events from intake of NSAIDs as a consequence of their disease, concurrent disease
(e.g., diabetes, CHD), concomitant medications (either anti-rheumatic, e.g.,
steroids, or other agents to control diabetes, hypertension, CV disorders, or subnor-
mal renal function), as well as socio-psychological stress or Helicobacter pylori
infection. Since many patients with rheumatic disorders take OTC analgesic
medications on a self-administered p.r.n. basis and as a reflection on costs of
prescription NSAIDs which for the elderly or members of lower socio-economic
classes could be a major issue, use of OTC analgesics in these patients can be
regarded as one of the “real-world” uses of these drugs.
Among the reports in GI suspect risk patients, Blot and McLaughlin (2000)
reported investigations conducted by a mail survey of members of the American
College of Gastroenterology, ACG, designed to identify risks of GI bleeding
associated with intake of analgesics at OTC dosages within the previous week of
drug intake. The methodology involved data collected from the ACG Registry (N ¼
627 patients) and “procedure-matched” endoscopy controls. Suspect factors (e.g.,
tobacco, alcohol intake, etc.) were also identified. These hospitalised patients had
a variety of upper or lower GI conditions that led to bleeding in the OTC analgesic
group but no bleeding in the control group. The number of patients in these groups
might be considered relatively small, and questions can be raised about the statisti-
cal validity of the subgroup analysis of risk factors. Moreover, the nature of the data
collection increases the bias in the cohorts examined.
The cases tended to be older subjects (mean 60 years) compared with controls
(55 years), with 45 % cases being over 65 years compared with 33 % controls, and
they were more often male cases (63 %) compared with controls (49 %). The
balance of races was comparable, with about two-third being non-Hispanic whites.
GI risk, especially in the upper tract, was greater in those that had consumed
alcoholic beverages, this being increased in smokers, but cigarette smoking was
unrelated to GI risks.
Of the major analgesics, reported intake of drugs was associated with GI
bleeding in 9.5 % aspirin-takers, 4.2 % ibuprofen- takers, and 5.4 % paracetamol-
users. A considerable number of patients had taken mixtures of two analgesics or
prescribed NSAIDs. It should be emphasised that the numbers of patients were
relatively small among the single-analgesic users (56 on aspirin, 25 on ibuprofen,
and 32 on paracetamol), so it is questionable to ascribe causality to individual
drugs. None-the-less, these data are instructive at least for assessment of potential
GI bleeding in at-risk patients. It is interesting that paracetamol was associated with
GI bleeding, as it is normally considered a low-risk GI “safe” drug. In this complex
group of patients with evident underlying disease, it was clear that ibuprofen is
somewhat safer than the other two analgesics.
6.10 ADR Risks in Oriental Populations 113

In conclusion: (a) the studies at prescription-level doses show that ibuprofen has
amongst the lowest risks for adverse events, (b) this drug is as good in safety and
efficacy terms as any of the newer coxibs (which were designed to have lower
incidence of adverse reactions), and serious events are rare, and (c) at OTC doses
ibuprofen has low or at least amongst the lowest rating for risks of developing
adverse reactions compared with other analgesics.

6.10 ADR Risks in Oriental Populations

Shi and co-workers (2003) reported a meta-analysis of adverse drug reactions and
efficacy of NSAIDs in patients with osteoarthritis and rheumatoid arthritis in
clinical trials that were reported in 19 articles in Chinese medical journals in the
period 1990–2001. A total of 2,925 patients were enrolled for safety evaluation and
1,723 for efficacy. The therapeutic effectiveness rates were somewhat comparable,
being in a range of about 65–79 % across all seven NSAIDs. Ibuprofen was
amongst the more efficacious drugs with an efficacy rating of 77 % (95 % CI
70.7–83.8 %) and was only slightly, but not statistically significantly, exceeded by
nimesulide with a rating of 79.8 % (95 % CI 75.7–84.0 %). The rates of ADRs were
about 10–20 %, with ibuprofen being 16.7 %, all these reactions being time-
dependent.
The same group performed a retrospective risk factor analysis of arthritic
patients who were receiving long-term treatment over the period of Jan 1, 1996 to
Jan 1, 2001 with ibuprofen which was obtained from outpatient clinics of hospitals
in the Shanghai region (Shi et al. 2004a). Extensive clinical, demographic, and
socio-economic data were collected, and risk factors were calculated using univar-
iate correlation analysis. Of 447 patients enrolled in the study, 144 (32.3 %) had
ADRs to ibuprofen. The female to male ratio was approximately 77 %. Approxi-
mately half of the patients had epigastric distress, and a further one-fifth had other
GI symptoms. Malaena was present in two subjects (1.4 %). Overall, gastro-
intestinal toxicity was evident in 115 patients (79.9 %) and was severe in three
subjects. Most of the ADRs were assessed to be mild (45.8 %) to moderate
(44.1 %), and 9.7 % were severe. The dosage level varied considerably, from 300
to 1,800 mg/day. Risk factor analysis from this study is summarised in Table 6.14.
It is important to note that most of the patients were receiving second-line anti-
rheumatic drugs as well as Chinese traditional medicines (CTM). This multiple use
of drugs contributed to the incidence of ADRs, as noted in Table 6.15. Most of the
patients were older (>55 years). The average period of dosage was around 2 years,
with the shortest being 1 and the longest being 5 years. Various factors contributed
to the development of ADRs, including smoking and stress. These data suggest that
the patients were quite severely rheumatic, as they required other anti-rheumatic
drugs along with a range of doses of ibuprofen. Being outpatients, they presumably
were being treated for rheumatic conditions in the long-term. The period of dosage
114 6 General Safety Profile

Table 6.14 Odds ratios (OR) of risk factors from ADRs attributed to ibuprofen in rheumatic
outpatients from hospitals in Shanghai
95 % confidence interval
No. Variables OR Upper limit Lower limit
1 Concomitant drug therapy 0.25 0.122 0.512
2 Smoking 0.564 0.334 0.915
3 Acceptance to unchangeable things 0.587 0.398 0.864
4 In general, how would assess your health 2.047 1.217 3.44
5 Do you drink cola everyday? 1.303 1.012 1.677
6 Compared to 6 months ago, how would 1.006 1.341 2.352
you rate your health in general now?
7 Impact of health status on activity (first 0.815 0.72 0.921
principle component)?
8 Impact of financial stress on your QOL 1.114 1.017 1.22
From Shi et al. (2004a). The variables relate to answers from questions presented to patients

with ibuprofen (1–5 years) was quite extensive. The occurrence of GI ADRs was
similar to that in non-Chinese populations, although it is not known if the severity
of the arthritic condition contributed to the development of the ADRs.
In another study in which the same methodology was employed, Shi et al.
(2004b), examined the effects of 12 NSAIDs (including aspirin) in 1,002 patients
with arthropathies, principally with RA (84.5 %) and a lesser number with OA
(5.7 %) and other miscellaneous conditions. The study was a retrospective epide-
miological survey performed according to ICH GCP guidelines, and involved
structured patient interviews. Ibuprofen was the second most-frequently taken of
the six NSAIDs. The occurrence of ADRs in patients who took ibuprofen was
32.3 %, compared with diclofenac 42.5 %, indomethacin 48.6 %, nimesulide
44.7 %, meloxicam 39.9 % and nabumetone 33.8 %. The most frequent ADRs
were stomach discomfort (33.0 %), and other GI symptoms and gastric bleeding
occurred in 2.1 % of patients. Most patients had taken the drugs for about 2 years.
When the risk factors were taken into account, those patients that took ibuprofen
showed significant benefit and quality of life benefits. The authors point out that this
was the first and most extensive study of the effects of NSAIDs in chinese arthritic
patients. The results show a pattern of ADRs not unlike that seen in studies in other
parts of the world. Thus, the predominance of GI effects is apparent in rheumatic
patients receiving NSAIDs. The occurrence of other ADRs seems lower than that
seen in other studies, but this may reflect the sensitivity of the epidemiological
procedures that were employed.
In a literature analysis of 80 cases of ADRs associated with ibuprofen, Liu and
co-workers (2008) undertook a survey of Chinese medical journals using literature
identified in the Chinese Journal Net. The patients who received ibuprofen had
a wide variety of conditions. Most took a sustained-release formulation (76.25 %)
and the remainder took conventional tablets (22.5 %) and other types. About 11 %
of patients took combinations of ibuprofen with other drugs, including some
NSAIDs. The most common ADRs were allergic reactions (36.25 %) and those
6.10 ADR Risks in Oriental Populations 115

Table 6.15 Twenty-five most frequent adulterants in traditional Chinese medicines

Rankings of Detected synthetic Frequency of
adulterations therapeutic substances detection
1 Caffeine 213
2 Paracetamol/acetaminophen 167
3 Indomethacin 152
4 Hydrochlorothiazide 127
5 Prednisolone 91
6 Chlorzoxazone 87
7 Ethoxybenzamidea 66
8 Phenylbutazone 26
9 Betamethasone 23
10 Theophylline 22
11 Dexamethasone 20
11 Diazepam 20
13 Bucetin 19
14 Chlorpheniramine maleate 16
14 Prednisone 16
16 Oxyphenbutazone 14
17 Diclofenac sodium 13
17 Ibuprofen 13
19 Cortisone 11
19 Ketoprofen 11
21 Phenobarbital 10
22 Hydrocortisone acetate 9
24 Niflimic acida 9
25 Diethylpropion 6
25 Mefenamic acid 6
25 Piroxicam 6
25 Salicylamide 6
a
Synthetic therapeutic substances not available in the United States.
The remaining frequencies of adulterations detected (FAD) in this survey are:
FAD ¼ 4: methylprednisolone, nicotinamide
FAD ¼ 3: alluprinol, aminophylline, diphenhydramine, chlordiazepoxide, propanolol,
raniditine
FAD ¼ 2: amino, aspirin, chlormezanone, dextromethorphan, methyltestosterone,
oxymetholone, sorbic acid, stulfanilamide, thiamine disulfide, thiamin
propyldisulfide
FAD ¼ 1: acetohexamide, barbital, benzafibrate, carbazepine, carisoprodol chloramphenicol,
cholione bitartrate, cimetidine, cyproheptadine, dilantin, flopropeione, flourouracil,
glibenamide, hydrazine, lorazepam, mephenesin, meprobamate, methocarbamol,
phenacetin, phenylephrine, riboflavin, tetracycline, vitamin E
From Huang et al. (1997) with permission of Sage Publications, publishers of Journal of Clinical
Pharmacology

in the digestive system (13.75 %), including four cases of GI haemorrhage, five
cases of asthma (including one fatality), and a variety of other conditions. The
ADRs occurred predominantly in the elderly, and most patients had rheumatic
disease, with others having complex histories. Cases of hypersensitivity with
angioedema and urticaria have been reported in patients from Singapore receiving
116 6 General Safety Profile

Table 6.16 Source of traditional Chinese medicines and frequency of adulterations from each
source
No. of No. of adulterated Percentage of
Source samples (%) samples (%) adulteration
TCM hospitals 111 (4.3) 10 (1.6) 9
TCM clinics 860 (33.0) 177 (28.6) 20.6
TCM drugstores 478 (18.0) 122 (19.7) 25.5
Chiropractors 200 (7.7) 92 (14.9) 46
Herbalists 81 (3.1) 28 (4.5) 34.6
Peddlers 46 (1.8) 22 (3.6) 47.8
Quacks 179 (6.7) 59 (9.5) 33
Others 654 (25.1) 108 (17.5) 16.5
Total 2,609 (100.0) 618 (100.0) 23.7
TCM Traditional Chinese medicine
Reproduced from Huang et al. (1997) with permission of Sage Publications, publishers of Journal
of Clinical Pharmacology

NSAIDs and paracetamol (Kidon et al. 2005). It may be that young Asian children
who are atopic have hypersensitivity to NSAIDs. There was no attempt to link these
hypersensitivity events to particular drugs. Likewise, retrospective studies have
identified NSAIDs among a range of drugs that are associated with angioedema in
Thai subjects, with diclofenac and ibuprofen being the most frequently implicated
(Leeyaphan et al. 2010). The frequency of this association may be related to these
drugs being employed most for therapy. HLA phenotypes and cytokines have been
linked to drug sensitivities in Chinese populations (Kim et al. 2010), though the
exact basis of this and drug types have not been fully evaluated.

6.11 Potential Concerns with Chinese Traditional

and Herbal Medicines

The data available on the associations of ibuprofen with the occurrence of specific
adverse events in Chinese populations is relatively limited. This is partly because
of: (a) variations in the regulatory requirements for reporting ADRs in different
countries with Chinese populations, (b) differences in the nature of the databases in
various countries, whether these are maintained by government agencies and/or
companies, and (c) the patterns of drug prescribing, dispensing and use of concom-
itant medications. The latter aspect is particularly relevant, since physicians in these
countries frequently prescribe or recommend and patients frequently self-medicate
with traditional medicines (CTM). Among these are a wide range of Chinese herbal
medicines (Ergil et al. 2002), many of which are widely used for treating pain and
inflammatory conditions, especially in Hong Kong (Lam et al. 1994). Chinese
patients base their decisions about using herbal medicines on family traditions
and self-medication, as well as professional and quasi-professional advice and
6.11 Potential Concerns with Chinese Traditional and Herbal Medicines 117

recommendations (Ergil et al. 2002). CTM is legal in Hong Kong, China, Taiwan,
Vietnam, Japan, Korea, and many countries in Europe, as well as in the USA (Ergil
et al. 2002). Quasi-professional advice is normally given in traditional herb stores,
and this has been widespread among Chinese communities worldwide for centuries
(Ergil et al. 2002). In contrast to the professional training by CTM practitioners, that
of quasi-professionals varies considerably (Ergil et al. 2002). It is against this
background of the established use of CTM that various potential aspects concerning
herb–ibuprofen interactions require consideration.
One major issue deserves consideration and this concerns the evidence for the
widespread practice of adulteration of Chinese herbal preparations, both with
NSAIDs (including ibuprofen) but also a wide range of other established medicines
(Huang et al. 1997; Ergil et al. 2002; Li et al. 2007; Lu et al. 2010; Table 6.16) and
natural product components (including steroids) which have varying anti-
inflammatory activities (Zheng et al. 2003; Sato et al. 1998; Wang et al. 1997;
Wang and Mineshita 1996; Gong and Sucher 2002; Yang et al. 2006; Liu et al.
2007, 2008; Xie et al. 2008; Wang et al. 2009; Xu et al. 2009a, b).
In an extensive survey of the adulteration of CTMs with established therapeutic
medications, Huang et al. (1997) showed that these were available from both
professional and quasi-professional sources as well as from herbalists, “peddlers”,
and “quacks” (Table 6.16).
The potential for untoward herb–NSAID or herb–medication interactions is
highlighted in Table 6.17 (Ergil et al. 2002). The toxicity of aconitine (present in
Cao Wu; Chan et al. 1993) is of particular concern, especially as small amounts of
this material which have not been properly prepared (i.e., by aqueous hydrolysis to
aqlycone) can be fatal. Gastrointestinal irritation is evident from the anthroquinone
glycosides and oxalic in rhubarb (of Da Huang; Table 6.17) and may exacerbate the
GI effects of ibuprofen and other NSAIDs. The vascular effects of Ephedra sinica
and Glyechiza glabara (Table 6.18) might be expected to interact with the
prostaglandin-inhibitory actions of NSAIDs such as ibuprofen. Moreover, the
effects of herbal medicines on the functions of cytochromes P450 (Foster et al.
2002), especially the CYP2C9 (Mo et al. 2009) and CYP C28 (Lai et al. 2009)
isoforms, may have particular consequences for the cytochrome oxidative metabo-
lism of ibuprofen and other NSAIDs that are oxidised via these pathways.
These issues about herbal–drug interactions that may affect the safety and effi-
cacy of ibuprofen are highlighted because there may be a case for recommending
that CTM practitioners, quasi-professionals, pharmacists, and herbalists should be
specifically educated and trained to advise patients or customers that they should
not take CTMs with ibuprofen and other NSAIDs or analgesics because of the risks
of herbal preparations interacting in an untoward manner with these drugs. More-
over, labelling of packages and advice to patients taking ibuprofen (as well as other
NSAIDs or paracetamol) should include specific warnings not to take these drugs
with CTMs/herbal preparations.
Table 6.17 Risks of reactions or drug-herb interactions from constituents of Chinese herbal medicines (TCM)
118

TCM Medicinal agent Common name Plant species Relevant constituent Risk/interaction
Ma Huang Ephedra Ephedra sinica Ephedrine, pseudoephedrine Can exacerbate hypertension, palpitations,
and dizziness. May interact with
monoamine oxidase inhibitors,
sympathomimetics, and epinephrine
Du Huo Pubescent angelica Angelica pubescens Effect may be associated Potentially photosensitizing
with furocoumarins
Cao Wu Aconite Aconitum carmichaeli, Aconitine Highly toxic in unprepared form; death
A. kuspexoffi can occur as a result of small doses of
unprepared forms
Gau Cau Licorice Glycrrhiza glabra Glycyrrhizin, glycrrhetinic acids Hypokalemia, sodium retention producing
hypertension, edema, and headache
with prolongled use or a high dose.
Synergistic effects with prednisolone,
hydrocortisone, and thiazides. May
counteract oral contraceptives
Da Huang Rhubarb Anthroquinone glycosides, Irritation of gastrointestinal tract,
oxalic acid abdominal cramping, nausea, kidney
irritation; should be avoided in
pregnancy
Ren Shen Ginseng Panax ginseng Ginsenosides Ginseng Abuse Syndrome (contraversial
syndrome, since may due to
6

adulterants; syndrome, rarely reported,

is considered to include hypertension,
anxiety, insomnia); interaction with
phenelzine sulfate reported
TCM Traditional Chinese medicine
Reproduced from Huang et al. (1997) with permission of Sage Publications, publishers of Journal of Clinical Pharmacology
General Safety Profile
6.12 Adverse Events and Safety in Paediatric Populations 119

Table 6.18 Incidence rates of adverse experiences between ibuprofen and paracetamol by age
Younger children Older Children
Ibuprofen (%) Paracetamol (%) Ibuprofen (%) Paracetamol (%)
Body system Type of AE (n ¼ 7,381) (n ¼ 9,600) (n ¼ 12,730) (n ¼ 3,133)
Any Any 17.6* 15.0* 11.9* 10.7
Body as a Pain in office 0.4* 0.2* 0.2 0.1
whole Procedure 0.0** 0.01 0.01 n/c 0
Digestive Any 3 2.1 2.1* 1.2
Abdominal 0.5* 0.1 0.6* 0.2
pain
Nervous Hyperkinesia 0.7* 0.1 0.4 0.4
Insomnia 0.6* 0.1 0.2 0.1
Stupor 0.0** 0.01 0.0 n/c 0
Twitch 0.0** 0.01 0.0 n/c 0
Respiratory Rhinitis 2.1 3.5 1.1* 1.5
Atelectasis 0.0* 0.03 0.0 n/c 0
Skin Any 2.6* 1.3 1.3 1.4
Sweat 0.05* 0 0.0 n/c 0
Special Any 3.9** 3.8 2 1.9
senses Otitis media 3.5* 3.4 1.7 1.4
*Statistically significant at P  0.05.
P values based upon CMH test controlling for health status at enrolment and first time use of study
education
**P  0.001.
*P  0.01 or 0.05.
N/c not computed

6.12 Adverse Events and Safety in Paediatric Populations

The safety profile of ibuprofen has been extensively evaluated in paediatric clinical
trials of fever and/or pain and in a number of trials or in critical reviews (Walson
et al. 1989; Rainsford et al. 1997, 1998, 1999, 2001; Diez-Domingo et al. 1998). All
have shown the low incidence of serious and non-serious adverse events (AEs) with
ibuprofen. While these data are useful, it is only in large-scale population-based
studies that it is possible to accrue sufficient data to obtain a sound basis for safety
evaluation.
In a series of publications, Lesko and Mitchell (1995, 1997; Lesko et al. 2002)
have compared the safety of ibuprofen and paracetamol with a focus in particular on
ibuprofen, in practitioner-based clinical trials, the methodologies of which were
reviewed by Lesko and Mitchell (1995). These studies have been supported by both
leading companies producing the antipyretics in the USA as well as the US FDA,
US NIH, and other pharmaceutical companies supporting the Sloane Epidemiology
Unit of Boston University School of Medicine (Brookline, MA, USA) where these
studies have been based. Among these studies, the use of advisory groups has been
employed, which helps retain the abilities to critically assess data and ensure proper
conduct of trials.
120 6 General Safety Profile

In their practitioner-based population study of 2,015 primary care physicians

throughout the continental United States of America, Lesko and Mitchell (1995)
undertook a randomised, double-blind, office-based paracetamol (acetaminophen)-
controlled trial: a total of 84,192 patients aged 6 months to 12 years of age were
randomly assigned to receive ibuprofen at 5 or 10 mg/kg suspensions (Children’s
Motrin®, McNeill), or 12 mg/kg paracetamol suspension (Calpol®, Burroughs
Wellcome) for the treatment of acute febrile illness. The study provided for a
4-week follow-up period to determine the occurrence of side-effects. The primary
outcome measures were hospitalisations for acute GI bleeding, acute renal failure,
and anaphylaxis. The occurrence of Reye’s syndrome was also monitored. Second-
ary outcomes included identification of previously unrecognised serious reactions.
Two patients died; one who had received paracetamol who died in a road accident,
and the other who had ibuprofen who died from bacterial meningitis; both these
fatalities could be considered to be unrelated to the drugs. A total of 1 % of the
patients were admitted to hospital in the 4 weeks following enrolment. Four
children were hospitalised for acute GI bleeding that was due to ibuprofen (two
from 10 mg/kg and two from 5 mg/kg of the drug) giving a risk of GI bleeding as
7.2 per 100,000 (95 % CI 2–38 per 1,000,000) with the risk from paracetamol being
zero, the difference being not statistically significant. Gastritis/vomiting was
observed in 20 patients that had received ibuprofen, with a risk of 36 per 100,000
(95 % CI 22–55) and in six patients on paracetamol, with a risk of 21 per 100,000
(95 % CI 7.9–46). There were 24 patients who had received paracetamol who had
asthma (RR ¼ 85, 95 % CI 55–150) and 44 on ibuprofen (RR ¼ 80 per 100,000;
95 % CI 57–110), thus showing there was no difference in risks between the two
drugs. There was no risk from Reye’s syndrome, acute renal failure, or anaphylaxis
among 55,785 children that received ibuprofen. Low white blood cell count was
observed in eight children that had received ibuprofen (but the causality could not
be established) and none in the paracetamol group. The authors considered that the
risks from less severe outcomes could not be ascertained because of the statistical
statistical power of the study. This study attests to the low risks for serious GI, renal,
or anaphylactic events from ibuprofen, and a lack of association with severe renal or
asthmatic events.
In what is probably the largest study designed to investigate the safety of
analgesics in children 2 years old, Lesko and Mitchell (1999) used data from
the Boston Collaborative Fever Study in a total of 27,065 febrile children who were
randomised to receive 5 mg/kg or 10 mg/kg ibuprofen or 12 mg/kg paracetamol
suspensions.
The study was double-blind and practitioner-based, with children being eligible
if, in the opinion of the attending physician, their illnesses warranted treatment with
an antipyretic; duration and height of fever were not criteria for participation.
Follow-up was achieved by mailed questionnaire or telephone interviews. The
most common cause of fever in children 6 months was otitis media (45 %),
upper respiratory tract infection (40 %), pharyngitis (15 %), lower respiratory
tract infection (7.4 %), and gastro-intestinal infection (2.2 %). Data from the two
doses of ibuprofen were combined because there were no discernible differences
6.12 Adverse Events and Safety in Paediatric Populations 121

between the groups; thus, the size of the ibuprofen group is about twice that of the
paracetamol group.
The risk of hospitalisation for any reason in the 4 weeks after enrolment
(N ¼ 385 patients in total) was the same in the ibuprofen group (relative risk,
RR¼1.1 (0.9–1.3) compared with that of the paracetamol group as a reference,
RR ¼ 1.0). The absolute risks were 1.5 % (1.3–1.6, 95 % CI) for the ibuprofen
group and 1.4 % (1.1–1.6 %) for the paracetamol group. None of the study
participants was hospitalised for acute renal failure, anaphylaxis, or Reye’s syn-
drome. Three children who received ibuprofen were hospitalised for evidence of GI
bleeding; these were non-serious, and were resolved with conservative manage-
ment. The risk of hospitalisation from GI bleeding was estimated to be 11 per
100,000 (95 % CI 2.2–32 per 100,000) for antipyretic assignment and 17 per
100,000 (95 % CI, 3.5–49 per 100,000) in those children 2 years who received
ibuprofen.
Among children <6 months of age, there was no observed risk for hospitali-
sation for any of the primary outcomes.
The risks for hospitalisation for asthma/bronchiolitis for ibuprofen were 0.9
(95 % CI, 0.5–1.4) compared with paracetamol, a total of 65 children being
hospitalised for this group of conditions (they were grouped together because of
frequent misdiagnosis of these two conditions). Of nine children hospitalised for
vomiting or gastritis, the risk did not vary according to antipyretic assignment.
Of the 385 who were hospitalised, those in whom creatinine levels were avail-
able (29 % of total) and was considered to be only of borderline statistical signifi-
cance between the ibuprofen and paracetamol groups. There was no significant
differences between these two treatment groups when age, weight, sex, or admis-
sion diagnosis of dehydration. When alternate cut-off points were used to define an
elevated creatinine level (44 or 53 mmol/L for the two treatment groups respec-
tively), there were no significant differences between the antipyretic groups.
While this was the largest controlled study ever undertaken of antipyretic use in
children 6 months of age, the authors admitted that the power to detect serious
adverse events is limited (especially those that occur infrequency). Some clinical
and demographic information suggested that the study participants probably
reflected a wide spread of febrile illnesses in the view of the authors, even though
socioeconomic data were limited.
These data are important in showing that there is a remarkably low incidence of
serious and even non-serious ADRs in children 2 years and especially 6 months
who receive antipyretic therapy for febrile illness.
Another large investigation into the overall safety of ibuprofen in paediatric
populations was performed by Ashraf et al. (1999). This study, known as the
Children’s Analgesic Medicines Project (CAMP), was a prospective, multicentre,
all-comers, multi-dose, open-randomised and open-label study designed to com-
pare the safety of ibuprofen (Children’s Advil®) with that of paracetamol
(Children’s Tylenol®) given for relief of pain and/or fever. A total of 41,810
children aged 1–18 years were enrolled in a naturalistic outpatient paediatric setting
(PEGASUS Research Inc., Salt Lake City, UT, USA) involving 68 clinics in the
122 6 General Safety Profile

USA. Among 30,144 children who took one dose of either ibuprofen or paraceta-
mol, 14,281 were “younger” aged 2 years and 15,863 were “older” and aged
2–12 years. There were no serious AEs in 1 % of patients in either group. There
were no cases of Reye’s syndrome, gastric bleeding and/or ulceration, renal failure,
necrotising fasciitis, Stevens–Johnson, or Lyell’s syndromes, anaphylaxis, or any
other serious condition that are known to be associated with either drug in any
population.
Small but clinically non-significant differences were observed in AEs in both
age groups that received ibuprofen, compared with those that had paracetamol
being 17.6 % vs 15 % respectively in the younger and 11.9 % and 10.7 %
respectively in the older groups. The increased incidence of AEs in the ibuprofen
groups was related to the greater disease severity in those groups. Four deaths were
recorded (herpes encephalitis, sepsis due to Staphyloccocus pneumoniae, medullo-
blastoma, and sudden death syndrome) and were unrelated to the study medications
but were related to the special senses followed by the digestive and respiratory
systems and skin (all in 3–4 % approximately in the younger and slightly lower in
the older group).
Chapter 7
Gastro-Intestinal Toxicity

Serious GI ADRs (upper GI bleeding and ulcers) are a major cause of concern and
in the past three to four decades have aroused much interest among clinicians,
experimentalists and regulators (Voutilainen et al. 1998; Wolfe et al. 1999; Lewis
et al. 2005; Schaffer et al. 2006; Arroyo and Lanas 2006; Lanas et al. 2006; Laine
et al. 2006; Lanas 2010). The problems are particularly apparent in rheumatic
patients (Singh et al. 1996; Singh and Rosen Ramey 1998) and the elderly (Griffin
et al. 1988; Beyth and Shorr 1999; Seinelä and Ahvenainen 2000; Mamdani et al.
2002; Kean et al. 2008). Definitions vary on what constitutes the elderly, but most
agree on >65, a time that seems to have been derived over a century ago from Otto
von Bismarck who required Prussian officers to retire at this age (Kean and
Buchanan 1987; Buchanan 1990). Early studies indicated that ibuprofen was
well-tolerated in elderly patients (Buckler et al. 1975).
A range of factors influence the development of NSAID-associated GI
ulcerations and bleeding (Table 7.1; Figs. 7.1 and 7.2). This makes it difficult to
ascribe a quantitative component of the NSAID to the occurrence of serious GI
events.
Several studies have reported that prescription doses of ibuprofen produce time-
and dose-dependent blood loss (assessed using the radiochromium blood loss
technique) from the GI tract of volunteers or patients (Teixeira et al. 1977;
Warrington et al. 1982; Aabakken et al. 1989a; Hunt et al. 2000; Bowen et al.
2005) and mild–moderate endoscopic changes compared with other NSAIDs in
fasted human volunteers (Lanza et al. 1979, 1981, 1987, 2008; Aabakken et al.
1989a; Friedman et al. 1990b; Bergmann et al. 1992; Roth et al. 1993; Müller et al.
1995) or those with rheumatic diseases (Teixeira et al. 1977). There appears to be an
inherent variability in the blood loss both within and between subjects (Bowen et al.
2005), the reasons for which are not fully understood. The extent of the loss of
blood may be overestimated using the radiochromium technique, as a consequence
of loss of 51Cr from the labelled red cells and subsequent biliary excretion of the
radiolabelled chromium (De Medicinis et al. 1988; Rainsford 2004a). Moreover,
some drugs such as the salicylates are choleretics and may stimulate biliary flow
(Schneider et al. 1990; Rainsford 2004a). The extent of the mucosal changes

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 123

DOI 10.1007/978-3-0348-0496-7_7, # Springer Basel 2012
124 7 Gastro-Intestinal Toxicity

Table 7.1 Risk factors for the development of NSAID-associated gastro-duodenal ulcers
Established risk factor Possible risk factor
Advancing age High alcohol consumption
High-dose NSAID or paracetamol Cigarette smoking
Use of more than two NSAIDs Helicobacter pylori infection
Concurrent paracetamol
Concurrent anti-coagulants
Concurrent aspirin (even low dose)
Prior history of peptic ulcer disease
Rheumatoid arthritis
Based on Wolfe et al. (1999), Wolfe (2003) and Laine (2001); modified and with additional
information from Rainsford (2004a, 2005b)

Fig. 7.1 Summary of factors involved in the development of gastric mucosal injury. Based on
Lanas (2010) and Rainsford (2009)

(lesions, ulcers) compared with blood loss varies considerably with different
NSAIDs, and is not always comparable (Aabakken et al. 1989b). The blood loss
from ibuprofen is relatively low compared with other NSAIDs, but is above that of
placebo and paracetamol (Rainsford 1999c).
7.1 Epidemiological Studies 125

Fig. 7.2 Relative contributions of complicating factors in the occurrence of upper GI

haemorrhage or ulcers. Reproduced from Lanas (2010) with permission of Oxford University
Press, publishers of Rheumatology

7.1 Epidemiological Studies

A considerable number of population studies have been reported over the past two
to three decades comparing the occurrence of serious GI events from ibuprofen and
other NSAIDs, at prescription-level dosages, with some studies being dose-ranging
(Kaufman et al. 1993; Langman et al. 1994; Henry et al. 1996; Henry and
McGettigan 2003; Hippisley-Cox et al. 2005; Thomsen et al. 2006; see also
Table 7.2). The study designs, outcome measures, and variables (dosage and
duration) vary considerably among these studies. Some measures have included
the occurrence of peptic ulcer bleeds (PUBs), upper GI bleeding, ulcers viewed at
endoscopy (usually investigated as a consequence of clinical symptoms or as part of
a planned investigation), or the more general grouping of “serious events”. While
these studies vary considerably, they are useful in comparing the risks of serious GI
events attributed to ibuprofen with that of a range of other NSAIDs with known
ulcerogenicity.
A summary of some of the population studies reported in the 1990s in the period
before the introduction of the newer class of coxib NSAIDs is shown in Table 7.2.
In a meta-analysis of published studies comparing the GI ADRs for various
NSAIDs, Henry et al. (1996, 1998) were able to show that the relative risks of these
events from different NSAIDs ranged considerably (Fig. 7.3). They found that
ibuprofen had the lowest risks for developing GI complications (Fig. 7.4).
Henry and co-workers also observed (a) dose-related occurrence of GI
complications with ibuprofen, naproxen, and indomethacin (Fig. 7.4), and (b) the
ranking of GI complications was directly related to the plasma elimination half-life
(t1/2) of the individual NSAIDs (Table 7.3). As in the overall analysis, ibuprofen
had the lowest rates of occurrence of GI complications, this being attributed to its
short t1/2 (~2 h). Thus, there is a good pharmacokinetic rationale to account for the
low GI ADRs with ibuprofen.
126 7 Gastro-Intestinal Toxicity

Table 7.2 Serious outcome gastro-intestinal toxicity ranking of NSAIDs

Kaufman Henry et al. Langman Rodriguez Henry et al. MacDonald
Drug et al. (1993) (1993) et al. (1994) et al. (2001) (1996) et al. (1997)
Aspirin 10
Azapropazone 1 1 2
Diclofenac 6 7 6 7 9 4
Diflunisal 1 8 7
Fenbufen 11
Fenoprofen 4 5 11 1
Ibuprofen 7 8 7 9 12 8
Indomethacin 5 3 4 4 5 9
Ketoprofen 1 2 2 2 2 5
Nabumetone 10
Naproxen 3 4 5 3 6 6
Mefenamic 7
acid
Piroxicam 2 5 3 1 3 3
Sulindac 6 6 8
Tolmetin 4
Toxicity rankings of NSAIDs, with those associated with the greatest risk of ulcer complication
being given the number 1. The studies used different methodologies. Reproduced with permission
of the publishers from Rainsford (2009)

Fig. 7.3 Redrawn from Henry et al. (1998)

Among the most comprehensive studies that have been performed to evaluate
overall adverse drug reactions in European populations was the study by Lugardon
and co-workers (2004). These authors undertook an analysis of spontaneous reports
to the French pharmacovigilance network, which is probably one of the most
extensive and comprehensive pharmacovigilance systems in Europe. A summary
of the data shown in the Table 7.4 compares the reporting odds ratios for GI events
of heteroarylacetic acids, which include ibuprofen, diclofenac, naproxen, and
ketoprofen with that of the two principal coxibs, rofecoxib and celecoxib, as well
7.1 Epidemiological Studies 127

Fig. 7.4 Dose-related development of GI haemorrhage associated with low and high doses of
ibuprofen, indomethacin and naproxen. Redrawn from Henry et al. (1998)

Table 7.3 Ranking of GI complications from NSAIDs with plasma elimination half-life (t1/2) of
the drugs
GI safety, dose and plasma half-life of NSAIDs
Ranking of RR of Ulcers compared with t1/2 (h):
Ibuprofen (2.5) < Diclofenac (1.5–5) < Diflunisal (10.8) < Fenprofen (2.2) < Aspirin
(0.5–4.5) < Sulindac (14.0) < Naproxen (14.0) < Indomethacin (3.8) < Piroxicam
(48.0) < Ketoprofen (8.5) < Tometin (6.8) < Azapropazone (22.0)
Dose relationships—low compared with high dose:
Ibuprofen RR 1.8–4.0
Naproxen RR 3.8–6.0
Indomethac in RR 2.3–6.5
From: Henry et al. (1998) and from Rainsford (2009) with permission of the publishers, Kluwer
Academic Publishers, now owned by Springer AG.

as the oxicams, principally meloxicam, piroxicam, and tenoxicam. The unadjusted

and adjusted odds ratios for ibuprofen ADRs are the lowest amongst all the drugs
that were studied by Lugardon and co-workers (2004).
A similar conclusion can be drawn from the case-control study of Laporte et al.
(2004), as shown in Table 7.5.
Case-control investigations by Garcia-Rodriguez and Hernandez-Diaz (2001)
using data from the UK General Practice Database also show the low risks of GI
events with ibuprofen in contracts with those from various doses and periods of
taking NSAIDs and aspirin (Table 7.6). These data have also instructive in
highlighting that high-dose paracetamol (hitherto regarded as a GI-safe drug)
when taken at doses of >2 g/day alone or in combination with NSAIDs is
associated with relative risks >2 (alone) or >6 (combination with NSAIDs) of
causing haemorrhage.
In rheumatic patients, Singh (2000) has produced data from the ARAMIS
(a rheumatic disease patient) database showing relatively high risks of GI bleeding
(or peptic ulcer bleeds) from all NSAIDs, with little difference between individual
128 7 Gastro-Intestinal Toxicity

Table 7.4 Adverse drug reaction reporting odds ratio (OR) (with their 95 % confidence interval)
according to main classes of non-steroidal anti-inflammatory drugs (NSAIDs) from the French
pharmacovigilance database
Drugs Adjusted ORa (95 % CI) Adjusted ORb (95 % CI)
Coxibs 4.6 (3.3–6.5)* 14.9 (9.3–23.7)*
Rofecoxib 5.2 (3.1–8.7)* 21.0 (10.6–41.6)*
Celecoxib 3.7 (2.4–5.8)* 11.7 (6.6–20.9)*
Oxicams 12.2 (6.7–22.2)* 25.3 (11.9–53.6)*
Heteroarylacetic acids
Ibuprofen 4.5 (3.2–8.8)* 7.3 (3.2–16.6)*
Diclofenac 3.9 (2.1–7.2)* 9.2 (3.8–22.2)*
Naproxen 10.6 ( 4.7–23.7)* 17.9 (6.7–47.6)*
Ketoprofen 8.6 (5.3–13.9)* 19.9 (10.7–37.0)*
*P < 0.0001.
a
Adjustment for matching factors (age, gender, period of occurrence).
b
Adjustment for matching factors (age, gender, period of occurrence) and confounding factors
(regional pharmacovigilance centre, work place of health professional and drug exposure:
anticoagulants, antiplatelet drugs, aspirin, gastroprotective and other NSAIDs).
Reproduced from Lugardon et al. (2004) with permission of Springer, publishers of the European
Journal of Clinical Pharmacology

Table 7.5 Gastro-intestinal bleeding from NSAIDs in a multicentre case-control study in Spain
and Italy
Cases Controls Odds ratio Population attributable
Drug [no (%)] [no (%)] (95 % CI) risk (%)
NSAIDs
Aceclofenac 15 (0.5) 30 (0.4) 1.4 (0.6, 3.3) –
Aspirin (acetylsalicylic acid) 591 (21.1) 403 (5.7) 8.0 (6.7,9.6) 18.5
Dexketoprofen 16 (0.6) 8 (0.1) 4.9 (1.7, 13.9) 0.5
Diclofenac 100 (3.6) 98 (1.4) 3.7 (2.6, 5.4) 2.6
Ibuprofen 60 (2.1) 58 (0.8) 3.1 (2.0, 4.9) 1.5
Indomethacin 29 (1.0) 16 (0.2) 10.0 (4.4, 22.6) 0.9
Ketoprofen 16 (0.6) 9 (0.1) 10.0 (3.9, 25.8) 0.5
Ketorolac 33 (1.2) 6 (0.1) 24.7 (8.0, 77.0) 1.1
Meloxicam 14 (0.5) 11 (0.2) 5.7 (2.2, 15.0) 0.4
Naproxen 52 (1.9) 27 (0.4) 10.0 (5.7, 17.6) 1.7
Nimesulide 48 (1.7) 46 (0.6) 3.2 (1.9, 5.6) 1.2
Piroxicam 119 (4.3) 40 (0.6) 15.5 (10.0, 24.2) 4
Rofecoxib 10 (0.4) 10 (0.1) 7.2 (2.3, 23.0) 0.3
Other NSAIDs 34 (1.2) 33 (0.5) 3.6 (2.0, 6.8) 0.9
NSAIDs + antiplatelet drugs 140 (5.0) 54 (0.8) 16.6 (11.3, 24.2) 4.7
Analgesics
Lysine clonixinate 26 (0.9) 47 (0.7) 1.3 (0.7, 2.6) –
Metamizole 117 (4.2) 155 (2.2) 1.9 (1.4, 2.6) 2
Paracetamol (acetaminophen) 376 (13.4) 612 (8.6) 1.2 (1.0, 1.5) –
Propyphenazone 17 (0.6) 38 (0.5) 1.3 (0.6, 2.8) –
From: Laporte et al. (2004). Reproduced with permission of Springer International Publishing AG,
for Adis Press, publishers of Drug Safety
7.1 Epidemiological Studies 129

Table 7.6 Epidemiological data from General Practice Database (UK) and other sources on
peptic ulcer bleeding risks from aspirin and other NSAIDs and paracetamol
Drug Usage/factor Relative risk
Ibuprofen Lowest risk (dose-dependent) ~1.0–2.0
Aspirin Overall use Users 2.0
Non-users 1.0
Recent users 1.5
Past users 1.1
Dose 75–300 mg/day 2.1
>400 mg/day 3.1
<50 mg/day 0.7
Period of use 1–60 day 4.5
61–180 day 2.7
181–730 day 1.0
>730 day 1.6
Paracetamol <1 g/day 1.0
1–2 g/day 0.9
2–4 g/day 3.4
>4 g/day 6.5
2 g with NSAID 4.2
>2 g with NSAID 13.5
cf. NSAID alone 3.5
NSAIDs Low dose 2.5
High dose 5.0
Duration 1–30 days 4.3
>730 days 3.5
Formulation Plasma T½
<12 h (high dose) 4.2
12 h (slow release) 5.4
6.2
<12 h (low dose) 2.4
12 h 2.8
Data from Garcia-Rodriguez and Hernandez Diaz (2001). Reproduced with permission of the
publishers from Rainsford (2009)

NSAIDs (including ibuprofen). Lower risks were associated with paracetamol.

While there have been claims made by this author that the GI risks are similar to
those from OTC dosages of these analgesics, there is little information available on
their duration of use, concomitant medications, and other risk factors.
More insight into the GI risks associated with OTC analgesics/NSAIDs has been
provided by Lewis and co-workers (2005) in a case-control study of hospitalised
patients recruited from 28 hospitals. The cases (N ¼ 359) had upper GI bleeding,
benign gastric outlet obstructions or perforations, while controls (N ¼ 1,889) were
obtained from random-digit phone dialling in the same region. Use of OTC doses of
non-aspirin NSAIDs 4 days in the past week was associated with an adjusted odds
ratio of 1.83 (95 % CI 1.14–2.95), the risks from ibuprofen being much lower. Risks
were increased with higher doses of the drugs, confirming what has been well-
130 7 Gastro-Intestinal Toxicity

Table 7.7 Upper gastro-intestinal bleeding from low dose (OTC ibuprofen and naproxen) in
relation to age in UK population
Age Number Number Incident
Drug (daily dose) (years) of users of cases rate/104 users 95 % CI
Ibuprofen (<1,200 mg) <70 47,323 1 0.2 0.01–1.20
(90 % used 1,200 mg) 70 7,505 1 1.3 0.03–7.40
All 54,830 2 0.4 0.04–1.30
Diclofenac (<75 mg) <70 18,407 3 1.6 0.3–4.80
(90 % used 75 mg) 70 3,739 1 2.7 0.1–14.9
All 22,946 4 1.8 0.3–4.6
Naproxen (<750 mg) <70 39,720 5 1.3 0.4–2.9
(60 % used 750 mg) 70 7,199 6 8.3 3.1–18.1
All 46,919 11 2.3 1.2–4.2
Overall, ibuprofen showed the lowest risks for upper GI bleeds, with an increased risk in over 70
year-olds, a trend which was also seen with the other frequently-prescribed NSAIDs
Data derived from the UK General Practice Research Database (GPRD) from patients that
received prescriptions for ibuprofen, diclofenac, and naproxen for 30 days
From: Pérez-Gutthann et al. (1999)

known about the dose–response relationships among most NSAIDs being

associated with serious GI AEs (Henry et al. 1996, 1998).
Estimations of the relationship between age and dose-related occurrence
of upper GI bleeding can be seen in data from the UK General Practice
Research Database (Table 7.7) which was analysed by Pérez-Gutthann and co-
workers (1999).

7.2 GI Risks in Coxib Studies at Prescription Doses

The data on ulcer complications in the CLASS study observed at 6 months showed
there were differences between celecoxib and NSAIDs (Silverstein et al. 2000).
However, as pointed out by Jüni et al. (2002) these differences were not apparent at
12 months (Table 7.8), suggesting there are time-dependent factors that are signifi-
cant in considering ulcer incidence with both coxibs and NSAIDs. The clinical
significance of these data, like that from other long-term studies, is that when coxibs
are taken for relatively short periods of time (2–4 weeks) they are less likely to
cause less ulcer complications than NSAIDs such as naproxen and diclofenac than
if they are taken for several months or longer. There is also the issue of what has
been described as “channelling”, where patients with a history of GI complaints or
GI ulcer disease may be prescribed coxibs in the belief that they will be “gastric-
safe”; this may be such that benefits for using these drugs may be less apparent and
the patients may require anti-ulcer co-therapy (e.g., with H2 receptor antagonists or
PPIs). The cost–benefit of coxib therapy may prove less favourable, as not only are
these drugs notably more expensive than conventional NSAIDs, but if PPIs or other
anti-ulcer therapies have to be employed they may as well be given with cheaper
7.2 GI Risks in Coxib Studies at Prescription Doses 131

Table 7.8 Summary of adverse events in the CLASS study

Event % Celecoxib Diclofenac Ibuprofen
GI 45.6 55.0 46.2
!withdrawal 12.2 16.6* 13.4
Renal 6.8 6.7 10.3*
!withdrawal 1.0 0.6 1.3
CV non-aspirin 1.6 1.2 0.4
Hepatic 1.8 6.9* 1.9
!withdrawal 0.3 3.5* 0.3
*Significantly different compared with celecoxib. p < 0.05
Based on data published by Silverstein et al. (2000). Reproduced with permission of the publishers
from Rainsford (2009)

Table 7.9 Estimation of serious gastrointestinal reactions from the CLASS trial of celecoxib
compared with NSAIDs
In the CLASS Trial (non-aspirin-using patients only)
Percentage of patients with serious NSAID-associated gastrointestinal complications was:
Celecoxib ¼ 0.44 % diclofenac ¼ 0.48 %
(no statistically significant difference between diclofenac and celecoxib)
Celecoxib ¼ 0.44 % Ibuprofen ¼ 1.14 %
ARR ¼ 1.14 %0.44 % ¼ 0.7 %
NNT ¼ 1/0.7 % ¼ 1/0.007 ¼ 143
RRR ¼ 1.14 %0.44 %/1.14 % ¼ 61 %
Results are reported as serious NSAID-associated gastro-intestinal complications (i.e., gastro-
intestinal bleeds, perforations, and obstructions) per 100 patient-years. ARR absolute risk reduc-
tion, RRR relative risk reduction, NNT number needed to treat
From: Schoenfeld (2001). Reproduced with permission of Springer, publishers of
Inflammopharmacology

NSAIDs, especially those with a lower propensity to cause CV complications (e.g.,

naproxen) or combinations with aspirin for cardioprotection.
These calculations (Table 7.9) show that although the percentage of relative risk
reduction (RRR) for celecoxib cf. NSAIDs (ibuprofen, diclofenac) is 61 % and for
rofecoxib cf. naproxen is 60 %, the values for absolute risk reduction (ARR) are
relatively small, being 0.7 % and 0.8 % respectively for the two trials. The latter
values represent the fact that the percentage incidence of GI complications for the
NSAID as well as for the two coxibs is in the low end range of 0.4–1.14 %, which
are very low percentages. Thus, with such small differences, calculations of RRR
are meaningless, and give a false impression of improved benefit to the GI tract of
the coxibs. This approach of using RRR percentage benefits has been extensively
exploited in published data on coxib trials and must, therefore, be regarded as
suspect statistical treatment of data which has little relevance clinically. Indeed
clinical significance in many coxib trials has rarely been considered in contrast to
statistical significance (Rainsford 2009).
In another large scale coxib study, Sikes et al. (2002) compared the incidence of
gastric and duodenal ulcers from two dose levels of valdecoxib (10 and 20 mg/day)
132 7 Gastro-Intestinal Toxicity

Table 7.10 Percentage incidence rate of upper-gastrointestinal ulcers

Ibuprofen Diclofenac
Valdecoxib Valdecoxib 800 mg three 75 mg
Placebo 10 mg daily 20 mg daily times daily twice daily
12-week cohort
No. patients 123 142 157 149 145
Gastroduodenal 7 5 4 16a,b,c 17a,b,c
Gastric 5 4 4 14a,b,c 14a,b,c
Duodenal 2 1 1 4 5c
ITT cohort [n (%)]
No. patients 178 189 198 184 187
Gastroduodenal 4 4 4 14a,b,c 13a,b,c,
Gastric 3 3 3 11a,b,c 11a,b,c
Duodenal 2 1 1 3 5c
a
Significantly different from placebo at P > 0.05.
b
Significantly different from valdecoxib 10 mg daily at P > 0.05.
c
Significantly different from valdecoxib 20 mg daily at P > 0.05.
12-week cohort includes patients who took the study medication for the entire 12-week period
ITT cohort includes all patients who had a post-treatment endoscopy irrespective of whether they
completed 12 weeks of treatment
Summary of data in modified form from Sikes et al. (2002) with permission of Wolters Kluwer
Health Publishers of European Journal of Gastroenterology and Hepatology

with that from ibuprofen 2,400 mg/day and diclofenac 150 mg/day taken for 12
weeks. This study is shorter than the other coxib studies reviewed previously.
There is a trend noted by Jüni et al. (2002) for differences in GI events between
celecoxib and the NSAIDs to become smaller with time, especially after 6 months
therapy, coinciding with an increase in GI events from celecoxib approaching those
from the NSAIDs. Thus, at the shorter time period it might have been expected that
if valdecoxib had a favourable GI profile, it would show a lower incidence of GI
events compared with the two comparator NSAIDs. The data in Table 7.10 shows
that there was a somewhat higher incidence of gastric and duodenal ulcers and all
GI ulcers from ibuprofen compared with valdecoxib, but these were fewer than seen
with diclofenac.
This study is of significance in that there was separate analysis of ulcer incidence
in (a) Helicobacter pylori negative and H. pylori positive subjects, and (b) aspirin
takers (for CV prophylaxis) and non-takers.
The data in Table 7.11 shows that H. pylori status made little if any difference to
the ulcer incidence in subjects who received any of the drugs, but taking aspirin did
increase the incidence of ulcers in the ibuprofen and naproxen groups, and to a
lesser extent in the valdecoxib groups.
From the point of view of GI safety, there may have been pathological
consequences of hepato-renal ADRs and hypertension that contributed to the
vascular aetiology of upper GI ulcer disease (Fig. 2.6), as well as the consequences
of treatment with diuretics and anti hypertensive drugs (which, as noted earlier,
increase the risk for developing ulcers) as well as interactions between NSAIDs and
drugs that patients with hepato-renal conditions and hypertension received for
7.2 GI Risks in Coxib Studies at Prescription Doses 133

Table 7.11 Gastroduodenal ulcer incidence [n (%)] by aspirin use, age, or Helicobacter pylori
status
Ibuprofen Diclofenac
800 mg three 75 mg twice Valdecoxib
Placebo times daily daily 20 mg daily
H. pylori-positive 4/46 (9)a,b 9/45 (20) 11/54 (20) 2/49 (4)a,b
a,b
H. pylori-negative 4/119 (3) 15/123 (12) 14/122 (12) 5/136 (4)a,b
H. pylori status unknown 0/2 (0) 0/7 (0) 0/5 (0) 0/6 (0)
Taking aspirin 0/26 (0)a,b 10/31 (32)c 10/33 (30)c 2/29 (7)a,b
Not taking aspirin 8/141 (6)a,b 14/144 (10) 15/148 (10) 5/162 (3)a,b
Age 65 years 4/65 (6) a,b
15/71 (21) d
14/78 (18) 3/67 (5)a,b
Age >65 years 4/102 (4) a,b 9/104 (9) 11/103 (11) 4/124 (3)a,b
a
P  0.014 vs ibuprofen, bP  0.008 vs diclofenac; cP  0.017 vs not taking aspirin; dP  0.025
vs age < 65 years.
Summary of data in modified form from Sikes et al. (2002). Reproduced in modified form by
permission of Wolters Kluwer Health Publishers of European Journal of Gastroentrology and
Hepatology

treatment of these conditions. In the end, from what has emerged in the safety
analysis of the coxibs (summarised in Table 7.7), it is clear that the benefits of what
now are classed as “first generation” coxibs (celecoxib, rofecoxib, valdecoxib) may
have been marginal compared with some conventional NSAIDs, among which
etodolac, ibuprofen, nabumetone, and possibly diclofenac (although the intestinal
ulceration and hepatotoxicity from this drug limits it being considered to have a
favourable safety profile).
An interesting and possibly important point that should be considered is the
arthritic condition in the CLASS study, as well as other studies with coxibs. Patients
in the VIGOR study only had RA, whereas those in the CLASS study had both RA
and OA. It has been claimed that there were no differences in ulcer complications
between patients with OA versus RA. This is in one sense surprising, since as noted
earlier it has been speculated that patients with RA may be more susceptible to
NSAIDs than those with OA. It could be that the selection criteria for patients
entered in the CLASS Study were such that RA as well as OA patients were
relatively “fit”, and without complicating chronic conditions that inevitably occur
in older more infirm patients, especially those with RA.
Indeed the ulcer incidence in the CLASS study (Tables 7.8 and 7.9) as well as in
the meta analysis of celecoxib trials by Moore et al. (2005) reveals a remarkably
low incidence in placebo and NSAID groups. This gives support to the view that
patients selected for inclusion in these studies may have been of relatively
favourable health. Another issue is that if there were any real differences in data
of ulcer complications in, say, a proportion of patients with RA versus those with
OA, these could have had been disguised in the grouping of data together such as in
the CLASS results.
In conclusion, the epidemiological and large-scale clinical trials show that
ibuprofen has amongst the lowest risk of NSAIDs for serious GI events. The
additional intake of aspirin may raise the risk of GI complications in a similar
way to that seen with celecoxib and rofecoxib.
134 7 Gastro-Intestinal Toxicity

7.3 GI Symptomatic Adverse Reactions

Meta-analysis of the tolerability and adverse events from a range of trials of

celecoxib compared with NS-NSAIDs, paracetamol, and placebo (using data
from the published and unpublished trials from Pfizer) (Moore et al. 2005) revealed
some interesting features and trends concerning the occurrence of GI symptoms,
notably nausea, dyspepsia, diarrhoea, abdominal pain, and vomiting. These consti-
tute main reasons (other than ulcer/bleeds or other serious ADRs) for withdrawal
from therapy, and indeed the data by Moore et al. confirmed this pattern.
Data on the GI symptoms from NSAIDs and coxibs summarised in the report by
Moore et al. (2005) highlight that (1) the occurrence and relative risks of most GI
symptoms in patients receiving celecoxib, rofecoxib, or paracetamol are greater
than that of placebo, (2) while there are trends for a lower incidence of some
symptoms with low-dose celecoxib, the differences are less distinct with higher-
dose celecoxib, and (3) the data on confidence intervals in relative risks with most
comparisons often overlaps to the extent that it is doubtful whether any differences,
especially those favouring celecoxib, have any meaning. Moore et al. (2005) noted
that the proportion of patients having dyspepsia was about 7 %, and that there were
no differences in comparison with placebo, paracetamol, or rofecoxib, but there
were more patients on NSAIDs. Celecoxib was responsible for abdominal pain in
about 5 % of patients, there being no difference compared with placebo or paracet-
amol, but more patients on NSAIDs and rofecoxib experienced this adverse effect.
In these and other GI symptomatic effects as well as overall GI tolerability, there
were trends in favour of celecoxib in comparison with the other treatments, but the
95 % confidence intervals for relative risk often overlapped those of comparator
drugs. Making much of what are relatively small values for incidence and percent-
age differences of symptomatic GI ADRs such as that of clinical ulcers and bleeds
in this meta analysis (Moore et al. 2005) is probably of limited value.

7.4 GI Events at OTC Dosages

GI symptoms (nausea, epigastric or abdominal pain, dyspepsia, diarrhoea, flatu-

lence, and constipation) are among more frequent reactions observed with OTC use
of ibuprofen as well as with paracetamol and aspirin, and generally the symptoms
are of the same order as in subjects who have received placebo (Rainsford et al.
1997, 2001; Doyle et al. 1999; Kellstein et al. 1999; Ashraf et al. 2001; Le Parc
et al. 2002; Boureau et al. 2004; Biskupiak et al. 2006).
The occurrence of GI symptoms with ibuprofen has often been found to be lower
than with aspirin, and comparable with those from paracetamol (Rainsford et al.
1997; Moore et al. 1999; Le Parc et al. 2002; Boureau et al. 2004). Serious
GI reactions are rare, and have not been reported in significant numbers in trials
with OTC ibuprofen (Doyle et al. 1999; Kellstein et al. 1999; Ashraf et al. 2001;
7.5 GI Safety in Paediatric Populations 135

Table 7.12 Endoscopically-observed ulcers and erosions from OTC ibuprofen compared with
naproxen and celecoxib
Treatment (dose mg/d)
Placebo lbuprofen (1200) Celecoxib (200) Naproxen (1000)
No. subjects 40 39 39 40
No. ulcers/subject (range) 0.03(0–1) 0.59(0–15) 0.3(0–1) 1.03(0–20)
No. erosions/subject 0 0.62(0–9) 0.15(0–3) 3.98(0–21)
(range)
Normal healthy volunteers (N ¼ 20) treatment group took the drugs for 10 days in a US-based
multi-centre, outpatient randomised, double-blind, 2-way crossover study with a 4–5 week
washout period. Although subjects were stratified for presence of H. pylori, this varied from 13
to 26.9 % subjects
From: Scheiman et al. (2004)

Le Parc et al. 2002; Boureau et al. 2004). Thus, it may be concluded that GI events
are essentially non-serious with OTC ibuprofen, are probably reversible upon
cessation of the drug (an action likely to be taken by most subjects), and are no
different than with paracetamol and less so than with aspirin. Epidemiological
studies in general practice patients (Table 7.7; Pérez-Gutthann et al. 1999) have
shown that there is a small age-related increase in GI bleeding in patients who took
ibuprofen at about OTC doses, but this is a small risk and much less than with
diclofenac and naproxen, the latter being amongst the most frequently prescribed
NSAIDs in general practice after ibuprofen.
Endoscopy studies using OTC doses of ibuprofen have shown that there is a
small increase in lesions or ulcers above placebo or low-dose celecoxib, but less so
than observed with naproxen (Scheiman et al. 2004; Table 7.12). While this study
was performed in healthy volunteers, an appreciable proportion of these subjects
were infected with the ulcerogenic bacterium H. pylori. The data from subjects that
had taken ibuprofen overlapped that from celecoxib in respect of confidence
intervals, showing that there was no significant difference between these treatment
groups and placebo. It should also be noted that subjects undergoing endoscopy will
have been fasted overnight, and the procedure can be regarded as stressful such that
it could have led to exacerbation of mucosal ulceration from the NSAIDs.

7.5 GI Safety in Paediatric Populations

In the large-scale paediatric study by Lesko and Mitchell (1995), four children were
hospitalised for acute GI bleeding that was due to ibuprofen (two from 10 mg/kg
and two from 5 mg/kg of the drug), which gives a risk of GI bleeding of 7.2 per
100,000 (95 % CI 2–38 per 1,000,000 patients), with the risk from paracetamol
being zero, the difference being not statistically significant. Gastritis/vomiting were
observed in 20 patients that had received ibuprofen, with a risk of 36 per 100,000
136 7 Gastro-Intestinal Toxicity

patients (95 % CI 22–55), and in six patients on paracetamol, with a risk of 21 per
100,000 patients (95 % CI 7.9–46).
In their later study on 2 year olds, Lesko and Mitchell (1999) observed that
three children who received ibuprofen were hospitalised due to evidence of GI
bleeding, these cases being non-serious and resolved with conservative manage-
ment. The risk of hospitalisation from GI bleeding was estimated to be 11 per
100,000 (95 % CI 2.2–32 per 100,000) for antipyretic assignment, and 17 per
100,000 (95 % CI, 3.5–49 per 100,000) in those children 2 years who received
ibuprofen.
As noted earlier in the discussion of the large-scale paediatric study by Ashraf
et al. (1999), no occurrences of gastric bleeding or ulcers were observed with either
ibuprofen or paracetamol. The incidence of adverse events (AEs) in the digestive
system was 3.0 % and 2.1 % in the younger group (2 years) that received
ibuprofen or paracetamol, and 2.1 % and 1.2 % for these drugs in the older group
(2–12 years); the statistical tests showed the former to be non-significant, and the
latter statistically significant. Abdominal pain occurred in 0.6 % of the younger
patients who had ibuprofen compared with 0.1 % that had paracetamol, while in the
older group the incidence was 0.6 % and 0.2 % for ibuprofen and paracetamol
respectively.
These results attesting to the gastric safety of ibuprofen in comparison with
paracetamol accord with earlier investigations (Walson et al. 1989; Rainsford et al.
1997; Diez-Domingo et al. 1998), and confirm the safety of both drugs to be
comparable and relatively low adverse events in the open clinical paediatric setting.

7.6 Reducing GI Risks

An obvious way of reducing GI risks from ibuprofen, like that from other NSAIDs,
is to take note of the risk factors for developing NSAID-induced GI injury
(Table 7.1; Figs. 7.1 and 7.2) and adopt preventative strategies (educational, patient
advisory leaflets and advice on packaging). One suggestion that is frequently made
is to take ibuprofen with food or drinks. In a review, the evidence in support of this
suggestion was analysed (Rainsford and Bjarnason 2012).
In essence, the evidence reviewed addressed issues concerning recomm-
endations to take OTC ibuprofen with food, or at various times before during or
after meals. This question has arisen as a result of some EU drug regulatory
agencies requiring a specific warning on labels to take the drug with food.
In order to gain scientific insight into what the benefits are from intake of
ibuprofen with food or at various stages around mealtimes, the published evidence
was reviewed for the effects on the pharmacokinetics, pharmacological, therapeutic
actions and safety of various ibuprofen formulations when taken orally with food or
fasting, and intake of the drug around mealtimes. The main conclusions were:
7.6 Reducing GI Risks 137

1. The recommendations to take ibuprofen with food or meals have raised a

number of important issues:
(a) The impact of intake of food, at various stages during meals and intake of
liquids on the absorption pharmacokinetics and the bioavailability of ibu-
profen in relation to the various formulations of the drug that may be taken
OTC.
(b) The types of food and the timing of drug intake in relation to that of foods,
the volumes and types of liquids may influence the pharmacokinetics,
therapeutic actions, and safety of various ibuprofen formulations that may
affect the advice which should be covered by any such recommendations.
(c) Current recommendations by various authorities and regulatory agencies on
the intake of ibuprofen formulations with food, at mealtimes, with fluids or
liquid foods (e.g., milk) or as a consequence of fasting.
(d) The evidence for any apparent safety benefits, which are assumed to be in
preventing gastro-intestinal symptoms, which may arise from intake of the
drug with food, at various stages in mealtimes, and/or with fluids.
(e) Influence of intake of food on gastric acidity and effects of ibuprofen on acid
production, both factors that are important in the pH-dependent gastro-
duodenal absorption of ibuprofen.
(f) Practical impact of any recommendations to take ibuprofen with food or at
various stages around mealtimes or with fluids or liquid foods.
2. The evidence shows that taking standard or conventional immediate-release
(IR) and extended (or modified) release (MR or SR) ibuprofen, or the lysine or
sodium salts of ibuprofen tablets during or after meals, delays the gastric
absorption of the drug but not its total bioavailability. However, the gastric
absorption of IR ibuprofen is not affected when taken immediately before
meals. The total bioavailability of the drug is generally unaffected when it is
taken at any stage with meals compared with that following fasting.
3. The extent of reduction in the maximal plasma or serum concentrations of
ibuprofen when the IR or solubilised formulations (e.g., sodium or lysine salts
or “liquigel” formulations) are taken with food or under conditions of fasting
followed by intake of meals is relatively small (~20–30 %).
Since the total bioavailability is unaffected, it is unlikely that conditions of food
intake have any pronounced negative impact on the therapeutic efficacy of the
IR or solubilised formulations of the drug, although these conditions may have
greater effects on ER or MR formulations, based on what is known about the
impact of food on the oral pharmacokinetics of these forms.
4. The evidence from published studies in various acute pain states (five of which
were in dental surgical pain) suggests that the lysine salt of ibuprofen has a
faster onset of action (approximately 30–45 min in dental pain studies) than
conventional ibuprofen IR tablets and, in some studies, compared with paracet-
amol or aspirin (about 0.75–2 h), or placebo. The pain relief from ibuprofen
lysine in the dental pain studies extended to about 6 h. This is in accord with the
absorption profile of this salt, but principally in the fasted state. In the absence
138 7 Gastro-Intestinal Toxicity

of any information on the instructions to subjects taking these drugs at various

stages under fasting or fed conditions (especially in the dental pain studies), it
can only be assumed that the presence of food in the stomach had little influence
on the speed of onset of analgesia of the lysine salt, and that this was faster than
that from conventional ibuprofen (acid) tablets or that from the other analgesics.
5. There is no published evidence available to indicate whether there are any
perceived benefits in reducing GI irritation or symptoms from taking ibuprofen
formulations with food or milk or other fluids. Indeed, the recommendations of
drug regulatory agencies or those in authoritative literature (formularies, lead-
ing clinical pharmacological texts, or advisory notices from agencies) are
inconsistent, and are not substantiated by any published recommendations or
investigations. Some of these sources recommend intake of ibuprofen (which
includes the conventional immediate-release or coated formulations) with
meals or milk in individuals prone to upset stomach or epigastric pain. This
may be regarded as “common sense”, but there is no evidence to support these
recommendations. There may be important “consumer-related” issues that
influence whether the public are prepared to take tablets with food, as this
may be a bulky combination and not pleasant, especially in the elderly or those
patients with some degree of dysphagia.
6. The absorption pharmacokinetics of extended- or modified-release formulations
(i.e., ER or MR) of ibuprofen appears to be more markedly reduced than that of
the immediate release or solubilised formulations. Thus, any recommendations
to take these formulations of ibuprofen with food or at mealtimes could reduce
the therapeutic efficacy if viewed from the negative influence of food on
pharmacokinetics of these formulations. However, there is no evidence to
suggest that there is reduced efficacy or risks of GI events from of intake of
ER or MR formulations with food or milk.
7. There is no clear indication of when ibuprofen formulations should be taken
with individual types of food (with variations in carbohydrates, proteins, fats) or
with milk, based on the available evidence. The conclusions are that there is
insufficient evidence to warrant mandatory warnings or statements to indicate
that ibuprofen formulations should be taken with meals, milk, or water to
reduce the likelihood or occurrence of GI upsets or severe GI adverse events.
Whether a consensus recommendation to take these products with food or milk
in individuals who are likely to have upset stomach might be voluntarily applied
in conformity with the recommendations, on the basis of this being a common-
sense recommendation, is debatable but may be useful to the patient.
Given the limited amount of data available, which suggests that the intake of
food has little if any clinically significant effects on the speed of onset of analgesia
from ibuprofen lysine and that the overall bioavailability of the drug is unaffected,
the issue of food intake does not represent a major issue for recommended usage of
this salt, nor indeed that of any other IR formulation of the drug.
7.6 Reducing GI Risks 139

Further investigations on the effects of intake of ibuprofen before during or after

food or various compositions would be necessary to determine the relative gastro-
protective effects of intake of food compared with the onset of analgesia in these
fed compared with fasted states.
In essence, therefore, there is no evidence to support the beneficial effects of
taking ibuprofen with foods or drink.
Chapter 8
Cardiovascular Safety

There are three main issues concerning cardio-vascular (CV) safety of ibuprofen.
The first of these concerns the possible risks of triggering serious CV conditions
such as congestive heart failure (CHF) and myocardial infarction (MI), a situation
which has arisen as a consequence of the re-evaluation of risks of MI from all
NSAIDs following the identification of risks of this condition with rofecoxib and
other coxibs. The second concerns the effects of NSAIDs, including ibuprofen, on
blood pressure in hypertensive individuals, elevation of blood pressure being
regarded as a surrogate marker for risks of MI or stroke. Linked to the effects of
NSAIDs in elevating blood pressure are their effects on renal functions, which can
contribute to their hypertensive potential as a consequence of inhibition of renal
prostaglandin production. This has given rise to the so-called “cardio-renal” syn-
drome of NSAIDs, and again has come from recognition of the pronounced renal
effects of coxibs as a consequence of inhibition of COX-2 in the macula
densa (Harris et al. 1994; Haas et al. 1998; Khan et al. 1998; Inoue et al. 1998;
Ichihara et al. 1999; Wolf et al. 1999; Roig et al. 2002); aspects of this are discussed
in Chap. 9. The third issue is the possibility that ibuprofen might reduce the anti-
platelet effects of aspirin, and thus reduce the anti-thrombotic effectiveness of the
latter.

8.1 Disease-related Issues

There is a fundamental disease-related issue with regard to the effects of coxibs and
NSAIDs in producing the range of cardio-vascular symptoms and life-threatening
conditions such as myocardial infarction, stroke, and congestive heart failure. The
emphasis since the identification of increased risks of these CV conditions has been
on the actions of the drugs per se. However, there is substantial evidence that in RA
and other rheumatic conditions these CV conditions are risk factors in themselves,
along with the influence of diabetes mellitus, hypertension, systemic inflammation,
and obesity (Turesson et al. 2004, Panoulas et al. 2007; Peters et al. 2009; Freise

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 141

DOI 10.1007/978-3-0348-0496-7_8, # Springer Basel 2012
142 8 Cardiovascular Safety

et al. 2009; Mathieu and Lemieux 2010; Rho et al. 2010). Indeed, there is growing
evidence that RA, like diabetes mellitus, may be an independent risk factor for CV
disease (Peters et al. 2009). Allied with this is the evidence that COX-2 inhibition
by coxibs, and NSAIDs may result in a shift in Th1-type immuno-inflammatory
response that is prevalent in atherosclerosis to produce instable atheromatous
plaque in coronary arterial disease which is associated with a Th2-type immuno-
logical response (Padol and Hunt 2010). Furthermore, concomitant infections with
Helicobacter pylori, Chlamydia, and other microbial agents may enhance the risk
of developing CV conditions (Miragliotta and Molineaux 1994; Gunn et al. 2000;
Freise et al. 2009; Rainsford 2010). H. pylori is prevalent in patients with arthritic
disease; this organism has been shown to have pro-thrombotic activity (Miragliotta
and Molineaux 1994) and to cause shifts in Th1/Th2 subsets (Rainsford 2010), and
the CagA positive pathogenic strain is associated with increased risks of premature
myocardial infarction (MI), thus making this organism a prime candidate for being
associated with MI and other CV conditions. As suggested, “the gun must be loaded
(i.e., presence of prior disease or infections) for the coxibs to pull the trigger and
produce CV disease” (Rainsford 2010).
The available evidence reviewed here shows that ibuprofen has low CV risks,
although this drug may have effects on blood pressure (Durrieu et al. 2005;
Panoulas et al. 2007) and on the actions of drugs used to control blood pressure.

8.2 Heightened Concerns from the Coxib Studies

Serious CV events, principally ischaemic heart conditions, were initially

highlighted by the initial long-term studies with rofecoxib, but then followed with
other coxibs and later some of the NSAIDs (Strand and Hochberg 2002; Topol
2004, 2005; Khanna et al. 2005; Östör and Hazleman 2005; Rainsford 2005a). The
CV events included myocardial infarction and hypertension, and were noted with
rofecoxib (VIOXX®) in the VIGOR study as well as in a number of other studies.
They were of sufficient concern for the company producing this drug, Merck Sharp
& Dohme, to withdraw it from the market on 29 September 2004 (Topol 2004,
2005; American College of Rheumatology, Hotline 2005; Psaty and Furberg 2005).
In the wake of the issues surrounding withdrawal of rofecoxib, the FDA determined
that valdecoxib (Pfizer) had similar CV risks, as well as the skin reactions that
emerged with this drug, which led to its withdrawal in 2005.
The FDA and other agencies worldwide were alerted and sufficiently concerned
with the CV ADRs with rofecoxib, such that extensive reviews were undertaken by
these agencies world-wide of both coxibs and NSAIDs based on the somewhat
unfounded premise that inhibition of COX-2 which occurs with all these drugs
might well underlie the increased risks of MI and elevation of blood pressure. It is
important to note that the VIGOR study investigating the long-term GI effects of
rofecoxib was performed in patients with rheumatoid arthritis (RA). RA patients are
known to have a markedly higher risk of developing MI and other serious CV
8.3 Epidemiological Studies 143

events (Nurmohamed et al. 2002; Assous et al. 2007), and this is not a feature
generally recognized in the assessment of CV risks of coxibs and NSAIDs.
Subsequent analysis of clinical trials performed with rofecoxib has confirmed
the higher risk of CV toxicity with this drug, especially in the high-dose range
(
50 mg/day) (Kerr et al. 2007; Strand 2007; Baron et al. 2008; Table 8.1).
Furthermore, there are indications from studies performed with the coxibs in
long-term preventative studies in cancers or Alzheimer’s disease that high doses
of these drugs were employed, and the patients were clearly very sick.
Etoricoxib (Arcoxia®) also developed by Merck Sharp and Dohme as a second-
generation coxib is probably the most selective inhibitor of COX-2 of those drugs
that have been developed to date. Large-scale trials have given indications that GI
and CV events from etoricoxib may be lower than with NSAIDs, such as
diclofenac, as well as celecoxib (Cannon et al. 2006).
Lumiracoxib (Prexige®; Novartis), although classed possibly incorrectly as a
coxib, is not chemically like other coxibs, as it is a derivative of diclofenac. It also
does not have the high COX-2 selectivity of etoricoxib or rofecoxib. In view of
commercial interest in the CV issue with NSAIDs, Novartis have undertaken large-
scale studies to determine the CV safety with lumiracoxib, which was compared
with ibuprofen and naproxen, all at prescription-level dosages (Schnitzer et al.
2004; Matchaba et al. 2005; Stricker et al. 2008).
Likewise, Pfizer through its collaborations undertook an extensive evaluation of
their data on celecoxib to determine the CV risks in clinical trials on patients
exposed to this drug compared with some other NSAIDs and rofecoxib (Moore
et al. 2005; White et al. 2007; Solomon et al. 2008a, b). Some of the data from these
large-scale clinical trials and subsequent analysis of CV risks of NSAIDs and
coxibs have featured comparisons with ibuprofen.
Thus, these data as well as that from large-scale epidemiological studies
are useful as a basis for determining the relative CV safety of ibuprofen compared
with its competitors including the coxibs (Table 8.1). Overall these data show
that although there is some variability in risk assessments between the studies
while ibuprofen has a relatively low CV risk.

8.3 Epidemiological Studies

The awareness of CV risks from coxibs and NSAIDs has led to a substantial number
of studies reported in which the risks of MI or other serious CV accidents have been
examined (McGettigan and Henry 2006; Antman et al. 2007; Waksman et al. 2007;
Ray et al. 2009; Ray 2010; Table 8.1).
Among these studies, that by Garcia-Rodriguez and co-workers (2004)
employed data from the UK General Practice Research Database (GPRD) which
records reports from GPs sent anonymously to the UK MHRA. This database
records demographic and patient data, and over 90 % of GP referrals along with
prescription details. The associations of MI with various patient and risk factors was
Table 8.1 Meta analysis, case–control and cohort studies of cardiovascular risk with ibuprofen and COX-2 (Coxib) inhibitors
144

Relative Risks (95 % CI)

Authors (year) Study type Ibuprofen Celecoxib Rofecoxib (all doses) Naproxen Diclofenac
Gislason et al. (2006) Cohort 1.390 (1.27–1.53) 2.06 (1.73–2.45) 2.29 (1.99–2.65) – –
MacDonald and Wei (2003) 1.73 (1.05–2.84) – – – 0.80 (0.49–1.31)
Ray et al. (2002) 0.91 (0.7–1.06) 0.96 (0.76–1.21) 1.70 (0.98–2.95) 0.93 (0.82–1.06) –
Curtis et al. (2003) 0.84 (0.7–1.01) – – – –
Ray et al. (2003) 1.15 (1.02–1.28) – – 0.95 (0.82–1.09) –
Summary relative risk 1.12 (0.90–1.38) 1.22 (0.69–2.16) 1.51 (0.73–3.13) 0.94 (0.85–1.04) 1.36 (0.51–3.65)
Hippisley-Cox Case–control studies 1.24 (1.11–1.39) 1.21 (0.96–1.54) 1.32 (1.09–1.61) 1.27 (1.01–1.60) 1.55 (1.39–1.72)
and Coupland (2005)
Graham et al. (2005) 1.06 (0.96–1.17) 0.84 (0.67–1.04) 1.34 (0.98–1.82) 1.14 (1.00–1.30) 1.60 (0.96–1.17)
McGettigan et al. (2006) 0.98 (0.53–1.81) 1.11 (0.59–2.11) 0.63 (0.31–1.28) – –
Kimmel et al. (2004) 0.52 (0.39–0.69) 0.43 (0.23–0.79) 1.16 (0.70–1.93) 0.48 (0.28–0.82) –
Singh et al. (2006) 1.11 (1.01–1.22) 1.09 (1.02–1.15) 1.32 (1.22–1.42) 1.08 (0.95–1.22) –
Fischer et al. (2005) 1.16 (0.92–1.46) – – 0.96 (0.66–1.38) 1.23 (1.00–1.51)
Garcı́a Rodrı́guez et al. (2004) 1.06 (0.87–1.29) – – 0.89 (0.64–1.24) 1.18 (0.99–1.40)
Bak et al. (2003) 1.30 (1.00–1.60) – – 0.70 (0.40–1.10) 1.10 (0.70–1.17)
Solomon et al. (2002) 1.02 (0.88–1.18) – – 0.84 (0.72–0.98) –
Schlienger et al. (2002) 1.17 (0.87–1.58) – – 0.68 (0.42–1.13) 1.38 (1.08–1.77)
Watson et al. (2002) 0.74 (0.35–1.55) – – 0.57 (0.31–1.06) 1.68 (1.14–2.49)
Summary relative risk 1.06 (0.95–1.18) 1.01 (0.90–1.13) 1.21 (1.08–1.36) 0.96 (0.84–1.10) 1.36 (1.21–1.54)
Overall summary relative risk 1.07 (0.97–1.18) 1.06 (0.91–1.23) 1.35 (1.15–1.59) 0.97 (0.87–1.07) 1.40 (1.16–1.70)
Antman et al. (2007) Meta analysis of RCTs 1.51 (0.96–2.37) – – 0.92 (0.67–1.26) 1.63 (1.12–2.37)
(vascular events)
(Observational 1.07 (0.97–1.18) – – 0.97 (0.87–1.07) 1.40 (1.16–1.70)
events Mostly MI)
Registry recurrent MI 1.25 (1.07–1.46) – – – 1.54 (1.23–1.93)
Registry mortality 1.50 (1.36–1.67) – – – 2.49 (2.09–2.80)
8 Cardiovascular Safety

Modified from Strand (2007) with additional data from Antman et al. (2007)
Data on summary relative risks for celecoxib, rofecoxib, naproxen and diclofenac represents all trials analysed by Strand (2007)
8.3 Epidemiological Studies 145

examined in this study. The odds ratios (ORs) for development of MI after multi-
variant adjustment with current use of NSAIDs were found to have an OR ¼ 1.06
(0.87–1.29; 95 % CI values) for ibuprofen, contrasted with those at the upper end of
risk with piroxicam with an OR of 1.25 (0.69–2.25). Prior history of CHD or
concomitant intake of aspirin did not increase the risk of MI from ibuprofen.
Jick and co-workers (2006) performed a case–control analysis of data from the
UK GPRD; they did not find any increased risk of acute MI with either ibuprofen or
naproxen, but did find increased risks with diclofenac, rofecoxib, and celecoxib.
Kimmel et al. (2004) performed a study of hospitalized patients for MI in a
5-county region around Philadelphia (USA). They observed reductions in the risks
of MI among non-aspirin NSAID users. This reduction was also observed with
ibuprofen, with the adjusted OR being 0.52 (0.39–0.69; 95 % CI) compared with
that of 0.53 (0.42–0.67) for aspirin and 0.48 (0.28–0.82) for naproxen, a drug which
has often been found to have low CV risk and in fact may have some cardio-
protective effects (Topol 2004, 2005; Khanna et al. 2005).
In a nested case–control study of data from a leading US health maintenance
organization, Kaiser Permanente, Graham and co-workers (2005) examined 8,143
cases of serious coronary disease (from 2,302,029 patient-years follow-up). They
found that the adjusted OR for ibuprofen for current use was 1.26 (1.00–1.60),
compared with that of naproxen OR ¼ 1.36 (1.06–1.75) and rofecoxib low dose
(<25 mg/day) OR ¼ 1.47 (0.99–2.17) and high dose (>25 mg/g) OR ¼ 3.58
(1.27–10.11). For “remote” use, the OR for ibuprofen was 1.06 (0.96–1.17),
contrasted with that of rofecoxib (high dose, >25 mg/day) with an OR of 3.0
(1.09–8.31) and naproxen.
In a combined study of CV and GI events in 49,711 US Medicare beneficiaries
(>65 years of age), Schneeweiss et al. (2006) found that the risks of acute MI was
1.20 with ibuprofen, compared with 1.01 with naproxen, 1.54 with diclofenac, 1.58
with celecoxib, and 1.56 with rofecoxib.
A summary of the risk calculations associated with the occurrence of these
conditions is shown in Table 8.2. Overall the data show that ibuprofen was amongst
the drugs with the risks of serious GI and CV events in these elderly patients
(Table 8.2). It should be noted that there is a degree of overlap in the confidence
intervals of relative or risk differences in these data. To overcome complications in
data analysis arising from unmeasured variables, the authors undertook an instru-
mental analysis of the data in which confounding variables were removed (see
Footnotes Table 8.2 for details). The results show that ibuprofen was amongst the
group of lower-risk drugs, and notably this was more striking in comparison with
diclofenac (high risk for both GI and MI events) and rofecoxib (high risk of MI, but
lower risk of GI complications, Table 8.2).
In another nested case–control study using clinical records of the UK general
practice database known as QRESERCH, Hippisley-Cox and Coupland (2005)
found that recent use (<3 months) of ibuprofen was associated with an adjusted
OR of 1.24 (1.11–1.39), compared with that of diclofenac, which had an OR of 1.55
(1.39–1.72), naproxen 1.09 (0.96–1.24), celecoxib 1.14 (0.93–1.40), and rofecoxib
1.05 (0.89–1.24). The lack of signals with rofecoxib and to some extent with
 146

Table 8.2 Risks and adjusted relative or risk differences for GI complications and acute MI after 180 days, stratified by NSAID group and calculated for GI
and MI groups
a b
GI complications Acute MI
c
Drug Events Exposed Risk Rel diff/100 (95 % CI) Events Exposed Risk Rel diff/100c (95 % C.I.)
Ibuprofen 68 5,353 1.27 0.88 (1.93, 3.68) 64 5,353 1.2 0.01 (2.49, 2.46)
Celecoxib 291 19,842 1.47 0 (reference) 313 19,842 1.58 0 (reference)
Diclofenac 29 1,817 1.6 5.09 (1.18, 11.36)d 28 1,817 1.54 6.07 (0.02, 12.15)d
Naproxen 60 4,139 1.45 0.74 (2.04, 3.52) 42 4,139 1.01 0.30 (2.74, 2.14)
Rofecoxib 212 12,232 1.73 0.30 (1.28, 1.89) 191 12,232 1.56 1.4 (0.20, 3.01)
Other NSAIDs 86 6,328 1.36 60 6,328 0.95
a
GI gastrointestinal, bMI myocardial infarction, 95 % CI 95 % confidence interval.
c
Relative (or risk) difference obtained in an instrumental variable model for differences in risks of GI and HI events, adjusted for age, sex, race, hypertension,
congestive heart failure, coronary heart disease, past and concurrent gastroprotective drug use, peptic ulcer disease, rheumatoid arthritis, osteoarthritis,
warfarin use, steroid use, Charlson index, physician visits, hospitalizations, and nursing home residence.
d
Statistically significant difference by Sargan test.
From Schneeweiss et al. (2006), with modifications
8 Cardiovascular Safety
8.3 Epidemiological Studies 147

celecoxib is odd, but may reflect more limited use of this drug according to the
guidelines by the UK National Institute for Clinical Excellence (NICE).
A recent retrospective study of hospitalization records of
65-year-old patients
admitted for acute MI (as well as GI events) in Québéc (Canada) by Rahme and
Nedjar (2007) showed that the adjusted hazard ratios (HR) were 1.05 (0.74–2.41)
for ibuprofen, 1.69 (1.35–2.10) for diclofenac, 1.59 (1.31–1.93) for naproxen, 1.34
(1.19–1.52) for celecoxib, 1.27 (1.13–1.42) for rofecoxib, and 1.29 (1.17–1.42) for
paracetamol.
Another large-scale epidemiological study undertaken using a US patient data-
base was performed by Motsko et al. (2006) using the US Department of Veterans
Affairs (VA) Veterans Integrated Service Network 17, in which Medicare data and
Texas Department of Health Mortality data was incorporated in order to capture
events outside the VA network. Of 12,188 exposure periods to the NSAIDs
(in 11,930 persons), long-term and 180 days, data from intake of ibuprofen
were used to set the data reference point at 1.0, with the other NSAIDs and two
coxibs being compared with this value. Thus, the CV risks (MI, stroke and MI-
related deaths) with long-term celecoxib and rofecoxib were associated with an
appreciably greater hazard ratio (HR) of 3.64 (95 % CI 1.36) and 6.64 (95 % CI
20.28) respectively. The risks were greater in patients aged 65 years. In contrast,
long-term intake of etodolac and naproxen short- or long-term resulted in HR
values within those of ibuprofen. Thus, none of these three drugs were associated
with any cardio-negative or cardio-protective effects (Motsko et al. 2006).
A study undertaken by Huang et al. (2006) in Taiwan is of particular interest, in
the context of establishing if the CV risks from NSAIDs and celecoxib that are
evident in Western/US-European populations are also observed in Oriental
communities (Tables 8.3 and 8.4). These authors undertook a population-based
analysis using data from the Taiwanese Bureau of National Health Insurance (NHI)
(Taipei); this health insurance system covers 99 % of Taiwan’s population of 23
million (data obtained in the period 2001–2003). This NHI database also contains
comprehensive records of diagnosis, treatment, and the occurrence of clinical
adverse events and other outcomes. A total of 16,326 patients (of equal numbers
of both sexes) were identified who received long-term treatment with ibuprofen
(32.09 % of patients), celecoxib (23.04 % of patients), etodolac (12.34 % of
patients), nabumetone (13.86 % of patients) and naproxen (18.68 % of patients).
The overall prevalence of acute MI, angina, cerebro-vascular accident (CVA),
and transient ischaemic attack (TIA) was higher in long-term users of these drugs
who had a prior history of CV disease (Table 8.3).
The data in Table 8.4 shows the prevalence of the individual CV events with
intake of the NSAIDs and celecoxib. The HR values for AMI, CVA, and TIA
NSAIDs were similar for all four NSAIDs, and in some cases higher for celecoxib.
Ibuprofen had a somewhat lower risk of angina (HR 0.78 [95 % CI 0.63–0.93]).
These data on the risk factors (Table 8.4) show that risk of CV events is greater
in subjects that are at CV-risk, and the pattern of CV events may be similar in the
population of Taiwanese compared with that in Western populations. As expected,
patients with diabetes mellitus and chronic renal disease were at highest risk for
Table 8.3 Cardiovascular events (CVDs) in long term >180 days users of one of four nonselective NSAIDs (etodolac, nabumetone, ibuprofen, or naproxen) or the
cyclooxygenase-2 inhibitor, celecoxib, in Taiwan
Etodolac Nabumetone Ibuprofen Naproxen Celecoxib All patients
History of No history of History of No history of History of No history of History of No history of History of No history of History of No history of
CVD CVD CVD CVD CVD CVD CVD CVD CVD CVD CVD CVD CVD
AMI
Events per 1/38 (2.63) 22/1,976 3/31 (9.68) 32/2,231 1/33 (3.03) 40/5,206 2/31 (6.45) 31/3,018 3/77 (3.90) 34/3,685 10/210 (4.76) 159/16,166
subgroup, no (1.11) (1.43) (0.77) (1.03) (0.92) (0.99)
(%)
Duration of use, 363.24 396.23 393.39 425.01 402.00 347.19 349.90 418.23 381.36 383.56 378.46 385.60
mean (SD), d (204.22) (207.54) (233.43) (234.18) (201.45) (200.18) (178.54) (240.62) (173.65) (176.00) (192.99) (211.28)
Angina
Events per 3/78 (3.85) 14/1,936 2/68 (2.94) 4/2,194 (0.18) 3/55 (5.45) 22/5,184 2/60 (3.33) 12/2,989 6/128 (4.69) 16/3,634 16/389 (4.11) 68/15,937
subgroup, no (0.72) (0.42) (0.40) (0.44) (0.43)
(%)
Duration of use, 360.12 397.04 372.96 426.18 368.38 347.32 348.88 418.91 371.83 383.93 365.65 385.99
mean (SD), d (199.47) (207.72) (210.83) (234.70) (231.69) (199.87) (199.87) (240.73) (158.22) (176.53) (193.25) (211.45)
CVA
Events per 23/266 (8.65) 26/1,748 14/202 (6.93) 39/2,060 12.177 (6.78) 58/5,062 16.136 51/2,913 23.256 (6.46) 55/3,406 88/1,137 229/151,889
subgroup, no (1.49) (1.89) (1.15) (11.76) (1.75) (1.61) (7.74) (1.51)
(%)
Duration of use, 374.47 398.82 418.13 425.21 423.14 344/89 414.68 417.67 346.39 387.40 385.48 385.82
mean (SD), d (183.58) (210.74) (226.64) (234.92) (245.59) (197.95) (240.47) (240.17) (151.03) (177.91) (211.63) (203.26)
TIA
Events per 2/48 (4.17) 16/1,966 2/37 (5.41) 14/2,225 0.35 (0) 18/5,204 2/40 (5.00) 17/3,009 4/88 (4.55) 18/3,674 10.248 (4.03) 83/16,078
subgroup, no (0.81) (0.63) (0.35) (0.56) (0.49) (0.52)
(%)
Duration of use, 318.79 397.48 372.54 425.44 384.49 347.29 395.28 417.83 351.91 384.27 385.90 360.17
mean (SD), d (128.13) (208.71) (234.8) (234.09) (209.28) (200.15) (219.12) (240.44) (147.52) (176.50) (211.45) (181.93)
CVD cardiovascular disease, AMI acute myocardial infarction, CVA cerebrovascular accident, TIA transient ischaemic attack
Source: Taiwanese Bureau of National Health Insurance database, January 1, 2001 to December 31, 2003
From Huang et al. (2006)
Table 8.4 Potential risk factors for cardiovascular events in long-term (>180 days) users of one of four nonselective NSAIDs (etodolac, nabumetone,
ibuprofen, or naproxen) or a cyclooxygenase (COX)-2 inhibitor (celecoxib) in Taiwan
AMI Angina CVA TIA
Variable HR 95 % CI P HR 95 % CI P HR 95 % CI P HR 95 % CI P
Age 1.05 1.04–1.06 <0.01 1.02 1.01–1.04 0.01 1.05 1.04–1.05 <0.01 1.04 1.02–1.06 <0.01
Male sexa 1.22 1.05–1.41 0.01 1.02 0.83–1.25 0.87 1.04 0.93–1.15 0.5 1.14 0.94–1.38 0.18
Medication prescribedb
Etodolac 1.09 0.89–1.34 0.41 1.1 0.83–1.45 0.52 1.07 0.93–1.24 0.35 1.07 0.81–1.40 0.64
8.3 Epidemiological Studies

Nabumetone 0.98 0.84–1.14 0.78 1.08 0.90–1.30 0.43 0.96 0.87–1.07 0.48 1.08 0.90–1.29 0.42
Ibuprofen 1.07 0.98–1.18 0.14 0.78 0.63–0.96 0.02 0.99 0.92–1.07 0.79 0.98 0.85–1.12 0.75
Naproxen 1.02 0.94–1.10 0.71 0.99 0.88–1.12 0.89 1.02 0.97–1.08 0.41 0.98 0.89–1.09 0.72
Prescription duration 1 1.00–1.00 0.01 1 1.00–1.00 0.41 1 1.00–1.00 0.01 1 1.00–1.00 0.21
History of CVDc 2.29 1.22–4.32 0.01 6.19 3.56–10.78 <0.01 3.56 2.80–4.52 <0.01 6.6 3.72–11.73 <0.01
Preexisting medical condition
CHFd 2.17 1.38–3.39 <0.01 2.04 1.08–3.85 0.03 1.46 1.01–2.10 0.04 0.86 0.37–2.00 0.73
Chronic renal diseasee 1.81 1.17–2.81 0.01 1.73 0.88–3.37 0.11 1.24 0.85–1.82 0.26 0.97 0.45–2.11 0.94
Diabetes mellitus 1.62 1.18–2.23 <0.01 1.26 0.78–2.02 0.35 1.41 1.11–1.7 <0.01 1.74 1.15–2.64 0.01
Hypertensionf 1.41 1.04–1.92 0.03 1.12 0.72–1.73 0.62 1.21 0.97–1.50 0.09 1.38 0.93–2.06 0.11
Dyslipidemiag 1.09 0.63–1.90 0.75 2.79 1.60–4.86 <0.01 0.77 0.48–1.23 0.27 0.67 0.27–1.66 0.39
AMI acute myocardial infarction; CVA cerebrovascular accident; TIA transient ischemic attack; HR hazard ratio; CVD cardiovascular disease; CHF
congestive heart failure
a
Female sex.
b
The COX-2 inhibitor.
c
No recurrence.
d
No preexisting CHF.
e
No preexisting chronic renal disease, no preexisting diabetes mellitus.
f
No preexisting hypertension.
g
No preexisting dyslipidemia (all, HR-1.00).
Based on data in Huang et al. (2006)
149
150 8 Cardiovascular Safety

AMI, angina, and CVA. Those with hypertension notably showed risk for AMI but
not for other CV conditions.
Gislason and colleagues (2006) employed data from the nationwide Danish
National Patient Registry, which since 1978 has registered all hospital admissions
in Denmark. Since 1995, the Danish Registry of Medicinal Product Statistics has
kept records of all prescriptions dispensed by pharmacies in Denmark. In addition
to recording data on the dispensed medication, the registry includes patient data.
The authors identified all patients with first-time MI between 1995 and 2002, and
determined the risk of death and hospitalization associated with use of NSAIDs or
COX-inhibitors. Of 58,432 patients (with first MI) who were discharged alive,
9,773 were subsequently re-hospitalized for MI and a total of 16,573 died. The
HR for death following any use of ibuprofen was 1.5 (95 % CI 1.36–11.67),
celecoxib 2.57 (95 % 2.15–3.08), diclofenac 2.40 (95 % CI 2.09–2.80), rofecoxib
2.80 (95 %CI 2.41–3.25), and for all other NSAIDs 1.29 (1.16–1.43).
The Cox Proportional Hazards analysis for HRs for death and rehospitalisation
for MI showed that there was a significantly increased risk of death associated with
all the NSAIDs and coxibs. This analysis applied to high and low intake dosages
showed there was a clear dose-related response. Of particular interest is that the
daily intake of 1,200 mg ibuprofen was associated with an HR for death of 0.75
(95 % CI 0.61–0.92) compared with no use of drug, which was not observed with
the other drugs. This same dosage of ibuprofen was associated with an HR for
hospital re-admission for MI of 1.28 (95 % CI 1.03–1.60) compared with the
reference of no use of NSAIDs. Both rofecoxib and celecoxib showed notably
higher HRs for both categories, and this was dose-related. High dose
(100 mg/day) was also associated with higher HRs in both categories, which is
of the same order as that observed with high doses of the coxibs.
In an Expert Opinion article, Fosbøl et al. (2010) stated inter alia “. . .Studies on
the cardiovascular safety of NSAIDs in healthy people have recently underlined
that healthy people (sic) are also at risk of cardiovascular adverse events. The
results showed increased risk with the use of selective COX-2 inhibitors and also
the traditional NSAID diclofenac. The results showed dose-dependency.
Ibuprofen in low doses (<1,200 mg/day) and naproxen seem to be safe
alternatives with regard to cardiovascular safety.”
The reference by Fosbøl et al. (2010) to “healthy people (sic) ” raises the issue
that the authors may consider that those who have no CV condition, even if it arises
with drugs, can hardly be described as healthy any longer!! It is, therefore, ques-
tionable whether the so-called “healthy” individuals were in fact healthy.
These data need to be interpreted in the context of being in high-risk patients.
They show that on a nationwide basis in this European population, OTC dosage of
ibuprofen is probably associated with the lowest risk for MI-related rehospita-
lisation and death. Even at higher doses (
1,200 mg/day), the risks of death from
ibuprofen, though higher than those in the lower dose or no-use categories, are
about twofold lower than associated with intake of the other drugs.
Dose-related incidence of myocardial infarction in patients taking NSAIDs is
shown in the data from van Staa et al. (2008) in Table 8.5.
8.3 Epidemiological Studies 151

Table 8.5 Relative risk (RR) of myocardial infarction in relation to dose of NSAID current users
compared with control patients
NSAID vs. Control cohort
Number of Age–sex–year adjusted Fully adjusted
NSAID use cases RRa (95 % CI) RRb (95 % CI)
c
Current 5,690 1.31 (1.27–1.36) 1.12 (1.08–1.17)
Ibuprofen (mg per day) 1,913 1.22 (1.16–1.28) 1.04(0.98–1.09)
<1,200 176 1.29(1.10–1.50) 1.05(0.91–1.22)
1,200 600 1.21(1.11–1.31) 1.02(0.94–1.11)
1,201–2,399 146 1.42(1.20–1.67) 1.22(1.03–1.44)
>2,400 10 2.28(1.23–4.24) 1.96(1.05–3.65)
Diclofenac (mg per day) 2,033 1.40(1.33–1.47) 1.21(1.15–1.28)
<150 675 1.30(1.20–1.40) 1.13(1.04–1.22)
150 650 1.50(1.38–1.62) 1.28(1.18–1.39)
150–299 35 1.35(0.97–1.88) 1.18(0.85–1.65)
>300 10 2.28(1.23–4.24) 2.03(1.09–3.77)
Naproxen (mg per day) 526 1.22(1.12–1.3) 1.03(0.94–1.13)
<1,000 155 1.19(1.01–1.40) 0.99(0.85–1.17)
1,000 250 1.31(1.15–1.48) 1.12(0.98–1.27)
>1,000 10 1.14(0.61–2.11) 0.92(0.49–1.71)
a
Age and sex, with years on therapy Adjusted Relative Risk
b
Fully adjusted for all variables Relative Risk
c
Represents all patients in study, some of whom received other NSIADs and were current or past
NSAID users. RR= relative risk
Reproduced from van Staa et al. (2008) with permission of John Wiley and Sons, publishers of
Journal of Internal Medicine

This retrospective cohort study using the UK GPR database performed by van
Staa et al. (2008) involved a total of 729,294 users of NSAIDs and 443,047 controls.
The relative rate for MI increased with cumulative and daily dose. Ibuprofen and
naproxen users had lower risks of MI than those that took diclofenac; these drugs
being amongst the most frequently prescribed NSAIDs in the UK. Indeed, the risks
with 0–4 prescriptions were around unity. In comparing the hazard rates (i.e., the
absolute risk) there were no overall differences between these three drugs.
The authors suggested that the increased risk of MI in these patients may relate to
the underlying disease severity.
The data in Table 8.5 show that ibuprofen at OTC doses (1,200 mg/day) has
low relative risks (fully adjusted RR) comparable to low-dose (OTC) naproxen, a
drug which has been indicated from several epidemiological studies to be amongst
the lowest risk for MI of any type.
Congestive heart failure (CHF) has been observed in patients taking NSAIDs
(Mamdani et al. 2004; McGettigan et al. 2008). In hospital-based case–control
studies in Newcastle (New South Wales) Australia during 2002–2005, involving
285 admissions for CHF. McGettigan et al. (2008) observed that celecoxib and
rofecoxib were amongst the most frequently associated NSAIDs in first and recur-
rent admission cases of CHF, and that there was a dose-related association. Also,
152 8 Cardiovascular Safety

Table 8.6 Odds ratios and 95 % confidence intervals for recurrent congestive heart failure in
patients exposed to current nonsteroidal anti-inflammatory drugs compared with current celecoxib
exposure
Crude odds ratio Adjusted odds ratioa 95 % Confidence interval
Celecoxib Reference
Naproxen 1.05 1.05 0.59–1.86
Diclofenac 0.92 0.82 0.51–1.33
Ibuprofen 1.29 1.46 0.66–3.21
Indomethacin 1.87 2.04 1.16–3.58
Rofecoxib 1.51 1.58 1.19–2.11
Acetaminophen 1.19 1.15 0.92–1.44
Nonexposed 0.9 0.93 0.75–1.15
a
Adjusted for age, sex, length of stay, dose, comorbidities, physician characteristics, and
medications to treat congestive heart failure.
Reproduced from Hudson et al. (2007) with permission of John Wiley and Sons, publishers of
Arthritis and Rheumatism

paracetamol was amongst the most frequently associated drug overall, but this was
no different than in controls. Ibuprofen showed no difference in association
between cases and controls (being approximately 31–32 % in all categories).
These data suggest that ibuprofen has a relatively low association with CHF in
comparison with celecoxib and rofecoxib.
Hudson and co-workers (2007) performed a nested case–control analysis of a
hospital administrative database in the Province of Québec, Canada in which
records for the health insurance agency covering inpatients and outpatients were
examined. The population cohort comprised 8,512 cases and 34,048 controls. As
shown in Table 8.6, the data from this study showed that there was a greater risk of
CHF in patients who have taken any NSAID (including coxibs) or paracetamol
(acetaminophen) compared with that in subjects who were not exposed to these
drugs. The incidence from intake of ibuprofen is lower than that of indomethacin
and rofecoxib, but slightly higher than diclofenac and naproxen (Table 8.6).
Overall, therefore, these epidemiological investigations highlight (with admit-
tedly some variability of ORs) the relatively low to moderate risk of ibuprofen at
prescription level dosages being associated with serious CV conditions such as MI.
These observations contrast with the higher risks with diclofenac, the coxibs, and in
one study with paracetamol, and variable risks with naproxen. The risks of cardio-
vascular events from ibuprofen at OTC dosages are appreciably lower than with
higher prescription dosages of this and other NSAIDs or the coxibs.

8.4 Recent Clinical Trials and Meta-Analyses

The CLASS study (Table 7.8) showed that ibuprofen had relatively low incidence
of cardiovascular events, and this has been confirmed in a number of other studies
comparing it with coxibs. These large-scale studies are valuable for highlighting
Table 8.7 Relative risks of acute cardiovascular events in randomized controlled trials of COX-2 (Coxib) inhibitors and NSAIDs
Ibuprofen (comparator drug) Coxib (investigational drug)
Number of Number of
events per events per
Number of Number of 100 patient Number of Number of 100 patient Relative risk
Authors (year) Study Analysis Dose subjects events years Dose subjects events years 95 % CI
Silverstein et al. CLASS Original 800 mg t.i.d. 1,985 20 1.8 Celecoxib 3,987 34 1.5 0.83
(2000) 400 mg b.d.
Strand and APTC 800 mg t.i.d. 1,985 21 1.9 Celecoxib 3,987 52 2.24 1.18
Hochberg 400 mg b.d.
(2002)
Farkouh et al. TARGET APTC 800 mg t.i.d. 4,397 23 0.52 Lumiracoxib 4,376 19 0.43 0.76
(2004) 400 mg o.d. (0.41–1.40)
APTC Antiplatelet Trialists’ Collaboration
In the CLASS and TARGET trials, 22 % of patients took aspirin. In the TARGET trial comparison, naproxen 500 mg b.d. showed number of events per 100 patient years
was 0.57, and this was comparable with ibuprofen (0.52/100 patient years). Relative risks are investigational of comparator drugs. These were crude risks in CLASS
trial. Modified from Strand (2007)
154 8 Cardiovascular Safety

Table 8.8 Cardiovascular events in patients receiving NSAIDs or coxibs: “Network”

meta-analysis rate ratio (95 % CI)
Drug Myocardial infarction Cardiovascular death
Celecoxib 1.35 (0.71–2.72) 2.07 (0.98–4.55)
Diclofenac 0.82 (0.29–2.20) 3.98 (1.48–12.70)
Etoricoxib 0.75 (0.23–2.39) 4.07 (1.23–15.70)
Ibuprofen 1.61 (0.50–5.77) 2.39 (0.69–8.64)
Lumiracoxib 2.00 (0.71–6.21) 1.89 (0.64–7.09)
Naproxen 0.82 (0.37–1.67) 0.98 (0.41–2.37)
Rofecoxib 2.12 (1.26–3.56) 1.58 (0.88–2.84)
Drug *Platelet Trialists’ Collaboration Stroke
Celecoxib 1.43 (0.94–2.16) 1.12 (0.60–2.06)
Diclofenac 1.60 (0.85–2.99) 2.86 (1.09–8.36)
Etoricoxib 1.53 (0.74–3.17) 2.67 (0.82–8.72)
Ibuprofen 2.26 (1.11–4.89) 3.36 (1.00–11.60)
Lumiracoxib 2.04 (1.13–4.24) 2.81 (1.05–7.48)
Rofecoxib 1.44 (1.00–1.99) 1.07 (0.60–1.82)
Rate ratios for the occurrence of various cardiovascular conditions in patients receiving NSAIDs and
coxibs compared with placebo, based on “network” meta-analysis of large-scale randomised con-
trolled trials
* Based on methodology of the Platelet Trialists’ Collaboration assessments of CV events.
Reproduced from Trelle et al. (2011) with permission of the BMJ Publishing Group Ltd.,
publishers of the British Medical Journal

under control conditions in clinical trials in patients with rheumatic disease that
ibuprofen has a low risk of developing cardiovascular effects.
An evaluation of the cardiovascular risks with coxibs and NSAIDs undertaken
by Antman et al. (2007), which was a study under the auspices of the American
Heart Association, has been instructive in critically evaluating and offering a clear
statement of cardiovascular risks of all NSAIDs including coxibs. As shown in
Table 8.7, which is a summary of the cardiovascular risk reported in randomized
placebo-controlled clinical trials with the non-selective NSAIDs, the various out-
come measures and natures of assessment from either randomized controlled trials,
observational studies, or registry data, showed that there is some variability in
cardiovascular risk with the different NSAIDs (Antman et al. 2007). Overall,
ibuprofen has a slightly lower relative risk than diclofenac, but naproxen has a
notably lower risk of cardiovascular events. Indeed, in the VIGOR study and
several other studies that were reviewed back in 2004, it was found that naproxen
had the lowest overall risk of all NSAIDs for developing CV events. For ibuprofen,
the relative risks range from 1.07 for all CV, mostly MI, to all vascular events 1.51.
However, the confidence intervals for these risks overlap considerably, and are
approximately unity in comparison with placebo.
A recent meta-analysis of published and unpublished randomised placebo-
controlled clinical trials (Trelle et al. 2011; Table 8.8) shows that the there is
with some data a relatively high confidence interval (or what is described as the
credibility interval, CI), making it difficult to ascribe clinical significance to some
of these data. The data from the Antiplatelet Trialists’ Collaboration suggests there
8.4 Recent Clinical Trials and Meta-Analyses 155

Fig. 8.1 Incidence of confirmed or probable myocardial infarctions (clinical and silent), from
ibuprofen compared with lumiracoxib and naproxen by sub-study and aspirin use. Reproduced
from Naldi et al. (1999) with permission of John Wiley and Sons, publishers of the British Journal
of Clinical Pharmacology

is an overall trend in favouring placebo with nearly all the drugs. The data on MIs
with rofecoxib show the most significant trend in increased risk, while the other
NSAIDs (including ibuprofen) show variable risks. Diclofenac, etoricoxib, and
celecoxib show the highest risks of CV death, with a lower trend being shown
with ibuprofen in MI, stroke and the APTC data.

8.4.1 Individual Trials

In the large multicentre trial intended to establish the risks of CV events from
lumiracoxib with those from ibuprofen or naproxen in some 14,000 patients, it was
found that the number of confirmed or probable myocardial infarctions and
ischaemic events in the ibuprofen group was comparable with that from
lumiracoxib as well as the naproxen treatment group (Fig. 8.1; Table 8.9; Farkouh
et al. 2004). These data suggest that ibuprofen is no more likely to be a risk of CV
events over that of the other drugs.
156 8 Cardiovascular Safety

Table 8.9 Percentage of confirmed or probable ischaemic events including myocardial

infarctions (clinical and silent), from ibuprofen compared with lumiracoxib and naproxen by
sub-study and aspirin use
Lumiracoxib vs
Both sub-studies ibuprofen sub-study
Lumiracoxib NSAIDs Lumiracoxib Ibuprofen
Number of patients in non-aspirin population 6,950 6,968 3,401 3,431
Patients with confirmed or probable ischaemic 0.49 0.39 0.38 0.35
events
All myocardial infarctions 0.20 0.13 0.12 0.15
Clinical 0.20 0.07 0.12 0.09
Silent 0 0.06 0 0.06
Ischaemic stroke 0.17 0.11 0.18 0.06
Unstable angina 0.07 0.07 0.03 0.12
Transient ischaemic attack 0.04 0.07 0.06 0.03
Number of patients in aspirin population 2,167 2,159 975 966
Patients with confirmed or probable ischaemic 1.34 1.11 0.92 0.93
events
All myocardial infarctions 0.42 0.37 0.10 0.21
Clinical 0.28 0.32 0.10 0.21
Silent 0.14 0.05 0 0
Ischaemic stroke 0.51 0.42 0.21 0.41
Unstable angina 0.23 0.28 0.31 0.31
Transient ischaemic attack 0.18 0.05 0.31 0
Data are percentage (%) of patients with event. NSAIDs non-steroidal anti-inflammatory drugs
Reproduced in part from Farkouh et al. (2004) with permission of Elsevier, publishers of The
Lancet

Table 8.10 Combined incidence of gastrointestinal and cardiovascular events from lumiracoxib,
compared with ibuprofen and naproxen, by sub-study (Safety Population) (Schnitzer et al. 2004)
Number of patients with
Both substudies{ events/number at risk (%) Hazard ratio (95 % CI) pa
Lumiracoxib 89/9,117 (0.98 %) 0.65 (0.49–0.84) 0.0014
Non-steroidal anti- 133/9,127 (1.46 %)
inflammatory drugs
Lumiracoxib vs ibuprofen substudy{
Lumiracoxib 30/4,376 (0.69 %) 0.50 (0.32–0.79) 0.0025
Ibuprofen 56/4,397 (1.27 %)
Lumiracoxib vs naproxen substudy{
Lumiracoxib 59/4,741 (1.24 %) 0.75 (0.53–1.05) 0.0961
Naproxen 77/4,730 (1.63 %)
a
Based on Wald Χ2 statistic for treatment group comparison. Cox proportional-hazards models
include, in addition to treatment group, the factors {sub study, low-dose aspirin, and age; and {low-
dose aspirin and age.
Reproduced from Schnitzer et al. (2004) with permission of Elsevier, publishers of The Lancet
8.5 Interaction of Ibuprofen with the Anti-platelet Effects of Aspirin 157

The combination of the risks of CV and GI events has been considered a major
element in determining the overall safety of coxibs and NSAIDs (Antman et al.
2007). To exemplify this, Schnitzer and co-workers attempted an analysis of the
combined risks of these drugs. A summary of their data showing the combined GI
and CV events is shown in Table 8.10 (Schnitzer et al. 2004). These data show that
the hazard ratio is significantly lower for lumiracoxib than the two NS-NSAIDs,
although there is considerable overlap of the values of the 95 % confidence
intervals. These data do show, however, that the combined risks of serious CV
and GI events with ibuprofen are relatively low. Overall, therefore, these studies
show that ibuprofen has a low risk of developing cardiovascular events, principally
serious conditions such as myocardial infarction, although vascular events might be
slightly increased in risk.

8.5 Interaction of Ibuprofen with the Anti-platelet Effects

of Aspirin

Low-dose (75–100 mg daily) aspirin has been found to reduce established coronary,
cerebrovascular, and peripheral vascular disease, including secondary myocardial
infarction (Webert and Kelton 2004). Although it is arguable that aspirin exerts a
range of non-platelet effects (e.g., actions on coagulation factors), its vascular
preventative actions are primarily due to the inhibition of thromboxane A2 and
consequent platelet aggregation (Webert and Kelton 2004). However, it is possible
that ibuprofen may interfere with the anti-platelet effects of aspirin (Catella-
Lawson et al. 2001). This drug interaction was investigated by Catella-Lawson
and co-workers (2001), who studied the effects of intake of aspirin (81 mg) 2 h
before ibuprofen (400 mg) each morning for 6 days. After this treatment, the order
of taking the two drugs was reversed, and a similar design was incorporated with
paracetamol 1,000 mg. Serum thromboxane B2 levels, determined as an indicator of
COX-1 activity in platelets, were found to be inhibited. Platelet aggregation was
found to be significantly inhibited by aspirin; the maximum inhibition being evident
on day 6 when the drug was taken alone. When aspirin was given, followed by
ibuprofen before taking aspirin, there was complete inhibition of the effect of
aspirin on serum thromboxane B2 and platelet aggregation. This impairment of
platelet aggregation and thromboxane production by ibuprofen was not evident
with paracetamol, diclofenac, or rofecoxib.
The consequence of these studies was that there were a considerable number of
pharmaco-epidemiological investigations to establish if NSAIDs would in general
impair the anti-thrombotic potential of aspirin and its prevention of myocardial
infarction. Thus, MacDonald and Wei (2003) analysed data from the Scottish
Administrative Pharmacy Database, and found that patients with cardiac disease
who had been prescribed combinations of ibuprofen and aspirin had an increase in
158 8 Cardiovascular Safety

cardiovascular mortality compared with that of patients who had taken aspirin
alone. This effect was not evident when diclofenac was taken with aspirin.
Kurth and co-workers (2003) published data from patients enrolled in the
Physicians Health Study whom had been randomized to receive aspirin and
NSAIDs, and who were at increased risk of cardiovascular events compared with
patients who did not use NSAIDs. The increased risk of NSAIDs causing increased
risk of adverse events when given with aspirin while dose-dependence was rela-
tively small, and required the drugs to be used for long periods. The study by
Kimmel et al. (2004) which has already been mentioned was interesting, because
this managed to put a completely different slant on the whole story. In patients with
no history of coronary artery disease, the use of aspirin was associated with the
lower risk of myocardial infarction as expected, but this benefit was not seen in
patients who took any NSAIDs in addition to aspirin. Patients who had established
coronary disease who used aspirin with NSAIDs were at similar risk at developing
myocardial infarction to those patients who had taken aspirin alone. Thus, there is
an important issue relating to whether patients have coronary disease or not in this
effect of NSAIDs. It should be noted that the earlier study of Catella-Lawson et al.
(2001) had been undertaken in normal subjects.
In a study in elderly patients who had already experienced a myocardial infarc-
tion, the mortality of those who had received aspirin and a non-steroidal was similar
to that of patients who been prescribed aspirin alone (Curtis et al. 2003; Ko et al.
2002). No apparent differences were observed in the mortality and analysis of
patients who had been prescribed aspirin and ibuprofen compared with those
prescribed aspirin alone (Curtis et al. 2003).
As a follow-up to the study by Catella-Lawson and co-workers (2001), Cryer
et al. (2005) investigated the effects of ibuprofen on aspirin-induced thromboxane
B2 production in 51 volunteers in a double-blind randomized parallel placebo-
controlled study. The objections to the Catella-Lawson study were that it did not
feature a placebo group, and there were issues about the study population. The basis
of single measurement of thromboxane production is that this correlates to a high
degree to the inhibition of platelet aggregation when aspirin is taken. Thromboxane
production was measured over 10 days at 1, 3, and 7 days (in the period prior to
randomization to treatment with ibuprofen or placebo) during 8 days treatment with
81 mg aspirin once daily in the morning. This resulted in greater than 90 %
thromboxane inhibition. On the 9th day and subsequently for 10 days, the subjects
were randomly assigned to receive ibuprofen or placebo, and their thromboxane B2
levels were measured on days 0, 1, 3, 7, and 10. In both groups there was greater
than or equal to 98 % inhibition of thromboxane B2 production, although there was
a small but clinically non-significant difference between the two treatment groups
of thromboxane inhibition on day 7; but since this was already in a group who had
greater than 98 % mean inhibition of thromboxane production, this could not be
regarded as clinically significant (Cryer et al. 2005). These results show that prior
treatment for 8 days with aspirin is not affected by subsequent ibuprofen treatment
in terms of platelet thromboxane production. A similar study was performed by
8.5 Interaction of Ibuprofen with the Anti-platelet Effects of Aspirin 159

Pongbhaesaj and co-workers (2003) and published in abstract form, which showed
almost identical results.
Recently, Schuijt et al. (2009) investigated the effects of 7 days treatment with
ibuprofen 2,400 mg t.i.d. or diclofenac 150 mg t.i.d. alone or taken concomitantly
with aspirin 80 mg o.d., or 30 mg aspirin o.d. alone, in normal healthy volunteers.
Aspirin 80 mg reduced thromboxane levels to about 90.3 % of baseline. However,
they found that while diclofenac reduced serum thromboxane B2 less than ibupro-
fen but with a high variability compared with baseline (range 69.7–97.7 %),
diclofenac with aspirin 80 mg reduced the thromboxane B2 levels to the same
extent as aspirin 80 mg, while ibuprofen with aspirin reduced these levels to 86.6 %,
but with a wider range (77.6–95.1 %) than observed with aspirin alone
(97.2–98.9 %). While the authors suggested that the concomitant treatment with
diclofenac and aspirin had less of an effect in reducing the production of thrombox-
ane B2 than ibuprofen with aspirin, it is surprising from these studies that the
impairment of platelet thromboxane B2 production is not as striking as in the earlier
studies of Catella-Lawson et al. (2001). Indeed, using thromboxane B2 levels as a
surrogate for anti-platelet effects of aspirin, it would appear that although there is
some variability in the effects of ibuprofen with aspirin, the anti-platelet effects are
not totally negated and indeed might be clinically significant. It is also possible that
by increasing the dose of aspirin to say 100–150 mg, the negative effects of
ibuprofen might be overcome. Moreover, in the context of the wide occurrence of
platelet unresponsiveness to aspirin or even the more effective antiplatelet drug,
clopidogrel (Galdding et al. 2008), the variability in effects of either ibuprofen or
diclofenac on aspirin-induced thromboxane B2 would appear to be manageable.
This could be achieved as suggested by either by upward dose adjustment with
aspirin and/or careful point-of-care platelet function technology to discriminate
aspirin-resistance (Gladding et al. 2008a).
Studies with other NSAIDs have shown that the impairment of aspirin-induced
platelet function ex vivo observed with ibuprofen were also observed with other
NSAIDs (indomethacin, naproxen, and tiaprofenac acid), but not with celecoxib or
sulindac (Galdding et al. 2008). While the antiplatelet effects of aspirin were
reduced by the former three drugs, they did not abolish the effects of aspirin, but
only showed wider variability (Galdding et al. 2008).
A consensus view would appear to suggest that the mode of action of ibuprofen
in impairing platelet function inhibited by aspirin is that there is competition
between ibuprofen and the active site of COX-1, which is irreversibly inhibited
by covalent modification by the acetyl group of aspirin at or near the active site
(Curtis and Krumholz 2004; Gaziano and Gibson 2006; Armstrong et al. 2008).
The US Food and Drug Administration (2006) have provided information for
healthcare professionals with regard to the concomitant use of ibuprofen and
aspirin, and have stated that with occasional use of ibuprofen, there is minimal
risk from any attenuation of the anti-platelet effect of low-dose aspirin, because of
its long-lasting effect on platelets. Moreover, patients who use immediate-release
aspirin (not enteric-coated) and take a single dose of ibuprofen should take the latter
160 8 Cardiovascular Safety

at least 30 min or longer after ingestion of aspirin, or more than 8 h before aspirin to
avoid attenuation of the effects of aspirin.
Thus, it may be concluded that the timing of aspirin and ibuprofen intake may
have considerable bearing on the interaction of ibuprofen with aspirin on platelets.
The clinical significance of this in terms of the prevention of cardiovascular disease
in patients, especially those taking OTC ibuprofen, that are at risk of developing
these conditions clearly is of low grade when viewed in the context of the study by
Kimmel and co-workers (2004).
Another important aspect arising from these studies is that ibuprofen itself
inhibits platelet aggregation or functions (Brooks et al. 1973; McIntyre et al.
1978; Barclay 2005). The mechanisms of the inhibition of platelet aggregation by
ibuprofen are, however, different from those of aspirin. Thus, Brooks et al. (1973)
observed that 4 weeks treatment of male volunteers with ibuprofen 1,800 mg/day
reduced aggregation induced by collagen and ADP, but not in recalcificated prior-
citrated blood (a thrombin-induced reaction that is inhibited by aspirin). Platelet
aggregation was inhibited, in blood drawn 40 minutes after 7 days treatment with
ibuprofen, but this returned to normal after 24 h; a situation where it would
normally be expected that aspirin would have produced 90 % inhibition of aggre-
gation and prolongation of bleeding time. Moreover, ibuprofen does not cause
inhibition of coagulation in recalcificated prior-citrated blood or increased pro-
thrombin times (Brooks et al. 1973).
Notwithstanding the obvious differing basis of the aspirin–ibuprofen interaction,
the US FDA pronounced a warning on the concomitant use of aspirin and ibuprofen
in patients who may be taking aspirin for the prevention of coronary vascular
disease (Ellison and Dager 2007). Indeed, the FDA has published on its MedWatch
Web site (http://www.fda.gov/medwatch/report.htm) information for health care
professionals and drug facts with regard to warning of the concomitant use of
ibuprofen and aspirin. In the information for healthcare professionals, it is stated
that with occasional use of aspirin there is likely to be a minimal risk from any
attenuation of the anti-platelet effects of low-dose aspirin because of the long-
lasting effect of aspirin on platelets. Moreover, they state that patients who use
immediate release aspirin (not enteric-coated) and take a single dose of ibuprofen
400 mg should take the dose of ibuprofen at least 30 min or longer after the aspirin
ingestion, and not more than 8 hours before aspirin ingestion to avoid attenuation of
the effect of aspirin on platelets. They state that recommendations about the timing
of concomitant use of ibuprofen and enteric-coated low-dose aspirin cannot be
made on the basis of available data. Thus, on the basis of information from the FDA
and the available published literature, it is clear that separation of the dose of aspirin
from that of ibuprofen is a practical means of being able to avoid the potential for
impairment of the anti-platelet effect of aspirin by ibuprofen.
It should be noted that an earlier study in patients with rheumatoid arthritis by
Grennan et al. (1979) showed that high-dose aspirin (3.6 g/day), but not a lower
dose of 2.4 g/day in combination with high- or low-dose ibuprofen, had a weak
clinical additive effect on indices of articular function and pain; this appeared to be
related to an increase in serum ibuprofen by aspirin, but ibuprofen administration
8.6 Effects in Hypertension 161

Fig. 8.2 Risks of death from cardiovascular and gastro-intestinal reactions to NSAIDs related to
life events. Redrawn from Moore et al. (2008)

did not affect serum salicylate levels. Thus, high doses of aspirin (not those usually
used for anti-thrombotic effects) may have some impact on the clinical efficacy of
ibuprofen in a positive way, but this is related to effects on ibuprofen concentration
in the plasma.

8.6 Effects in Hypertension

Elevation of blood pressure is regarded as a surrogate for CV risk, especially in

patients who are at risk of CV events. Studies with the coxibs, especially rofecoxib,
indicated that they could increase blood pressure and produce oedema in patients
with rheumatic conditions (Topol 2004, 2005; Khanna et al. 2005; Östör and
Hazleman 2005; Rainsford 2005a; Antman et al. 2007). NSAIDs, including ibupro-
fen, cause little or no increase in blood pressure in normotensive individuals (Pope
et al. 1993; Johnson et al. 1994; Miwa and Jones 1999; Nurmohamed et al. 2002).
This has been confirmed in extensive meta-analyses of various clinical trials
(Johnson et al. 1994). The issue is, however, that NSAIDs interfere with the actions
of b-blockers (Johnson et al. 1994). In a controlled clinical trial in patients with
mild to moderate hypertension receiving anti-hypertensive medications (b-blockers
and diuretics), 3 weeks treatment with ibuprofen 1,200 mg/day caused an increase
in supine blood pressure of 5.3 mmHg and in sitting mean arterial pressure of
5.8 mmHg, compared with placebo (Radack et al. 1987). Similarly, increased blood
pressure was noted in a placebo-controlled clinical trial in patients receiving
hydrochlorothiazide and 1,800 mg/day ibuprofen (Gurwitz et al. 1996). However,
in a study in stage 1 and 2 hypertensive patients on low- and high-sodium diets
162 8 Cardiovascular Safety

receiving the angiotensin-converting enzyme (ACE) inhibitor enalapril, ibuprofen

1,200 mg/day did not affect systolic or diastolic blood pressure, although in another
study indomethacin reduced the effects of capropril (Velo et al. 1987). NSAIDs are
well-known to interfere with the actions of ACE inhibitors (Badin et al. 1997).
Calcium channel blockers do not appear to be affected by ibuprofen and other
NSAIDs in hypertensive patients (Miwa and Jones 1999).

8.7 Congestive Heart Failure and Cardio-Renal Effects

Several studies have indicated that use of NSAIDs in patients with a history of heart
disease may cause an increased risk of congestive heart failure (McGettigan et al.
2000, 2008). It appears that this effect of NSAID intake may be a class effect, and
confined to patients that have been taking the normal anti-arthritis doses of these
drugs. The risk of increased occurrence of congestive heart failure is overall an odds
ratio of 2.8, but for those with a history of heart disease this may be increased to
10.5. It appears that plasma half-life of elimination plays a role in the risk of
coronary heart failure, inasmuch as this risk seems to be doubled in long half-life
versus short half-life NSAIDs (McGettigan et al. 2000; McGettigan et al. 2008).
Since inevitably the interference by NSAIDs in prostaglandin-dependent pro-
cesses including haemostasis, vasodilation, vasoconstrictor balance, and renal
functions including electrolyte balance influences the potential for cardiac toxicity
via renal effects, this class effect with NSAIDs usually seen at high doses
of NSAIDs with long half-lives may be a significant feature in the increase
in hypertension and subsequent risk of cardiovascular disease (McGettigan
et al. 2000).

8.8 Balancing CV and GI Risks of NSAIDs

To give some perspective of the concept of risk associated with GU and MI events,
Moore and co-workers (2008) attempted to rate the risks of events against known
life events (Fig. 8.2). Their estimates suggest that ibuprofen, like several other
NSAIDs, with the exception of the risks of a heart attack with diclofenac, and
celecoxib have relatively low risks for CV and GI events. This kind of analysis may
be helpful to the public but may well disguise inherent risks, many of which have
been discussed earlier.
Chapter 9
Renal Toxicity

Renal effects of ibuprofen are common to all those syndromes that are known to be
produced by NSAIDs (Dunn et al. 1984; Breyer 1999; Murray and Brater 1999;
Mounier et al. 2006). The four main primary types of renal impairments observed
by NSAIDs are: (1) acute ischaemic renal insufficiency, (2) effects on sodium
potassium and water homeostasis with interference with the effects of diuretics
and anti-hypertensive therapy, (3) acute interstitial nephritis, and (4) renal papillary
necrosis. The association of ibuprofen intake with the development of adverse renal
effects is probably due to its widespread use rather than any particular characteristic
of the drug per se, since irreversible effects are rare (Murray and Brater 1999).
Renal dysfunction may be more pronounced in patients that have known risk factors
including prior renal disease, stress, or impaired renal function (for example,
changes in creatinine clearance) (Chen et al. 1994; Bennett 1997; Castellani et al.
1997; Galzin et al. 1997; Schwartz et al. 2002). The issue is probably of greater
concern in elderly subjects, because of the higher prevalence of arthritic disease
among them and the greater need for NSAID therapy (Murray and Brater 1999). On
rare occasions, serious renal pathology has been observed with ibuprofen
(Carmichael and Shankel 1985; Radford et al. 1996; Cook et al. 1997; Silvarajan
and Wasse 1997; Murray and Brater 1999), but this has not been observed in trials
with OTC ibuprofen (Whelton et al. 1990; Whelton 1995), and the evidence from
literature analysis and clinical trials suggests OTC use of ibuprofen has not been
found to cause significant renal injury (Rainsford et al. 1997, 2001; Doyle et al.
1999; Kellstein et al. 1999; Hersh et al. 2000a; Ashraf et al. 2001; Le Parc et al.
2002; Boureau et al. 2004).
Griffin and co-workers (2000), using Tennessee (USA) Medicaid US Federal
State Program Database with patients at greater than 65 years of age, undertook an
analysis of the effects of NSAIDs on the development of acute renal failure in these
elderly patients. Their analysis included consideration of conventional population
variables as well as the concomitant intake of prescription drugs and aspirin. In their
study they identified 1,799 persons aged greater than 65 years of age with a
community-acquired pre-renal failure or intrinsic renal failure that required hospi-
talization for varying periods of time. Patients with acute renal failure differed from

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 163

DOI 10.1007/978-3-0348-0496-7_9, # Springer Basel 2012
164 9 Renal Toxicity

controls in a variety of population-related and drug-related factors. NSAIDs fea-

tured in the increasing risk for pre-renal failure among those without any underlying
renal insufficiency. The data on the odds-ratio estimates and the confidence
intervals of 95 % of the risk of association between use of individual NSAIDs
and hospitalization for acute renal failure among this population in a case-control
comparison showed that ibuprofen had an odds ratio of 1.63 (1.23–2.08 95 % CI),
exceeded only by piroxicam, fenoprofen and several other single or multiple-use
NSAIDs. The slightly higher risk associated with ibuprofen intake may be a
reflection of its widespread use.
In relation to over-the-counter use of ibuprofen and its possible association with
the development of nephrotoxicity adverse reactions, it is been noted that analgesic
nephropathy is not a widely recognized or reported effect of OTC ibuprofen (Mann
et al. 1993), and certainly this is only infrequently reported in ADR reports made to
the UK CSM (Prescott and Martin 1992). In the analysis of risks of renal side-
effects of ibuprofen by Mann et al. (1993), it was found that the renal effects are
dose-dependent, and that these effects are almost exclusively in elderly subjects
with low intravascular volume and low cardiac output. Furey et al. (1993) observed
that renal-vascular effects of OTC ibuprofen in elderly patients with mild thiazide-
treated hypertension and renal insufficiency do not appear to be a risk factor for the
development of renal compromise or hypertension.
Farquhar et al. (1999) and Farquhar and Kenney (1999) have shown that OTC
dose of ibuprofen (1.2 g/day) in normal subjects subjected to heat-stress, low-
sodium diet or dehydration may cause impairment of renal blood flow, glomerular
filtration and electrolyte excretion which is related to inhibition of prostaglandin
production. Studies in rabbits suggest that those with pre-existing renal failure
receiving ibuprofen may have alterations in the pharmacokinetics of the two
enantiomers of the drug (Chen et al. 1994), with the active (S+) isomer clearance
being significantly impaired in this model of renal dysfunction. Thus, there may be
increased prostaglandin inhibition in the renal tubular systems in individuals with
renal impairment.
Overall, these studies suggest that OTC ibuprofen is a low risk factor for
developing acute or chronic renal conditions, but that as with other NSAIDs there
is increasing risk, particularly in elderly individuals or those with compromised
renal function when the drug is taken at high prescription anti-arthritic doses.
Chapter 10
Hepatic Toxicity

Hepatic reactions have been of concern because of serious liver injury being
reported with some NSAIDs and coxibs, e.g., diclofenac, sulindac (in the USA),
celecoxib, and lumiracoxib (O’Brien and Bagby 1985; O’Brien 1987; Stricker
1992; Cameron et al. 1996; Tolman 1998; Zimmerman 2000; Lacroix et al. 2004;
Bannwarth and Berenbaum 2005; Chang and Schiano 2007), as well as paracetamol
even at usual OTC doses (Watkins et al. 2006; Heard et al. 2006, 2007). The
problem with attributing hepatic reactions to a particular drug, whether it be an
NSAID or otherwise, is that there are so many commonly used drugs that are
hepatotoxic, especially those drugs used by rheumatic patients, e.g., antibiotics,
anti-hypertensives, statins etc. (Stricker 1992; Cameron et al. 1996; Zimmerman
2000; Motola et al. 2007). Moreover, the pattern of hepatopathies varies consider-
ably among the different drugs which may be taken with ibuprofen (or other
NSAIDs) and that are associated with hepatoxicity (Sabaté et al. 2007).
As illustrated in Fig. 2.6, the complexities of the demands on the liver metabo-
lism of so many commonly used drugs inevitably make for complex interactions
leading to hepatotoxicity.
To obtain some indication of the incidence of hepatic reactions in patients taking
NSAIDs, Traversa et al. (2003) investigated the occurrence of hepatotoxicity in a
cohort study in Umbria (Northern Italy) in subjects that had recently taken NSAIDs.
A total of two events were recorded as “all hepatopathies” (of 122 cases that had
taken NSAIDs) and two with liver injury associated with recent use of ibuprofen (of
126 cases that had NSAIDs). Considering the extensive use of ibuprofen, this is a
low incidence.
In a “case/non-case” compilation of reports extracted from the FDA and WHO
(NIMBUS) databases, Sanchez-Matienzo and co-workers (2006) of the Pfizer
Global Epidemiology group in Barcelona (Spain) attempted to give proportional
estimates of the occurrence of different liver reactions attributed to individual
NSAIDs. Tables 10.1 and 10.2 summarise data from Sanchez-Matienzo et al.
Unfortunately, there are a number of critical issues about this data, among them:
(a) there are no assessments of the likelihood of the event being associated
with intake of a specific drug, (b) there is no information on confounding

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 165

DOI 10.1007/978-3-0348-0496-7_10, # Springer Basel 2012
166 10 Hepatic Toxicity

Table 10.1 Proportion of reports (PRs) of various hepatic disorders among cyclo-oxygenase
(COX)-2 selective inhibitors and NSAIDs in the World Health Organization Uppsala Monitoring
Centre data source, updated to the end of quarter 3 of 2003
Overall Abnormal Hepato- Non- Total
hepatic hepatic cellular infectious Hepatic no. of
Drug disorders function Jaundice damage hepatitis failure reports Rank
Bromfenac 20.7 10.8 3.2 3.5 4.3 2.2 2,057 14
Celecoxib 2.1 1.3 0.4 0.2 0.5 0.2 17,748 12
Diclofenac 4.7 3.2 1.0 0.2 1.4 0.1 21,082 5
Etodolac 3.6 2.5 1.0 0.4 1.2 0.3 3,553 9
Ibuprofen 1.8 1.1 0.4 0.2 0.5 0.1 32,973 13
Indomethacin 1.8 1.0 0.5 0.1 0.5 0.1 14,576 7
Ketorolac 0.6 0.4 0.1 0.1 0.1 0.2 1,867 6
Meloxicam 0.8 0.4 0.1 0.0 0.4 0.0 3,042 11
Multiple 5.0 3.1 1.2 0.4 1.4 0.4 33,660 4
NSAIDsa
Naproxen 1.6 0.8 0.3 0.2 0.3 0.1 13,646 1
Nimesulide 14.4 7.2 2.0 1.0 5.7 0.4 1,057 3
Proxicam 2.0 1.2 0.4 0.1 0.6 0.1 13,973 8
Rofecoxib 1.5 0.8 0.2 0.1 0.4 0.1 20,429 2
Sulindac 9.9 5.2 3.2 0.5 3.1 0.2 5,777 10
Values are percentages
PRs of concomitant use of other hepatotoxic drugs excluded
a
Includes reports involving >1 COX-2 selective inhibitor and/or NSAID.
Reproduced from Sanchez-Matienzo et al. (2006) with permission of Elsevier, publishers of
Clinical Therapeutics

Table 10.2 Frequencies of potential confounders in the US Food and Drug Administration (under
Freedom of Information) (FDA/FOI) and World Health Organization Uppsala Monitoring Centre
(WHO/UMC) data sources
Concomitant use of hepatotoxic drugs Age
65 years
Drug FDA/FOI WHO/UMC FDA/FOI WHO/UMC
Nimesulide 46.8 13.2 27.8 20.3
Celecoxib 35.0 17.4 35.3 34.2
Sulindac 31.0 16.7 33.4 33.2
Meloxicam 30.1 5.9 38.0 13.5
Diclofenac 29.4 11.0 34.0 17.6
Etodolac 28.0 13.5 29.8 21.7
Indomethacin 27.9 17.1 25.0 18.0
Ibuprofen 25.0 18.1 17.6 13.8
Rofecoxib 20.9 5.8 38.4 21.4
Piroxicam 19.4 7.5 29.4 17.9
Naproxen 18.7 15.3 21.6 16.7
Ketorolac 17.6 69.6 22.0 19.1
Bromfenac 15.5 8.7 8.7 9.1
Multiple NSAIDsa 48.1 15.0 34.8 22.5
Values are percentages
a
Includes reports involving >1 cyclooxygenase-2 selective inhibitor and/or non-selective NSAID.
Reproduced from Sanchez-Matienzo et al. (2006) with permission of Elsevier, publishers of
Clinical Therapeutics
 10
Hepatic Toxicity

Table 10.3 Percent liver reactions in rheumatoid- and osteo-arthritis patients in randomised-controlled trials (% of patients, 95 % CI)
Condition/reaction
Liver-related Liver-related
Treatment Elevated aminotransferases >3X, ULN discontinuations Liver-related SAEs hospitalisation Liver-related deaths
Ibuprofen 0.43 (0.26–0.70) 0.06 (0.02–0.23) 0 0 0
Celecoxib 0.42 (0.32–0.54) 0.08 (0.04–0.15) 0 0 0
Diclofenac 3.55 (3.12–4.03) 2.17 (1.78–2.64) 0.04 (0.01–0.16) 0 0
Meloxicam 0.19 (0.12–0.03) 0 0 0 0
Naproxen 0.43 (0.30–0.63) 0.06 (0.03–0.14) 0.06 (0.02–0.15) 0.01 (0.00–0.08) 0.01 (0.00–0.05)
Rofecoxib 1.80 (1.52–2.13) 0.16 (0.09–0.26) 0.05 (0.02–0.14) 0 0
Valdecoxib 0.04 (0.01–0.22) N/A 0.02 (0.00–0.13) 0 0
Placebo 0.29 (0.17–0.51) 0.08 (0.02–0.29) 0 0 0
Reproduced from Rostrom et al. (2005) with permission from Elsevier, publishers of Clinical Gastroenterology and HepatologyThe data are principally from
patients with osteo-arthritis. Analysis by arthritis type did not influence the overall results. One patient in the VIGOR trial, which involved rofecoxib, had toxic
hepatitis and died from hepatic failure. This patient had received methotrexate and paracetamol, both established hepatotoxic drugs
Data derived from literature searches (N ¼ 67 articles), the Cochrane Library and US Food and Drug Administration public archives (N ¼ 65 studies)
ULN = upper limit of normal
SAEs = serious adverse events
167
168 10 Hepatic Toxicity

patient-, disease- or drug-related factors, (c) there is probably considerable double

counting between the FDA and WHO data, (d) there is no information on the
intake of drugs in Defined Daily Doses (DDD)/100,000 patients, and (e) these data
are in no sense quantitative, and the WHO cautions especially on the use of the
data from what are spontaneous reports. At best, these data only give signals.
Thus, the data only show that ibuprofen has been reported to produce liver
reactions with concomitant use of hepatotoxic drugs being implicated in a con-
siderable proportion of cases.
An extensive bibliographic analysis by Rostom and co-workers (2005)
highlighted the differing liver reactions from NSAIDs from what is effectively a
large database (Table 10.3). These data show that diclofenac and rofecoxib have
the highest incidence of severe liver reactions requiring discontinuation of the
drug, and also cause a high frequency of elevated transaminases. Meloxicam
and valdecoxib (now discontinued) have the lowest incidence of liver reactions.
Ibuprofen like several other NSAIDs showed low–moderate reactions. The
variations in the incidence of these liver reactions may reflect patterns and total
use of the drugs.
In patients with rheumatoid arthritis and ankylosing spondilitis who receive
methotrexate, this hepatotoxic drug may complicate the associations with NSAIDs
and liver reactions (Colebatch et al. 2011). However, the numbers of liver reactions
reported implicating NSAIDs and methotrexate appear small, and are most signifi-
cant for aspirin (Colebatch et al. 2011).
Overall, the available data suggest that hepatic reactions are probably rarely
associated with ibuprofen. Since there have been no specific indications of reports
of hepatic reactions with OTC use of ibuprofen from trials (Doyle et al. 1999;
Kellstein et al. 1999; Boureau et al. 2004) or in literature analyses (Whelton 1995;
Rainsford et al. 1997), it is likely that hepatotoxicity is not a significant risk factor at
OTC dosages.
Hepatic reactions do not appear to have been reported in any of the large-scale
hospitalisation practitioner-based studies in children (Lesko and Mitchell 1995,
1999; Ashraf et al. 1999) or in critical reviews of clinical trials (Rainsford et al.
1997, 1999b, 2001). Hepatitis has been frequently reported in trials of NSAIDs
including ibuprofen and aspirin in JRA or JIA (Giannini et al. 1990), but in a small
long-term study, Ansell (1973) found that liver function tests were unaltered in
these patients. The risks of liver reactions, especially in JRA or JIA, would appear
to be low except where concomitant hepatotoxic drugs are taken (e.g., paracetamol,
methotrexate) (Furst 1992; Hollingworth 1993).
Chapter 11
Other Adverse Reactions

Rare adverse events that have been reported at prescription level doses with
ibuprofen, and less frequently with OTC doses, are common to those seen
with all NSAIDs. Among these are thrombocytopaenia, agranulocytosis, anaemia,
aseptic meningitis, and anaphylactoid reactions, interactions with the immune,
endocrine, and metabolic systems, central nervous system and ocular effects, and
some skin conditions including erythema multiforme, bullus dermatitis, Stevens-
Johnson and Lyell’s syndromes (Hoffman and Gray 1982; O’Brien and Bagby
1985; Haupt et al. 1991; Miwa and Jones 1999; Jackson et al. 2006; Layton et al.
2006; Neuman and Nicar 2007). Most but not all of these adverse events are rare,
with the exception of allergies including aspirin-sensitive asthma, especially with
OTC dosages of ibuprofen.

11.1 Hypersensitivity Reactions and Asthma

NSAIDs are associated with the development of a range of hypersensitivity

reactions including asthma. The symptoms of intolerance to these drugs range
from severe bronchospasm that is often associated with nasal polyposis, rhino-
conjunctivitis, urticaria, cervico-facial erythema, angio-oedema, hypotension, and
digestive disturbances (Arnaud 1995). These symptoms may occur individually or
in any combination (Arnaud 1995; de Weck et al. 2006). The symptoms may be
manifest within a few minutes to several hours after ingestion of the drug.
Recently, Nanau and Neuman (2010) described features of a type B hypersensi-
tivity reaction which is idiosyncratic and is observed with NSAIDs including
ibuprofen. These reactions occur in susceptible individuals, and are characterized
by systemic disease involving a triad of fever, rash, and ‘internal organ involve-
ment’ which is initiated from day 1 up to 12 weeks following drug intake. Host-
dependent reactions involve a combination of T-cell and the effects on the production
of cytokines and chemokines which exacerbate immune reactions.

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 169

DOI 10.1007/978-3-0348-0496-7_11, # Springer Basel 2012
170 11 Other Adverse Reactions

Hypersensitivity reactions of the respiratory system have been frequently reported

with aspirin, and the terms “aspirin-associated asthma”, “aspirin-sensitive asthma” or
“aspirin-interant asthma (AIA)” have been employed to describe the association of
symptoms of asthma with aspirin (Arnaud 1995; Rainsford 2004a: de Weck et al.
2006; Quiralte et al. 2007). In patients with ASA, small doses of aspirin can lead to
severe attacks. Frequently, sensitivity to NSAIDs overlaps that with aspirin, as well as
with ibuprofen (Jenkins et al. 2004). This has given rise to the concept of sensitization
and the use of desensitizing procedures to treat this condition (Rainsford 2004a;
Jenkins et al. 2004; de Weck et al. 2006; Quiralte et al. 2007). Paracetamol has been
found to be tolerated in some patients with NSAID intolerance, but has in recent years
been reported to be associated with asthma and hypersensitivity reactions (Arnaud
1995).
The incidence of NSAID intolerance has been variously estimated depending on
the method of evaluation, study design, and population. Overall, the incidence can
be 0.6–2.5 % of the general population (de Weck et al. 2006). The incidence is 4 %
when asthmatic patients are interviewed, and can range up to 10–29 % in adult
patients with asthma or those that have been challenged for presence of allergies
(Arnaud 1995; de Weck et al. 2006). Hypersensitivity to NSAIDs usually appears in
the second or third decade, and occurs in atopic subjects over the age of 40 years,
this reaction being more common in females than males (Arnaud 1995; de Weck
et al. 2006). Aspirin or NSAID intolerance is occurs infrequently in children (de
Weck et al. 2006). AIA does not normally involve sensitization through IgE
(Arnaud 1995; de Weck et al. 2006).
The mechanisms of NSAID sensitivity have been debated over the years but
there is some consensus that it is due to COX inhibition in susceptible individuals,
leading to over-production of peptidoleukotrienes causing bronchoconstriction and
other asthmatic symptoms (Arnaud 1995; Rainsford 2005b). Other hypotheses
suggest that there may be genetic influences relating to variability in leukotriene
or prostanoid receptors (de Weck et al. 2006). Altered expression of COX-1, but not
COX-2 with LT synthases have been considered as underlying the development of
AIA (Harrington et al. 2008; Dobovišek et al. 2011). In a theoretical study,
decreased expression of PGH synthase-1 and increased leukotriene C4 synthase
were considered key factors in the development of AIA (Dobovišek et al. 2012). In
AIA, patients being given either aspirin or ibuprofen followed by a PGE2 analogue
enabled both drugs to be administered (Dobovišek et al. 2012), implying that
regulating the immunopathogenic basis of AIA might be achieved via PGE2.
Asthma and hypersensitivity reactions have long been a cause for concern in
children, and the cross-reactions of ibuprofen with aspirin-sensitive asthma have
been highlighted by several authors (Body and Potier 2004; Kidon et al. 2005;
Mascia et al. 2005; Debley et al. 2005; Kanabar et al. 2007; Ponvert and
Scheinmann 2007; Bousquet et al. 2009). On rare occasions, deaths have been
reported in children or adults from intake of ibuprofen (Ayres et al. 1987;
Antonicelli and Tagliabracci 1995). In a study in Finland, it was suggested that
one death from ibuprofen might have been in a child that had a previous history of
11.2 Cutaneous Reactions 171

allergy (Malmström et al. 2007). These authors also considered drugs were acting
as triggers in some patients.
Two large-scale studies in febrile asthmatic children (McIntyre and Hull 1996;
Lesko et al. 2002) found that ibuprofen, far from being associated with increased
risk of asthma compared with paracetamol, actually showed a slightly reduced risk.
Debley et al. (2005) performed a randomised, double-blind, placebo-controlled,
crossover bronchoprovocation challenge study in 100 pre-screened school-aged
children (6–18 years) and found that ibuprofen-induced bronchospasm was preva-
lent in 2 % of asthmatic subjects. Another 2 % had clinically relevant decreases in
spirometric measurements after ibuprofen administration, but these did not meet the
authors’ a priori criteria for a positive challenge test. These authors considered that
ibuprofen-sensitive asthma has a low prevalence, but nonetheless ibuprofen-
induced bronchospasm should be considered as a risk in childhood asthma.
Literature reviews of clinical trials (Kanabar et al. 2007) have indicated that
there is a low risk for asthma with ibuprofen, and that in contrast paracetamol might
be associated with wheezing in children. Ibuprofen might have protective effects in
some subjects with asthma, in contrast to paracetamol (Mazur 2002; Kanabar et al.
2007), but caution should be emphasized in any attempts to exploit this suggestion
by trying ibuprofen in children with asthma.

11.2 Cutaneous Reactions

Minor or “non-serious” skin reactions are among the more frequent reactions
observed with NSAIDs including ibuprofen (Bigby and Stern 1985; O’Brien 1987;
Ponvert and Scheinmann 2007). The risks of various skin reactions occurring with
“ibuprofen-containing medications” have been highlighted by Sánchez-Borges et al.
(2005). Their review drew attention to the different types of skin reactions and the
lack of quantitative information on the associations with ibuprofen.
A case–control study performed in a region in Denmark of the occurrence of
angio-oedema among NSAID and coxib users in hospital admissions by Downing
et al. (2006) showed that the relative risks for this condition were higher in coxib
users than in those taking traditional NSAIDs. There were 25 cases out of a total of
377 patients.
Data from reports of serious and non-serious cutaneous reactions for NSAIDs
reported in Italy as part of an overall programme of drug surveillance by Naldi and
co-workers (1999) are shown in Fig. 11.1.
These show that ibuprofen ranked in the mid-range of reports.
Ibuprofen, like other NSAIDs, is associated with the occurrence of skin
reactions, many of which can be rated as mild. Serious ADRs in the skin are rare.
There have been occasional reports of Stevens–Johnson and Lyell’s syndromes as
well as severe bullous reactions (Bigby and Stern 1985; Miwa and Jones 1999;
Sánchez-Borges et al. 2005). However, these serious conditions have not been
reported in controlled trials or in literature with OTC events with ibuprofen
172 11 Other Adverse Reactions

Fig. 11.1 Reporting rates of serious (black bars) and non-serious cutaneous reactions to NSAIDs
and analgesics compared with reports/consumption in DDD’s/1,000 inhabitants/day in four
regions in Italy. Drug consumption data was derived from pharmacy sales data or hospital
pharmacies. Numbers of reports for each drug are shown in brackets. Redrawn from Naldi et al.
(1999) with permission of Wiley-Blackwell for the British Journal of Clinical Pharmacology

(Rainsford et al. 1997, 2001; Doyle et al. 1999; Kellstein et al. 1999; Hersh et al.
2000a; Ashraf et al. 2001; Le Parc et al. 2002; Boureau et al. 2004).
In their large-scale Boston University Fever studies, Lesko, Mitchell and
colleagues (Lesko and Mitchell 1995; Lesko et al. 2002; Lesko 2003) did not
observe any hospitalizations for anaphylaxis. However, three cases of erythema
multiforme occurred in patients that had received ibuprofen and one that had
received paracetamol, thus making the risks of these events very low (Lesko and
Mitchell 1995). Ashraf et al. (2001) in their large-scale OA trial also noted there
were no cases of Stevens–Johnson syndrome among their patients.

11.3 Risk of Fractures

The possibility of fractures being associated with NSAID use has been identified in
patients with rheumatoid and osteoarthritis (Vestergaard et al. 2006). In these
epidemiological studies, adjustments were made for stratifying two cumulative
daily dosages (defined daily dose—DDD) and other confounders. There was an
odd disease association that was observed in these studies, in that osteoarthritis was
associated with a decreased risk of any fracture, and rheumatoid arthritis was
11.3 Risk of Fractures 173

associated with increased development of fractures. These studies highlighted that

high-dosage intake of aspirin, paracetamol, diclofenac, meloxicam, and some other
NSAIDs but not coxibs was associated with an increased risk of fractures. Ibupro-
fen showed an odd inverse dose-related effect, in as much as the adjusted odds
ratios (less than or 20–74 DDDs, approx. 1.8–1.82) were higher than those where
the drug was taken in greater quantities (1.42). Thus, hip fractures and other bone
fractures being a risk factor in elderly rheumatic patients taking NSAIDs for long
periods of time may be more a class indication as distinct from a specific risk factor
associated with any one drug.
Using the UK General Practice Research Database, Van Staa et al. (2000)
examined the factor risk of being exposed to NSAIDs, using a case–control
approach. Regular NSAID intake was associated with an increase of risk compared
with control of 1.47 (1.42–1.52 95 % CI) for non-vertebral fractures, while the risk
of hip fractures was relatively low, being 1.08 (0.9–1.19 95 % CI). It appeared from
this study that ibuprofen had the lowest risk of non-vertebral fractures, as it was
used as the reference, but there was a larger number of cases of ibuprofen compared
with other NSAIDs, probably reflecting a wider-spread use. In contrast to these
observations in development of fractures, studies by Persson and co-workers (2005)
suggest that long-term treatment of patients with who have undergone surgical
revision of hip arthroplasty.
Chapter 12
Global Assessment of Adverse Reactions
and Human Toxicology

In this chapter, experience in the regulation of ibuprofen by international drug

regulatory agencies is reviewed and analyzed. In this review, some of the major
issues are highlighted which have occurred over the two and a half decades since
ibuprofen was first approved for OTC use in the UK and USA, and how these have
been assessed and managed. Recent experience in Australia is reviewed, where the
drug was granted GSL status having been previously pharmacy-only sale at the
accepted OTC dosage (1,200 mg/day) in that country.

12.1 Initial Basis for Approval for OTC sale in UK and USA

It is now nearly 30 years since ibuprofen has been approved in the UK for non-
prescription OTC sale to the public (Rainsford 1999a). This was undoubtedly a
landmark decision, based on a review of safety data that had been accrued from a
relatively large number of studies where the drug had been taken at or below the
1,200 mg/day dose in earlier trials in rheumatic diseases and later, following dose-
incrementation, at the upper dose level of 2,400 mg/day for these conditions
(Rainsford 1999a, 2003). While dose-incrementation had been largely physician-
led, in the belief that patients (especially those with RA) might have better response
to the drug in more painful inflammatory conditions, the lower dose was still
regarded as being effective for control of pain and joint symptoms in mild–moderate
rheumatic conditions; higher dosage was needed, it was perceived, in patients with
more severe rheumatoid arthritis (RA). In the determination of safety of the drug, a
large body of evidence was accumulated at the 1,200 mg/day dosage in rheumatic
disease. This showed that the drug had low ADRs and a favourable safety profile.
In the assessment of the suitability of ibuprofen for over-the-counter sale, the UK
Dunlop Committee (later the Committee on the Safety of Medicines, CSM), consid-
ered a priori the safety of ibuprofen as its efficacy was accepted and not of concern.
Since the data on 1,200 mg/day dosage was primarily derived from patients with RA,
a condition that is well-known today to have profound systemic consequences,

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 175

DOI 10.1007/978-3-0348-0496-7_12, # Springer Basel 2012
176 12 Global Assessment of Adverse Reactions and Human Toxicology

leading to increase risks of gastrointestinal (GI) hepato-renal and cardiovascular (CV)

conditions, it would appear in retrospect that the data on safety would have been
derived from a critical patient group. If any untoward effect should occur or be
evident, then it would surely have been revealed in this patient group.
Thus, the approval by the UK CSM in 1983 enabled ibuprofen to be made
available, initially in pharmacies, but during the growth of supermarket chains
during the last one to two decades, in this retail outlet direct to the public without
intervention specifically of the pharmacist.
In practice, ibuprofen was effectively the third choice by the public after aspirin
and paracetamol for use by nearly all age groups except infants. The wave of
concern about the risks of Reye’s syndrome in the 1980s, with its relatively high
fatal outcome in children receiving aspirin, led to extensive publicity and later
proscribing of the use of aspirin in children. It is possible that there was a shift in use
of paracetamol, especially in paediatric formulations, to replace aspirin use in
children with febrile conditions, but ibuprofen was only “second choice”.
In 1984, ibuprofen was approved by the FDA for OTC sale in the USA. The
application was made by Upjohn (Kalamazoo, MI, USA) who had licensed the drug
from Boots Pharmaceuticals (Nottingham, UK) and had performed extensive
investigations on ibuprofen, including a considerable number of large-scale clinical
trials (Altman 1984). In these studies in RA patients, the drug dosage was increased
to 3.4 g daily, which was exceptional. The reasons for undertaking studies at this
high dose level are not clear, except to prove a perceived unmet need for a highly
effective pain-relieving drug in rheumatic disease. The majority of doses in the
trials in the USA were at 2.4 g/day.
Again, as with the UK CSM, the decision to allow ibuprofen to be granted OTC
status by the FDA was based a priori on safety. It was given that the drug worked in
pain relief and in controlling the fever symptoms in respiratory and other mild
febrile conditions. Doubtless, reasoning in a consumer society such as in the USA
would be that patients would not buy the drug if it was ineffective.
Since these two landmark approvals, ibuprofen has been granted OTC approval
in a number of countries. In Canada, impetus for OTC approval was from the
legislation designed to promote the use of generic drugs with their lower costs to the
consumer and healthcare systems, this legislation being enacted in the late 1980s.
Several countries in Europe have granted P to GSL status.

12.2 Experience in the UK

The UK Medicines and Healthcare Products Regulatory Agency (MHRA), for-

merly the Committee on the Safety of Medicines (CSM) operates an ADR reporting
system through the UK Department of Health. Medical practitioners, pharmacists,
and other healthcare professionals are encouraged to report adverse reactions to this
agency through what is termed the “yellow card” system. The reports are evaluated
by experts, and assessments are made regarding possible causality.
12.2 Experience in the UK 177

Fig. 12.1 Pattern of adverse drug reaction reporting to the UK CSM for a range of NSAIDs in the
first 5 years post-marketing. Redrawn from Weber (1984), reproduced with permission of
Springer, owners of Raven Press

In more recent years, more critical attention has been given to assessment of
ADRs, but even so the reliability of reporting and the quality of reports can vary.
Also, as noted by one of the Department of Health scientists, Dr JCP Weber, there
are a variety of factors influencing reporting of ADRs in the yellow card system
(Weber 1984). Amongst these, reports of ADRs for anti-inflammatory/analgesic
drugs often peak at about 2 years after the introduction of a new drug, then taper off
(Fig. 12.1).
Such features as the “novelty” of the reaction, concerns about the occurrence of
particular reactions, “awareness” by physicians or other healthcare professionals,
and even commercial interests may influence reporting frequencies.
A summary of the adverse events recorded in the UK from ibuprofen, aspirin,
and paracetamol covering the period of 1963–2010 are summarized in Fig. 12.2. It
should be noted that these data have been obtained from all dose levels (i.e.,
prescription as well and non-prescription or OTC doses) and for varying periods
of time.
This covers the period of 1963–2010, and there is no differentiation according to
period or amount of drug taken. There is, however, discrimination of data according
to (a) single active constituent, (b) multiple active constituent (i.e., intake with other
medications), and (c) total of what is described as unique reports, a term which is
not clearly defined but presumably related to toxic phenomena which may be
related to the specific drug. Fatal and non-fatal reports are shown. Fatal and
non-fatal reports data are presented graphically in Fig. 12.2.
178 12 Global Assessment of Adverse Reactions and Human Toxicology

Fig. 12.2 Reports of adverse events to the UK Medicines and Healthcare Products
Agency (MHRA, formerly the Committee on the Safety of Medicine, CSM) attributed to aspirin,
ibuprofen, and paracetamol. The data were obtained from the UK MHRA courtesy of Dr. Phil
Berry, Reckitt Benckiser Healthcare. Total unique reports refers to those in which drug is
suspected
12.3 Cases of Poisoning in UK 179

Taking the data from single active constituent, the total and percentage of total
reactions primarily involve GI disorders in decreasing order with aspirin, ibuprofen,
and to a lesser extent with paracetamol. This is in accordance with what would be
expected. This order of data also parallels the number and percent of fatal ADRs
involving GI disorders. The number of reaction fatalities and number of ADR
reports associated with hepatic disorders is relatively low with ibuprofen and
aspirin, but as expected is relatively higher than with paracetamol. Skin, blood,
and CNS disorders appear more prevalent with ibuprofen and paracetamol, but the
number of fatalities is low with all three drugs.
The number of reaction fatal reports and ADR reports in the category of Unique
Reports predominates in the GI tract, in parallel with the reports under single
active constituent. Likewise the low prevalence of liver disorders with aspirin and
ibuprofen contrasts with the high prevalence associated with paracetamol.
Considering the period of 37 years over which this data has been accumulated,
the total number of fatal reports from ibuprofen (199) contrasts with those from
paracetamol (289) and aspirin (310).
It should be emphasized that these data can only be interpreted quantitatively
with estimates of drug intake on a defined daily dose intake (DDD).
It is not possible to determine incidence rates for ADRs reported or attributed to
ibuprofen, since no denominator information is available about the population size
or drug packs consumed by the subjects from whom reports have been volunteered.
These data, when considered in relation to widespread use of the drug, show that
there is a relatively low occurrence of major adverse events attributed to ibuprofen
in the UK.

12.3 Cases of Poisoning in UK

As noted earlier, the number of reports to the NPIS (the main referral centre in the
UK for enquiries and reports of poisonings) about ibuprofen are now second to
those for paracetamol.
Reviews by Volans (2001, 2012) and Volans and Fitzpatrick (1999) serve as
background information on poisoning cases from the drug, principally in the period
when the drug was prescription or P-only in the UK, although more recent infor-
mation up to the time of writing at the beginning of 1999 contained early
observations in the period after 1996 when there was P to GSL reclassification in
the UK. Dr. Volans notes the following key points:
(a) The switch to GSL licence in 1996 doubled sales of ibuprofen, but this was
without a corresponding increase in ADRs reported to the MHRA.
(b) The shift to GSL in Australia in January 2004 has not resulted in increasing
reports of poisonings.
(c) Poisonings in the USA have not been seen to be a major concern in that country,
where OTC ibuprofen has been widely available OTC for two decades or more.
(d) There is evident low toxicity from overdose of ibuprofen.
180 12 Global Assessment of Adverse Reactions and Human Toxicology

With respect to the last point, it is clear from a large number of studies
(Rainsford 1999b, 2004a, 2009) that ibuprofen has the lowest toxicity of all
analgesics. Mechanistically, there is no evidence of irreversible toxic actions that
would be attributed to the covalent modification of endogenous biomolecules
analogous to that observed in the liver toxicity from the quinine–imine metabolite
of paracetamol (Graham and Hicks 2004), or the GI ulceration and bleeding arising
from irreversible acetylation of platelets and other cyclo-oxygenases or biomole-
cules from the acetyl-moiety of acetylsalicylic acid (aspirin) (Rainsford et al. 1981;
Rainsford 2004a).

12.4 Limitations on Analgesic Pack Sizes in UK

During the 1990s, there was growing concern in the UK about the toxicity to the
liver from paracetamol. This drug is known to cause irreversible liver damage, often
with fatal outcome in poisoning. There is also evidence that paracetamol may cause
severe liver injury in certain conditions in doses 4 g/day. As a consequence of
these concerns, the UK MHRA reviewed the safety of all analgesics, since there
have also been ongoing concerns about gastro-intestinal and renal effects of aspirin
in particular, and to a lesser extent from ibuprofen.
A consequence of this was that legislation was introduced in September 1998 to
limit the general sales and sales by pharmacies of paracetamol and aspirin by
restricting the pack size (Hawton et al. 2001; Morgan et al. 2007). Ibuprofen,
with or without codeine, had already been sold in small pack sizes consistent
with its OTC labelling. The limitation of pack sizes of paracetamol and aspirin
has had a significant impact in reducing cases of poisoning, accidental or deliberate,
with a trend to reducing serious outcomes including deaths (Hawton et al. 2001;
Morgan et al. 2007).
Statistics from the UK National Poisonings Information Service (Anonymous
2006) show that over 115,000 enquiries have been received about paracetamol
annually, which comprised 99,000 visits to paracetamol poisoning information on
TOXBASE—the NPIS’s online information database—and about 16,000 telephone
calls. In comparison, 42,000 enquiries were received by the NPIS about ibuprofen
and 25,000 about aspirin.

12.5 Concerns About Misuse of Analgesics in USA

During the early part of this decade, the US FDA has been increasingly concerned
about the safety of OTC analgesics. Initially, concern was about the dangers of
paracetamol causing hepatotoxicity and deaths in an increasing number of reports.
However, the GI and renal effects of OTC NSAIDs (which include naproxen and
ketoprofen as well as aspirin and ibuprofen) were also highlighted. Among the
12.5 Concerns About Misuse of Analgesics in USA 181

reviews of safety issues of OTC analgesics was a meeting of the Nonprescription

Drugs Advisory Committee (FDA) on September 19–20, 2002 with experts from
other advisory committees to the FDA, who reviewed and discussed available data
on US case reports regarding accidental and unintentional overdoses with paracet-
amol and NSAID-related GI bleeding and renal toxicity. A number of actions
resulted from these discussions, including:
• A national education campaign on the safe use of OTC pain relief products
which was announced in January 2004 (http://www.fda.gov/fdac/features/2004/
204_otc.html).
• A Letter to State Boards of Pharmacy highlighting and advising especially about
the danger of hepatotoxicity in association with paracetamol and GI and renal
effects of NSAIDs (http://www.fda.gov/cder/drg/analgesics/letter.html).
Chapter 13
Overall Assessment

It is clear from this review of available evidence on the safety and efficacy of
ibuprofen that this drug is amongst the safest and most effective of the analgesics
available to the public for relief of symptoms of mild to moderate pain and
inflammation.
The evidence of the adverse reaction profile from ibuprofen has been derived
from published studies at the prescription dose level (1,800–2,400 mg/day). The
higher prescription-level dose range gives information that in relation to the OTC
level can be regarded as the upper limit of toxic reactions that are likely from this
drug. In terms of dose–response, the most frequent adverse reactions are seen in the
GI tract, skin, and possibly renal systems.
While serious GI events (GI ulceration, bleeding) occur with prescription-level
ibuprofen, the consensus of data support the conclusion that ibuprofen has the
lowest GI risk of all NSAIDs, although this is dose-related. The low OTC dosage
studies in controlled clinical trials show that GI and other ADRs are rare and have
minor outcomes (Rainsford et al. 1997; Doyle et al. 1999; Rainsford 1999a, b, c;
Ashraf et al. 2001; Le Parc et al. 2002; Moore et al. 1999, 2002, 2003).

13.1 Spontaneous ADRs and Toxicity

Spontaneous events from OTC ibuprofen in the UK, the USA, and Australia
indicate that serious ADRs are rare. Most involve the GI system, renal, and
respiratory systems. Oedema and minor respiratory reactions along with some
minor skin reactions occur infrequently asthma, bronchoconstriction, and cardio-
vascular events are rare.
Relatively few deaths have been noted with ibuprofen, and mostly in patients
with other serious complications.
While an increase in cases of ibuprofen poisoning has been reported to the
National Poisons Advisory Service, London, in the period post-1996 when ibupro-
fen was granted GSL status in the UK, this has not been accompanied by serious

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 183

DOI 10.1007/978-3-0348-0496-7_13, # Springer Basel 2012
184 13 Overall Assessment

outcomes or deaths. Indeed, OTC ibuprofen has very rarely ever produced deaths,
even in accidental or deliberate acute overdose.
Ibuprofen must, in comparison with paracetamol or aspirin (let alone other
analgesics), be considered a drug least likely to result in mortality in overdose. It
is associated with morbidity from GI haemorrhage at OTC doses, but very rarely
has this resulted in fatality.
In comparison with paracetamol and aspirin, ibuprofen has the lowest risks of
GI, CV, and hepato-renal toxicities. While GI toxicity is probably the most signifi-
cant, it is markedly less than that of aspirin, but more than that from paracetamol.
However, the pharmacoepidemiologic observations (Henry et al. 1996, 1998;
Garcia-Rodriguez and Hernandez-Diaz 2001; Bjarnason 2007), supported by stud-
ies in laboratory animal models of GI toxicity, suggest that under some conditions
paracetamol may not be entirely without GI toxicity (e.g., in certain patients with
hypersecretory functions in the stomach, those with profound inflammatory
conditions, or those taking NSAIDs concomitantly) (Whitehouse and Rainsford
2006). Serious GI reactions may occur, but are relatively rare and are dose- and
time-dependent (Bjarnason 2007).
In contrast to the situation of liver toxicity associated with paracetamol, and to a
lesser extent with aspirin, serious liver reactions are rare with ibuprofen. Indeed, it
should be recalled that ibuprofen was developed as a drug without liver toxicity, in
the light experience with its progenitor, ibufenac (Rainsford 1999a).
Renal effects of low-dose NSAIDs may contribute to reversible alterations
in excretion of sodium and potassium, and reduction in the efficacy of anti-
hypertensive agents and diuretics as a consequence of inhibitory effects on renal
prostaglandin production (Brater 1998). This also applies to ibuprofen. Consequent
exacerbation of hypertension in patients with this and related CV conditions may
represent a risk factor. However, even at prescription-level doses the risk of serious
CV reactions is low, and certainly not in the order of those for coxibs (Antman et al.
2007; Strand 2007; Trelle et al. 2011).
Concerns have been raised about ibuprofen affecting the anti-platelet, and thus
anti-thrombotic activity of aspirin, especially at low dose. It appears this may
possibly occur when the two drugs are taken concomitantly. The suggestion has
been made to recommend that these two drugs not be taken concomitantly, but to
separate the time of taking these drugs. Certainly, this would appear to make sense
pharmacokinetically and pharmacodynamically. The short plasma elimination half-
life of ibuprofen, and the short period (~15–30 min) when aspirin acetylates
platelets COX-1 would seem to make this a feasible recommendation. It has been
postulated that ibuprofen interferes with aspirin, at the level of competing with the
COX-1 binding site for aspirin. Given this specific nature of the pharmacodynamic
interference, it is likely that even short periods of separation of the intake of these
two drugs will notably reduce the risk of ibuprofen interfering with the anti-
thrombotic effects of aspirin. It would also be preferable to take the dose of aspirin
before ibuprofen.
It does seem that as aspirin increases the risk of NSAIDs causing serious GI
reactions, taking aspirin and ibuprofen would not seem a safe procedure.
13.3 Assessment of Risks and Procedures for Their Reduction 185

Another aspect that has not been considered is the possibility that use of aspirin
to prevent platelet aggregation in patients with thrombo-embolic diseases may not
be necessary in patients taking ibuprofen, since it has been shown that ibuprofen
can inhibit certain components of platelet aggregation. The clinical significance of
this effect in prevention of CV disease has not been explored. It has, however, been
noted that naproxen has low CV risks, and this may be related to the inhibition of
platelet aggregation by this drug.
Meta-analysis studies in the large-scale coxib trials suggest that ibuprofen has
low CV risk, which in most studies does not appear to have been greater that a RR
of unity (Antman et al. 2007; Trelle et al. 2011), so that this component of the
overall safety of ibuprofen would appear to be a low possibility with ibuprofen.

13.2 Benefit/Risk Analysis

In terms of benefits, ibuprofen at OTC recommended doses has been proven to have
either comparable or in many cases superior therapeutic effects to those of other
NSAIDs or analgesics in the treatment of a wide variety of painful and associated
inflammatory conditions, including the following:
• Inflammatory arthropathies and other musculo-skeletal conditions
• Dental pain
• Primary dysmenorrhoea
• Upper respiratory tract infections, colds and influenza
• Sports and other minor injuries
In most of the conditions where there is a pronounced inflammatory component,
ibuprofen is superior to the alternative analgesic, paracetamol, because of its
substantial anti-inflammatory component. Paracetamol does not have appreciable
anti-inflammatory activity. Ibuprofen is more potent than aspirin as an analgesic
and anti-inflammatory agent. Thus, in respect of therapeutic benefits ibuprofen is
clinically superior to the other two OTC analgesics. It clearly affords an important
therapeutic alternative for the public which is widely recognized in the UK, North
America, Australia, New Zealand, Switzerland, and many other European, Central
and South American as well as Asian countries. In these countries, it is widely
recognised for its relative safety which is clearly superior to that of (a) paracetamol,
especially in relation to the hepatic risks factors from this drug, and (b) aspirin,
where there are appreciable GI risks.

13.3 Assessment of Risks and Procedures for Their Reduction

The potential risks to the public taking ibuprofen at OTC doses arise from:
186 13 Overall Assessment

• Upper GI distress comprising principally dyspepsia and epigastric or abdominal

pain, as well nausea, diarrhoea, and to a lesser extent vomiting. The evidence
suggests that the risk of serious upper GI events is low at OTC doses. In
“real-world” situations, OTC ibuprofen has been found to have relatively few
reports of serious GI ADRs, cutaneous reactions, and superficial oedema, which
are reversible upon cessation of the drug. Warning the patient of the occurrence
of these symptoms should be adequate to prevent their occurrence.
• On rare occasion, renal and hepatic reactions, which in the normal course of
events would inevitably lead the patient to seek medical advice. Some
precautions might be advisable to warn of the risks of taking medications that
are known to affect these organ systems.
• The risks of symptomatic events (dyspepsia, pain, nausea, etc.) are more
common with ibuprofen but no different than those of paracetamol (which
has been used in extensive studies as a bench-mark for comparison) and
placebo in those studies where this has been employed as a basis of compari-
son. These ADRs can be considered largely “self-limiting”, inasmuch as they
mostly result in cessation of use of the drug.
Well-known factors are associated with increased risks of all NSAIDs in devel-
oping serious GI reactions, among them (a) concurrent high intake of alcohol,
corticosteroids, other ulcerogenic drugs, (b) ageing and impaired hepato-renal
functions, (c) presence of Helicobacter pylori, (d) long plasma elimination half-
life, and (e) high relative potency as inhibitors of COX-1 derived mucosal protec-
tive prostaglandins.
Some of these factors can be reduced by recommending avoidance of intake of
drugs such as those in (a) above, and patients who are “at risk” such as in (b). The
properties of being a short half-life drug and relatively low potency as a cox
inhibitor (especially as it is reversible, in contrast to many NSAIDs and coxibs
that have pseudo-irreversible inhibitory properties) reduces the likelihood of these
factors underlying the development of serious GI events with ibuprofen. H. pylori is
a different matter. This may only emerge when there are untoward upper GI events
that highlight the need to investigate for the presence of this pathologic organism.
Risk reduction also involves advising patients with pre-existent states, e.g., history
or presence of peptic ulcer disease, renal, and hepatic diseases from taking ibuprofen.
Clearly, safety is a feature of ibuprofen that is to its advantage, but use of the
drug by patients that may be at risk of developing a particular side-effect raises the
prospect that there may be “channelling” of high-risk subjects. There is also an
important role for education in risk reduction. This may take several forms, e.g.,
advertising and publicity directed to the public, package labelling, and patient
information leaflets.
13.4 Examples of Advice for Ibuprofen Packages and PILs 187

Many of these educational issues have application to the safe use of all analgesic
preparations and not to ibuprofen alone. Some of the principles and suggestions
outlined here could well apply to aspirin and paracetamol in particular.
However, this could be made a generic approach, especially when cautioning on
drug interactions, prior- or concurrent conditions likely to exacerbate or trigger
adverse reactions, and appropriate use of these medications.
It is possible that some members of the public who may not be adequately in
formed or appreciate the problems with taking medications that are available in
stores or even pharmacies may be at risk because of lack of knowledge, literacy, or
understanding (cognition). It is of course a world-wide problem that there are
different levels of literacy in various socio-economic classes or groups. This situa-
tion has been highlighted in relation to concomitant intake of Chinese Traditional
medicines CTMs and other herbal remedies, which raises issues about herbal–drug
interactions that may affect the safety and efficacy of ibuprofen (Sect. 6.10). There
may be a case for recommending that CTM practitioners, quasi-professionals,
pharmacists, and herbalists should be specifically educated and trained to advise
patients or customers not to take CTMs with ibuprofen and other NSAIDs or
analgesics because of the risks of herbal preparations interacting in an untoward
manner with these drugs. The labelling of packages and advice to patients taking
ibuprofen as well as other NSAIDs or paracetamol should include specific warnings
not to take these drugs with CTMs/herbal preparations.
An approach to improve understanding by members of the public when not to
take analgesics, and when it is appropriate for them to do so, is to simplify and make
more meaningful recommendations on the package as well in the patient informa-
tion leaflets (PILS).

13.4 Examples of Advice for Ibuprofen Packages and PILs

Don’t take this pain-killer with

• Alcohol (beer, wine, whiskey)
• Other pain killers
• If you have stomach pains
• If you take blood thinners
• If you are receiving treatment for cancer, heart disease, or other serious diseases
unless specifically advised by your doctor
• If you have problems or reactions to this drug, then immediately consult your
pharmacist or doctor
• Chinese traditional medicines or herbal preparations
Many examples of complex labelling and PILS derive from over-riding concerns
that statements made on packs and PILS should be legally sound, without
188 13 Overall Assessment

consideration of the perception of the confusing nature of information which is

often provided with medications. For analgesics this is a particular issue, and one
which could be addressed by having simple do’s and don’ts, even the use of iconic
easy-to-understand symbols.
Chapter 14
Summary

Ibuprofen has become one of the most widely used analgesic and anti-inflammatory
drugs in the world today. In the USA alone, this drug is the largest selling analgesic
sold over the counter (OTC) for non-prescription use. Its success as an OTC drug
has been due partly to its relative effectiveness and safety in low dosages, and the
low risks of serious toxicity in the population at large. Moreover, as a prescription-
only drug taken at higher doses for the treatment of arthritic and related chronic
inflammatory diseases, it still has wide acceptability for short-term use, despite
competition from the newer non-steroidal anti-inflammatory drugs (NSAIDs),
including the coxibs, as well as the non-narcotic analgesics (including paracetamol
or acetaminophen).
This book reviews the mechanisms of action of ibuprofen, and its therapeutic
applications in a wide variety of painful and inflammatory diseases. Aspects of the
safety of this drug are reviewed, including (a) the overall safety profile of ibuprofen
at current prescription dosage 1,800–2,400 mg/day, wherein the drug is
recommended for the short- and long-term treatment of acute and chronic moderate
to severe inflammatory pain conditions, including rheumatoid- and osteoarthritis,
spondylo-arthropathies and other rheumatic conditions, (b) specifically the safety of
ibuprofen 1,200 mg/day for a maximum dosage period of 7–14 days, which in
over 80 countries worldwide is sold as an OTC analgesic for the relief of mild to
moderate painful conditions, many of which have a moderate acute inflammatory
component, (c) the efficacy and therapeutic activities of ibuprofen principally at
OTC dosage, and (d) assessment of the risks/benefits of ibuprofen compared with
other analgesics (paracetamol) and OTC NSAIDs (ketoprofen, naproxen) that are
also sold as OTC analgesics in some countries.
The main conclusions are that:
1. Ibuprofen at OTC doses has low risks of developing serious GI events, renal and
associated CV events, cutaneous and hepatic injury. Among the NSAIDs sold for
prescription use, ibuprofen has the lowest risks of developing these and other
adverse effects observed with NSAIDs in general. Thus, at the high end of the

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 189

DOI 10.1007/978-3-0348-0496-7_14, # Springer Basel 2012
190 14 Summary

prescription doses employed therapeutically, ibuprofen is of low overall relative

risk.
2. Ibuprofen OTC does not represent a risk for developing liver injury, especially
the irreversible liver damage observed with paracetamol and the occasional liver
reactions from aspirin.
3. The pharmacokinetic properties of ibuprofen, especially short plasma half-life
of elimination, and lack of development of pathologically-related metabolites
(e.g., covalent modification of liver proteins by the quinine–imine metabolite
of paracetamol or irreversible acetylation of biomolecules by aspirin), are
support for the view that these pharmacokinetic and notably metabolic effects
of ibuprofen favour its low toxic potential.
4. Moderate inhibition of COX-1 and COX-2, combined with low residence time of
the drug in the body, may account for the low GI, CV, and renal risks from
ibuprofen, especially at OTC doses.
5. Despite ethnic differences in cytochrome P450 metabolism, this does not appear
of major significance in the overall safety profile of the drug in different
populations in relation to its pharmacokinetic parameters.
The place of OTC ibuprofen in OTC as a pain-relieving drugs for use by the
population at large should be considered in relation to cautious use, and recognition
of adverse symptoms when they occur. Like all drugs, ibuprofen can have untoward
reactions when used inappropriately or in those at risk of developing known side-
effects (e.g., in the gastro-intestinal tract, cardiovascular system, skin, or the
hepato-renal systems). This book reviews the case for safe use of ibuprofen and
understanding of its modes of action.
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Index

A Adverse drug reaction (ADR), 105

Abdominal pain, 134 reporting, 128, 176, 177
Absorption, 87 reports, 179
Absorption, distribution, metabolism, and risks, 113–116
elimination (ADME), 14 Adverse events, 68, 107–113, 119–122,
Absorption pharmacokinetics, 137, 138 131, 177
Aceclofenac, 128 Adverse reactions, 102, 104, 107, 175–181
Acetaminophen, 152 Age, 149, 156
Acetic acid induced constriction, 83 Agranulocytosis, 169
Acetylsalicylic acid (aspirin), 65 Alkaline phosphatase, 75, 76
Acid production, 137 All body systems, 110
Acute fever, 70–75 Alluprinol, 115
Acute GI bleeding, 120 Alternating ibuprofen and paracetamol, 83
Acute inflammation, 43, 44 Aluminium, 87
Acute injuries, 66 Alzheimer’s disease, 143
Acute interstitial nephritis, 163 American College of Rheumatology, 142
Acute ischaemic renal insufficiency, 163 American Heart Association, 154
Acute MI, 147 Americans, 94
Acute pain,, 25–26, 59, 65 Aminoethanol, 87
Acute renal failure, 120 Aminopyrine, 47
Acyl glucuronides, 51 Aminotransferases, 167
Adams, Stewart, 1 Amphiphilic, 77
Adenosine A2A-receptor, 80 Anaemia, 169
Adenosine receptors, 82 Anaesthesia, 35
Adenosine triphosphate, 54 Analgesia, 13–26, 47, 65
Adhesion molecules, 51, 80 Analgesic(s), 59, 77, 94, 107, 128
ADME. See Absorption, distribution, abuse syndrome, 81
metabolism, and elimination activity, 66
(ADME) ceiling, 79, 82, 86
ADP, 160 effects, 49–50
ADR. See Adverse drug reaction (ADR) pack sizes, 180
Adulteration of Chinese herbal response, 25
preparations, 117 Anandamide, 47, 53, 84
Adults, 33–37 Anandamide hydrolase, 47

K.D. Rainsford, Ibuprofen: Pharmacology, Therapeutics and Side Effects, 231

DOI 10.1007/978-3-0348-0496-7, # Springer Basel 2012
232 Index

Anaphylactoid reactions, 169 Asthma, 169–171, 183

Anaphylaxis, 120–122 Asthma/bronchiolitis, 121
Angelica pubescens, 118 “At risk” patients, 112
Angina, 147 Aura, 65
Angioedema, 115, 116 Australia, 82, 179, 183
Angiotensin-converting enzyme (ACE) Azapropazone, 126, 127
inhibitor, 162
Animal models, 88
Ankle joint injury, 78 B
Ankylosing spondilitis, 78 Bacterial meningitis, 120
Anthroquinone glycosides, oxalic acid, 118 B-and T-cell, 46
Antihistamines, 44 Benchmark, 108
Anti-hypertensive therapy, 163 Benefit/risk analysis, 185
Anti-inflammatory, 77 Betamethasone, 115
activity, 51 Biliary flow, 123
doses, 68 Bilirubin, 76
effects, 68, 88 Bioavailability, 35, 39, 85, 93, 137
Antinociceptive interaction, 82 Bleeding, 45, 180
Antiplatelet Trialists’ Collaboration, 154 Blood pressure, 141, 161
Antipyretic(s), 72, 73, 119 Body-as-a-whole, 110
activity, 56–57 Boots Company, 1, 2, 91
agents, 72 Boston Collaborative Fever Study, 120
effects, 26, 71, 74 Boston University Fever, 172
interventions, 73 Bradykinin, 44
response, 56 Brain, 84
Anti-thrombotic activity of aspirin, 184 Bromfenac, 166
Anti-thrombotic effects, 161 Bronchoconstriction, 183
Anti-thrombotic potential of aspirin, 157 Bronchospasm, 171
Anxiety, 81 Brufen®, 49
Apoptosis, 44 Bucetin, 115
Arachidonic acid, 44, 47 Bullus dermatitis, 169
Arachidonic acid metabolism, 47 Burana®, 35
ARAMIS, 127 Burroughs Wellcome, 120
ARAMIS database, 104
Arcoxia, 143
Arginine, 87, 88 C
Arthritic patients, 51, 67 Caffeine, 79–81, 115
Arthritis, Rheumatism, and Aging Medical Caffeine containing beverage, 82
Information System (ARAMIS), 103 Ca2+ in flux in nerves, 51
Arthritis, therapy of, 106 Calcitonin gene-related peptide (CGRP),
Articular cartilage, 46 53–55
Aseptic meningitis, 169 Calpol, 120
Asian children, 116 Canada, 147, 152
Asian Indians, 94 Cancers, 143
Aspirin, 48, 60, 62, 68, 76, 78, 79, 104, 108, Cannabinoid, 53, 84
115, 126–129, 133, 156, 158, 159, Cardio pulmonary disease, 72
163, 168, 173, 177, 179, 180, 184, Cardio-renal effects, 162
185, 187 Cardio-renal syndrome, 141
Aspirin-associated asthma, 170 Cardio-vascular (CV), 141
Aspirin–ibuprofen interaction, 160 death, 154
Aspirin-interant asthma (AIA), 170 disease, 78‘
Aspirin-sensitive asthma, 170 disorders, 112
Assessment of risks, 185–187 events, 3, 106, 154, 183
Index 233

and gastro-intestinal reactions, 161 Codeine ibuprofen abuse, 82

non-aspirin, 131 Coding Symbol Thesaurus for Adverse
safety, 141–162 Reaction Terms (COSTART), 109
toxicity, 143 Coffee, 81
Caucasian, 94, 97–101 Colds, 59, 66, 185
CB1 receptor activation, 84 Collagen, 160
CB receptors, 47 Collagenases, 46
Celebrex, 105 College of Gastroenterology, ACG, 112
Celecoxib, 3, 12, 48, 56, 60, 62, 105, 106, 126, Combination antipyretic therapies, 72
128, 131–135, 143, 146–148, 150, Combinations of caffeine, 79
152, 154, 159, 165–167 Combination with ibuprofen, 80
Central nervous system (CNS), 169 Committee on the Safety of Medicines
actions, 56 (CSMs), 175, 176, 178
adverse reactions, 81 Congestive heart failure (CHF), 98, 141,
reaction, 109 151, 162
Central neural afferent pathways, 53 Coronary artery disease, 98
Cerebral vascular disease, 98 Coronary heart disease (CHD), 112
Cerebro-vascular accident (CVA), 147 Coronary renal failure, 98
Channelling, 130 Cortisone, 115
CHD. See Coronary heart disease (CHD) Cost–benefits, 88
Chemokines, 169 Cost-effectiveness, 88
Chemo-somatosensory model, 21 Covalent tissue binding, 51
Children, 33–42, 70–76, 83, 176 COX-1, 47–50, 52, 53, 55, 66, 77, 84, 96, 102,
Children’s Advil®, 121 159, 184
Children’s Analgesic Medicines Project COX-1–/+, 55
(CAMP), 121 COX-2, 47–50, 53–55, 66, 77, 80, 84, 96, 102
Children’s headache, 79 COX-2–/+, 55
Children’s Tylenol®, 121 COX-3, 84
Chindrocytes, 46 COX activities, 83
Chinese, 94–96, 99, 113, 116 COX-1/COX-2, 56
herbal medicines, 116 Coxibs, 3, 67, 75, 113, 126, 128, 141, 165, 173
subjects, 100 Coxib studies, 130–133
traditional and herbal medicines, 116–119 COX inhibition, 170
Chinese traditional medicines (CTMs), Cox proportional hazards analysis, 150
113, 187 Creatinine clearance, 163
Chlamydia, 142 Cross-reactions of ibuprofen, 170
Chlordiazepoxide, 115 CSF, 13
Chlorpheniramine maleate, 115 CTMs. See Chinese traditional medicines
Chlorzoxazone, 115 (CTMs)
Choleretics, 123 Cutaneous reactions, 171–172
Class, 130 Cyclic-3’, 5’-adenosine monophosphate, 80
Class study, 131, 133, 152 Cyclooxygenase activities, 48
Clearance (CL/F), 37 Cyclo-oxygenases, 180
Clinical efficacy, 59–76 CYP2C8, 94, 96
Clinical response, 30 CYP2C8*3, 94, 96
Clinical significance, 131 CYP2C9, 94, 96, 117
Clonal proliferation, 46 CYP2C9*1, 11, 96
CNS. See Central nervous system (CNS) CYP2C9*2, 11, 94, 96
Coagulation factors, 157 CYP2C9*3, 11, 94, 96
Cochrane assessments, 88 CYP C28, 117
Cochrane Library, 167 CYP2C9 and CYP2C8, 94
Cochrane Review, 69 CYP2C9 polymorphisms, 11, 96
Codeine, 62, 81 CYP-2C19, 11
234 Index

CYP polymorphisms, 12 Dominant lethal changes, 81

Cystic fibrosis, 40–41, 76 Dorsal horn, 55
Cytochrome metabolism, 94 Dorsal root ganglion, 54
Cytochrome P450, 42, 94, 117 Dose-dependency, 150
Cytokine(s), 44, 116, 169 Dose-dependent blood loss, 123
(IL-1,TNFa) production, 44 Dose range of ibuprofen, 50
interactions, 46 Dose-response effect, 67
Drug derivatives, 77–90
Dyslipidemia, 149
D Dysmenorrhoea, 59, 78
D-amino acid oxidases, 87 Dyspepsia, 75, 134, 186
Danish National Patient Registry, 150
Danish Registry of Medicinal Product
Statistics, 150 E
Death, 150, 161 Education campaign, 181
Defined daily doses, 168 Effects in hypertension, 161–162
Delayed onset muscle soreness (DOMS), 109 Effects of diuretics, 163
Dental pain, 59–65, 185 Efferent modulating pathways, 53
Dental pain model, 16–20, 79 Effervescent ibuprofen, 67
Dental surgery, 15, 59 Elderly, 93, 111
Department of Health, 177 patients, 158
Detergent like characteristics, 77 subjects, 164
Deutsche Gesellschaft für Neurologie Elevated transaminases, 168
(DGN), 65 Enalapril, 162
Deutsche Migräne und Endocannabinoid, 84
Kopfschmerzgesellschaft Endogenous cannabinoid, 47
(DMKG), 65 Endogenous pyrogen, 56
Dexamethasone, 115 Endoscopy, 125, 135
Dexibuprofen, 77–79 Endothelial cells, 51
crystal structure, 78 Enteric-coated low-dose aspirin, 160
peak Cp, 78 Environmental (dietary) differences, 97
pharmacokinetics, 78 Ephedra, 118
physico-chemical properties, 78 Ephedra sinica, 117, 118
Dexketoprofen, 62, 128 Ephedrine, pseudoephedrine, 118
Dextropropoxyphene + paracetamol, 62, 63 Epidemiological data, 129
Diabetes, 112 Epidemiological studies, 102–104, 143–152
Diabetes mellitus, 98, 141, 149 Epigastric, 134
Diarrhoea, 134 Episiotomy, 81
Diastolic blood pressure, 162 Erosion of bone, 46
Diazepam, 115 Erythema multiforme, 169
Diclofenac, 12, 48–50, 60, 62, 65, 105, 106, Ethnic, 97
115, 116, 126–128, 130–133, 146, Ethoxybenzamide, 115
150–152, 157, 159, 165–168, 173 Etodolac, 62, 133, 147, 148, 166
Diflunisal, 62, 126, 127 Etoricoxib, 62, 143
Digestive system, 115 European populations, 126, 150
Diphenhydramine, 115 Europeans, 94
Discontinuations, 107 Evidenced-based evaluation, 88
Disease states, 101–102 Exacerbate immune reactions, 169
Diuretics, 161 Ex-vivo inhibition
Dizziness, 109 COX-1, 49
D/J-type prostaglandins, 44 COX-2, 49
DL-lysine, 87 Ex-vivo production, 49
Dolormin®, 88 PGs, 49
Index 235

F symptomatic adverse reactions, 134

Facial swelling, 86 symptoms, 68, 86, 113
FDA. See Food and Drug Administration toxicity, 113, 123–139, 184
(FDA) tract, 102
Febrile asthmatic children, 171 ulceration, 180
Febrile children, 26, 74, 78 ulcers, 45
Febrile conditions, 70 Gender, 37
Febrile seizures, 72 Gene-knockout experiments (k/o) mice, 55
Fenbufen, 126 General Practice Database (UK), 129
Fenoprofen, 104, 126, 164 General Sales Listing (GSL), 2
Fenprofen, 127 licence, 179
Fever, 33, 72, 73, 76, 83, 119, 176 Genetic changes, 81
Fever-phobia, 72 Ginseng, 118
Finland, 170 Ginsenosides, 118
First pass metabolism, 13 Global Epidemiology group in Barcelona
First perceptible pain relief (TFPR), 67 (Spain), 165
Fixed dose combinations, 85 Glucuronyl-transferase enzyme, 42
Flatulence, 134 Glutamate, 53, 55
Fluids, 138 Glutaminergic activation, 84
Flurbiprofen, 63 Glycrrhiza glabra, 118
Food, 136–138 Glycyrrhizin, glycrrhetinic acids, 118
Food and Drug Administration (FDA), 2, 142, Guaiacol, 87
165, 168 Gynaecological surgery, 81
Formulations, 77–90
French pharmacovigilance database, 128
French pharmacovigilance network, 126 H
Furocoumarins Aconitine, 118 Half-life, 67
Han Chinese, 97, 99
Headache, 59, 66, 79
G Health Assessment Questionnaire (HAQ-
Gastric acidity, 137 Stanford University), 28, 68
Gastric adverse effects, 80 Heart failure, 86
Gastric bleeding, 122 Helicobacter pylori, 112, 132, 133, 142, 186
Gastric distress, 80 CagA positive, 142
Gastric mucosa COX, 48 Hepatic, 131
Gastric outlet obstructions, 129 reactions, 165
Gastritis/vomiting, 120, 135 toxicity, 165–168
Gastroduodenal ulcer incidence, 133 Hepatitis, 168
Gastrointestinal (GI), 131 Hepato-renal ADRs, 132
ADRs, 78, 114, 125 Hepatotoxic drug, 168
adverse reactions, 88 Hepatotoxicity, 133, 165
bleeding, 75, 76, 120, 127, 128, 136 Hepatotoxic reactions, 72
complications, 127, 146 Herbal remedies, 187
disorder, 179 Herb–medication interactions, 117
effects, 142 Herb–NSAID, 117
events, 126 Herpes encephalitis, 122
at OTC dosages, 134–135 Heteroarylacetic acids, 128
haemorrhage, 115 High-dose aspirin, 160
infection, 120 Hispanic, 112
reactions, 2, 110 Histamine phase, 44
risks, 96, 130–133 HLA phenotypes, 116
safety, 106 H2 receptor antagonists, 130
in paediatric populations, 135–136 5-HT3, 84
236 Index

5-HT1B, 84 cardiovascular events, 148, 149

Human toxicology, 175–181 caffeine combination, 80
Hydrochlorothiazide, 115, 161 celecoxib, 152
Hydrocodone, 82 CL, 99
Hydrocortisone acetate, 115 Cl, 97, 100
5-Hydroxy tryptamine, 54, 84 CL/F, 9, 39, 95
Hyperlipidaemia, 98 Cmax, 6, 9, 10, 36, 40, 41, 85, 95, 99–101
Hypersensitivity, 115, 116 complications, 146
Hypersensitivity reactions, 169–171 concentrations, plasma, 33
Hypertension, 93, 98, 132, 141, 149 congestive heart failure, 152
Hyperuricaemia, 98 coxib, 152
Hypothalamic pathways, 26 CSF, 10, 31
Hypothalamus, 56 CV events
acute MI, 145
case–control, 144
I celecoxib, 145
Ibufenac, 91 cohort studies, 144
Ibuprofen, 39, 48, 60, 62, 66, 71, 104, 106–108, coxib, 144
115, 116, 125–133, 136, 146, 148, diclofenac, 145
152, 157–159, 166–168, 173, meta analysis, 144
177, 179 naproxen, 145
absorption, 35 QRESERCH, 145
abuse, 82 risks, 146
acute fever, 71 rofecoxib, 145
ADRs, 114 UK general practice database, 145
adverse events cyclooxygenase, 48
abdominal pain, 111 cytochromes P450, 5
AE leading to discontinuation, 111 derivatives, 77
all AE, 111 detoxification, 7
body as a whole, 111 dose-escalation, 40
digestive system, 111 dose relationships, 10
dyspepsia, 111 dose–response, 19
headache, 111 EEG activity, 20
moderate AE, 111 effects on ion flux, 50
nausea, 111 enantiomers, 8, 11, 20, 27, 36, 92
nervous system, 111 etodolac, 148, 149
rates, 108 extended/modified release (MR/SR), 137
respiratory system, 111 formulations, 77, 100
severe AE, 111 gastrointestinal and cardiovascular
SGAE, 111 events, 156
aluminium salts, 34 GI complications, 146
amino acid formulations, 87–88 glucuronides, 6, 8
analgesia, 20 glucuronyl transferases, 5
analgesic, 10 hindpaw, 56
antipyretic effects, 56 hird molar extraction, 60
Antiplatelet Trialists’ Collaboration immediate-release (IR), 137
(APTC), 153 formulations, 101
arginine, 88 inhibition, 48
assays, 48 ischaemic events, 156
AUC, 6, 10, 36, 41, 42, 85, 95, 99–101 isomers, 6
bioavailability, 34, 35 i.v. lysine, 42
biodisposition, 5 Ka, 99, 100
cardiovascular conditions, 154 Ke, 9
Index 237

kel, 85 risk factors, 114

kinetics, 10 safety profile, 91, 93
laser-induced, 20 salt formulations, 87–88
linear kinetic, 13 salts, 42
lumiracoxib, 152, 156 serum concentrations, 9, 17
lysinate, 88 serum elimination half-lives (t½ ), 34
lysine, 87 Shanghai, 114
lysine salt, 34 short plasma elimination half-life, 47
metabolism, 7 S(+) ibuprofen, 11
MRT, 6, 9, 99 sodium salt, 8
myocardial infarctions, 156 S:R ratio, 10, 99
nabumetone, 148, 149 stereospecific disposition, 32
naproxen, 148, 149 substudy, 156
non prescription/OTC doses, 4 sum of pain intensity difference (SPID), 19
NSAIDs, 148, 149 suppositories, 35
oral absorption, 38 suspension, 39, 71, 76, 101
oral administration, 77 synovial fluids, 10, 11, 31, 32, 40
oral suspension, 35 t½, 9, 38, 39, 42, 85, 97, 100
OTC status, 176 t½ (h), 95
oxidative metabolism, 11 Taiwanese, 98
pain evoked potentials, 23 temperature, 72
pain ratings (PR), 23 thioester of coenzyme A, 7
and paracetamol, 82, 85 time-course, 19, 20
parenteral administration, 77 Tmax, 8, 9, 36, 40, 41, 85, 99–101
peak concentration, 72 Tmax (h), 95
pharmacokinetic(s), 5, 11, 39, 95, 98, 100 tooth pulp stimulation, 24
aspects, 93 triglycerides, 7
parameters, 6, 9, 29, 30, 94 TRPC, 21, 66
properties, 38 Vd, 38, 42, 97, 100
variables, 36 VD/F, 9, 95
variations, 94 volume of distribution at steady state, 39
physicochemical properties, 77 Vp apparent volume of distribution, 39
PK/PD properties, 16 Vss, 39
plasma concentration profiles (S)-(+)-Ibuprofen-CoA, 51
poloxamer, 8 Ibuprofen + codeine, 69
sodium salt, 8 Ibuprofen Codeine Combinations, 81–82
plasma concentrations, 6, 21, 25, 32, 71, 72 Ibuprofen–Paracetamol Combination, 83–86
plasma serum concentrations, 22 ICH GCP guidelines, 114
poloxamer, 8 Immediate response (IR) formulations, 67
post-marketing data, 91 Immunoinflammatory cells, 46
post-operative pain, 62 Impaired clearance, 96
potential risk factors, 148, 149 Impaired renal function, 163
prescription doses, 4 Increased accumulation in elderly, 92
pre-systemic inversion, 8 Increased blood pressure, 81, 161
racemate, 71 Increased diuresis, 81
racemic ibuprofen, 101 Increased free fatty acids, 81
racemic mixture, 5 Increased risk of fractures, 173
rats, 56 Indomethacin, 48, 104, 115, 125–128,
rectal absorption, 33 152, 166
rectal solution, 35 Induced pain models, 20–25
rectal suspension, 35 Inducible COX-2, 45
relative risk (RR) of myocardial Infants, 37, 39, 76
infarction, 151 Inflamed joints, 51, 67
rheumatic outpatients, 114 Inflammation, 43–57, 59
R(–) ibuprofen, 11 Inflammation development, 45
238 Index

Inflammatory arthropathies, 185 Liver malfunctions, 93

Inflammatory reactions, 53 Liver reactions, 167
Inflammatory soup, 54 Liver-related deaths, 167
Influenza, 59, 185 Liver-related discontinuations, 167
iNOS, 52, 54, 84 Liver-related hospitalisation, 167
Interleukin-1, 50, 52, 56 Liver-related SAEs, 167
Interleukin-1b (IL-1b), 56 L-lysine, 87
Interleukins, 26 L negative, 133
Intestinal ulceration, 133 Lornoxicam, 63
Ion flux, 50 Lowdose aspirin, 156, 157
IPSO, 69 Low-dose ibuprofen, 160
Irritability, 81 Low dose OTC ibuprofen, 130
Ischaemic heart conditions, 142 Lower respiratory tract infection, 120
Ischaemic stroke, 156 Lower socio-economic classes, 112
i.v. ibuprofen, 42 Lumbar vertebral pain, 78
Lumiracoxib, 63, 106, 107, 143, 154, 165
Lyell’s syndrome, 122, 169, 171
J Lymphadenopathy, 75
Joint-destructive enzymes, 43 Lysine, 87
Joint inflammatory disease, 46 clonixinate, 128
Joint symptoms, 69 salt of ibuprofen, 137
Joint tenderness, 68 salts, 137
Juvenile idiopathic arthritis (JIA), 40, 75–76
Juvenile rheumatoid, 73
M
Macrophage, 44, 46
K Malaena, 113
K+, 82 Mast cell activation, 44
Ketolorac, 68 McNeill, 120
Ketoprofen, 3, 48, 63, 104, 115, 126–128 Meals, 137
Ketorolac, 128, 166 Mean residence times (MTTsynovial), 32
Kidneys, 102 Mean VAS Pain scores, 17
Kinins, 44 Meclofenamate, 104
Knee joints, 69 Medicines for Children, 73
Knee or back pain, 88 Medulloblastoma, 122
MedWatch, 160
Mefenamic acid, 126
L Meglumine, 87
L-arginine, 56 Meloxicam, 49, 50, 128, 166, 167, 173
L-arginine complex, 79 Menthol, 34
Leucocyte-derived, 56 Merck Sharp and Dohme, 142, 143
Leucocyte-derived inflammogens, 50 Meta-analyses, 152, 154
Leucocytes, 44, 50–52, 56 Metabolic disorders, 72
accumulation, 51 Metabolic systems, 169
vessels, 46 Metalloproteinases (MMP), 52
Leukotriene B4, 50 Metamizole, 128
Leukotriene C4 synthase, 170 Methotrexate, 168
Leukotrienes, 44 Methylprednisolone, 115
Licorice, 118 Migraine headaches, 26
Life events, 161 Mild–moderate musculoskeletal pain, 90
Lipid membranes, 77 Milk, 138
Lipoxins/resolvins, 44 Minophy, 115
Liquigel, 137 Minor injuries, 185
Liver enzymes, 75 Misuse of Analgesics, 180–181
Liver function tests, 168 Mobic®, 49
Index 239

Molar dental surgery pain, 66 post-operative pain, 62

Monocytes, 44 relative risk (RR) of myocardial
Monocytes macrophages, 50 infarction, 151
Morphine, 60 third molar extraction, 60
Motrin, 120 NSAIDs + antiplatelet drugs, 128
Multiple-day studies, 109 Nuclear kappa B (NFkB), 80
Multiple NSAIDs, 166 Number Needed to Treat (NNT), 59, 67
Musculo-skeletal conditions, 59, 185 Nurofen, 67
Musculo skeletal pain, 88 Nurofen®Express, 88
Myocardial infarction (MI), 81, 86, 141,
154, 155
O
OA. See Osteoarthritis (OA)
N Obesity, 141
Nabumetone, 126, 133, 147, 148 Ocular effects, 169
Na+ from synapses, 51 Oedema, 16, 183
Naproxen, 3, 48, 60, 104, 106, 125–128, On-Chinese population, 114
130, 135, 146–148, 151, 152, On COX-1, 46
154, 156, 166, 167 Oral bioavailability, 78
Naratriptan, 65 Oral clearance, 71
National Poisons Advisory Service, Oral formulations, 78
London, 183 Oriental, 97–101
Nausea, 86, 186 communities, 147
Neutral proteases, 46 populations, 101, 113–116
Neutrophil PMNs, 50 Orthopaedic surgery, 35
New Zealand, 82 Osteoarthritis (OA), 27, 29, 68–69, 78, 93,
NFkB, 84 105, 114, 172
NFkB/IkB dissociation, 52 Osteoclasts, 46
NICE recommendations, 73 Österreichische Kopfschmerzgesellschaft
Nicotinamide, 115 (ÖKSG), 65
Nimbus, 165 OTC. See Over the counter (OTC)
Nimesulide, 128, 166 Otitis media, 71
Nitric oxide, 52, 56, 88, 102 Overdose, 86
Nitric oxide synthesis, 52 Over the counter (OTC), 1, 2, 59, 108
NMDA, 56 analgesic medications, 112
nNOS, 84 dosages, 65–68
NNT. See Number Needed to Treat (NNT) doses, 151
Nonprescription Drugs Advisory Committee ibuprofen, 135, 164
(FDA), 181 doses of, 108
Non-prescription (OTC) dosages, 107–113 use of, 163
Non-prescription OTC sale, 175 sale, 175–176
“Non-serious” skin reaction, 171 treatments, 69
Non-vertebral fractures, 173 Oxicams, 128
Normotensive individuals, 161 Oxycodone + paracetamol, 63
Novartis, 143 Oxyphenbutazone, 115
NSAIDs, 26, 32, 34, 43–57, 59, 68, 69, 75, 77, Oxyradials, 51
79, 81, 83, 88, 89, 91, 93, 94, 96, Oxyradical scavengers, 52
102–105, 107, 112, 114, 116, 117,
126–129, 132, 134, 141, 150, 152,
154, 157, 159, 161, 163–165, 168, P
169, 173, 177, 184 Paediatric formulations, 176
associated gastro-duodenal ulcers, 124 Paediatricians, 83
2 COX inhibition, 48 Paediatric patients, 72
intolerance, 170 Paediatric populations
plasma concentrations, 14 body as a whole, 119
240 Index

Paediatric populations (cont.) variations, 94–96

digestive, 119 Pharyngitis, 120
ibuprofen, 119 Phase 1 pathway, 94
nervous, 119 pH-dissolution, 87
older children, 119 Phenazone, 65
paracetamol, 119 Phenobarbital, 115
respiratory, 119 Phenolic compounds, 84
skin, 119 Phenylbutazone, 115
special senses, 119 Physico-chemical, 34
younger children, 119 Physiological, 45
Paediatric uses, 70–76 Piroxicam, 48, 104, 126–128, 164
Pain, 44, 45, 54, 59, 73, 75, 119, 186 Placebo-controlled trials, 89
control, 52–56, 79 Plasma concentration, 48, 49, 66
management, 68 Plasma elimination half-life (T1/2 ), 92, 93, 127
mediating peptides, 53 Plasma/Serum Concentrations, 13–26
mediators, 53 Platelet, 70
transmission, 53, 55 aggregation, 157, 158, 160, 185
Pain intensity difference (PID), 18 effects
Pain relief (PAR), 18, 65–69, 79, 176 aspirin, 160
PAIN study, 110 collagen, 160
Panax ginseng, 118 ibuprofen, 160
Panolol, 115 function, 159
Paracetamol, 2, 34, 47, 52, 56, 63, 65, 68, 69, Platelet Trialists Collaboration, 154
71, 74, 79, 81, 83, 85, 94, 106–108, Poisoning in UK, 179–180
111, 115, 129, 134–136, 152, 157, Polyethylene glycols (PEG), 34
165, 168, 170, 173, 177, 179, 180, Polymorphisms, 96
184, 187 Polymorphonuclear neutrophil leucocytes
Paracetamol (acetaminophen), 128 (PMN), 44
Paracetamol +codeine, 60 Population PK, 41
Paracetamol hepatotoxicity, 72 Post-operative dental pain, 81
Paracetamolinduced hepatic injury, 92 Post-operative pain, 83
Patent ductus arteriosus, 42 Potassium, 87
Patient information leaflets (PILS), 187 PPIs, 130
Peptic ulcer bleeds (PUBs), 125 Prednisolone, 115
Perforations, 129 Prednisone, 115
Pericarditis, 75 Prescription doses, 59, 130–133
Peripheral analgesia, 56 Prescription-level doses, 102, 113, 125
Peripheral pain pathways, 54 Preventative strategies, 136
Peroxidative reactions, 84 Prexige, 106, 143
Pfizer, 134, 143, 165 Primary dysmenorrhoea, 185
PGE2, 45 Procedures for reduction in risks, 185–187
production, 26, 56 Pro-inflammatory cytokines, 50–52, 70
production ex vivo, 96 Pro-inflammatory mediators, 80
PGEs, 52 Propyphenazone, 128
PGH synthase-1, 170 Prostaglandins (PG), 44, 45, 53
PG production, 83, 84 inhibition, 47
Phagocytosis, 44 phase, 44
Pharmacodynamics, 45–48 production, 47
Pharmacokinetic(s), 37–42, 45–48, 51, 91, receptors, 47
97–101 Prostanoids, 45, 50
parameters, 29, 39, 97, 99 Proxicam, 166
properties, 13 Pseudomonas, 40
rationale, 125 Pubescent angelica, 118
Index 241

Purinergic P2X3 receptors, 84 R(–)-ibuprofen, 27, 51, 56, 92

Pyrexia, 73, 75 non-prostaglandin-dependent
Pyridoxine, 87 mechanisms, 77
Risk factors, 124
Risk of death, 150
Q Risk of fractures, 172–173
Quebec, 147, 152 Risk of hospitalisation, 121
Risk reduction, 186
Rofecoxib, 3, 48, 56, 60, 63, 67, 106, 126, 128,
R 133, 134, 142, 146, 150, 152, 154,
Racemic ibuprofen, 27, 66, 101 157, 166–168
Radiochromium blood loss technique, 123 Royal College of Paediatrics and Child Health
Randomised controlled trials, 80 with the Neonatal and Paediatric
Raniditine, 115 Pharmacists Group, 73
Rare adverse events, 169 R(–) to S(+) conversion, 96
Rashes, 75
Rates of discontinuation of NSAIDs, 106
Reactive oxygen species, 80 S
Recent clinical, 152–157 Safety in paediatric populations, 119–122
Receptor signalling, 52 Safety Profile of Antirheumatics in Long-term
Reckitt Benckiser Healthcare, 178 Administration (SPALA), 103, 104
Rectal absorption, 34 Salicylate, 52, 84, 123, 161
Rectal Administration, 33–37 Salsalate, 104
Rectal mucosa, 33, 34 Salts of ibuprofen, 87
Rectal temperature, 74, 83 Schweizerische Kopfwehgesellschaft
Red Bull®, 82 (SKG), 65
Reducing GI risks, 136–139 Scottish Administrative Pharmacy
Rehospitalisation, 150 Database, 157
Relative risk reduction (RRR), 131 Secondary myocardial infarction, 157
Renal, 131 Selective COX-2 activities, 105
Renal abnormalities, 45 Sepsis, 122
adverse reactions, 2 Serious CV events, 142
capillary necrosis, 163 Serious gastrointestinal reactions, 131
effects, 184 Serious GI ADRs, 123
failure, 86 Serious GI reactions, 184
necrotising fasciitis, 122 Serious liver injury, 165
functions, 141 Serious outcome gastro-intestinal toxicity, 126
impairment, 93, 163 Serum concentrations, 66, 71, 97
insufficiency, 164 Serum kinetics, 85
prostaglandin production, 141 Severe adverse reaction, 109
toxicity, 163–164 Severe liver reactions, 168
R(–) enantiomer, 77 Sex, 149
Reports of adverse events, 178 SGOT, 75
Resolution, 44 SGPT, 75
Respiratory system, 170 S(+)-ibuprofen, 27, 51, 56, 70, 77
Reye’s syndrome, 120, 122, 176 serum concentrations, 19
Rheumatic diseases, 123 Single-day studies, 109
Rheumatic patients, 123 Single nucleotide polymorphism, 12
Rheumatoid arthritis (RA), 27, 30, 43, 78, 91, Skin conditions, 169
103, 105, 142, 160, 172 Sloane Epidemiology Unit of Boston
pathogenesis, 46 University School of Medicine, 119
patients, 93 Small intestinal membrane, 34
Rheumatoid factors, 46 Socio-economic classes, 187
Rhubarb, 118 Sodium, 35, 87, 137
242 Index

Sodium (cont.) Therapeutically relevant plasma

potassium and water homeostasis, 163 concentrations (TRPC), 14, 28, 65
salicylate, 79 ibuprofen, 15
Soft-tissue inflammation, 43 Therapeutic properties, 78
Solubility properties, 34 Thiazide-treated hypertension, 164
Sore throat, 26 Third molar dental pain model, 88
Specific system organ classes (SOC), 103 Third molar dental surgery, 14
SPID. See Sum of pain intensity difference Third molar extraction, 65
(SPID) Third molar extraction model, 23
Spinal cord, 53 Third molar surgery
Splenomegaly, 75 ibuprofen and paracetamol, 85
Spontaneous ADRs, 183–185 Thrombin-induced reaction, 160
Sports injuries, 59, 185 Thrombocytopaenia, 169
Staphyloccocus pneumoniae, 122 Thrombo-embolic and CV conditions, 78
Statistical significance, 131 Thrombo-embolic diseases, 185
Steroids, 117 Thromboxane, 45, 158, 159
Stevens–Johnson syndrome, A2, 70, 157
122, 169, 171 B2, 96
Stiffness, 75 Th1/Th2 subsets, 142
Still’s disease, 75 Th1-type immuno-inflammatory
Streptococcal pharyngit, 71 response, 142
Stroke, 86, 87, 154 Time course of inhibition
Substance P, 53, 55, 56 of cyclooxygenases, 50
Sudden death syndrome, 122 Time to meaningful pain relief (TMPR), 67
Sulindac, 104, 126, 127, 159, 165, 166 Time to remedication (REMD), 67
Sum of pain intensity difference (SPID), Tolerability
16, 18, 86 coxibs, 105
Suppository formulations, 33, 35 ibuprofen, 105
Surgical conditions, 59 NSAIDs, 105
Sustained-release formulation, 114 Tolmetin, 104, 126
Swelling (oedema), 44, 68 Tometin, 127
Synovial fluids, 13, 30–33 Tonsillectomy, 81
Systemic accumulation, 93 Tonsillitis, 26
Systemic inflammation, 141 Tonsillo-pharyngitis, 71
Topical, 88, 89
formulations, 88
T ibuprofen, 90
Tachycardia, 81 Total pain relief (TOTPAR), 18
Taiwan, 147 Toxicity, 105, 183–185
Taiwanese Bureau of National Health Toxicity indices, 104
Insurance (NHI), 147 Traditional Chinese medicines, 116
Taiwanese patients, 97 adulterants, 115
T-and B-cell, 43 Traffic-light system, 73
TARGET study, 107 Transient ischaemic attack (TIA), 147
T-cell, 169 Tremor, 81
99m
Tc uptake, 69 TRPC. See Therapeutically relevant plasma
Tennessee (USA) Medicaid US Federal State concentrations (TRPC)
Program Database, 163 Tumour necrosis factor-a, 26, 50, 52, 80
Tenseness, 81 Type B hypersensitivity reaction, 169
Tension headache, 79 Type 2 renal acidosis, 82
Tension-type headache, 65
TGFb1, 44
Theophylline, 115 U
Therapeutically-relevant concentrations, UK, 175–176, 183
27–37 UK Department of Health, 176
Index 243

UK Dunlop Committee, 175 Viral infections, 74

UK General Practice Research Database Visual analogue scales (VAS),
(GPRD), 143, 151, 173 21, 69
UK Medicines and Healthcare Products Voltaren®, 49
Regulatory Agency (MHRA), Volume of distribution
176, 178 (Vd/F), 37
UK National Institute for Health and Clinical Vomiting, 86
Excellence (NICE), 73, 147
UK National Poisonings Information
Service, 180 W
Ulceration, 133 Weber, J.C.P., 177
Ulcers, 123 Western, 94, 99
Unstable angina, 156 Western Ontario McMaster University
Upper gastro-intestinal bleeding, 123, 125, (WOMAC), 69
129, 130, 132 Western subjects, 95
Upper gastro-intestinal distress, 186 Western/US-European, 147
Upper gastro-intestinal disturbances, 76 Whitehall–Robbins Healthcare, 109, 111
Upper gastro-intestinal events, 86 WHO. See World Health Organization
Upper gastro-intestinal haemorrhage or Whole blood assay, 49
ulcers, 125 Whole blood COX-1, 48
Upper respiratory tract conditions, 59 Whole blood COX-2, 48
Upper respiratory tract infections, 71, 74, WOMAC. SeeWestern Ontario McMaster
120, 185 University
Urticaria, 81, 115 World Health Organization (WHO),
USA, 119, 175–176, 179–181, 183 165, 168
US Department of Veterans Affairs (VA) World Health Organization Uppsala
Veterans Integrated Service Monitoring Centre (WHO/
Network, 147 UMC), 166
US Food and Drug Administration, 81, 159, Writhing assay in mice, 83
160, 166, 167 Writhing in mice, 82

V
Valdecoxib, 3, 132, 133, 142, 167 Y
VIGOR study, 133, 142 Yellow card system, 176, 177
VIOXX®, 142