Analgesics
Jarir At Thobari
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Aspirin consumption worldwide
12
15x10 tablets per year or 45,000 tons per year
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Burden of pain
15% moderate to severe
at least 50% of time
Seriously ill
Hospitalized patients
15% dissatisfied with
pain treatment
50% incidence
of pain
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Pain
Pain is subjective
and difficult to
quantify
Pain scale, 1-10
Analog scale
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Numeric Scale
0
No Pain
10
Worst Pain
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Simple (Category) Descriptive Scale
No Pain
Mild
Moderate
Severe
Very Severe
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Worst
Visual-Analogue Scale
No Pain
Worst Pain
Usually 0-10 cm long line.
Placed either vertical or horizontal.
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
VAS: Coloured Analogue Scale
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Wong-Baker FACES
Pain Rating Scale
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Photographic/ Numeric Pain Scale
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Pain Treatment Methods
Physical
Physical Methods
Methods
Psychological
Psychological Method
Method
Removed
Removed the
the cause
cause of
of pain
pain
Regional
Regional Anesthesia
Anesthesia
Medication
Medication
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
WHO Pain Ladder
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Overall Management Pain
Mild pain
Non opioid analgesics paracetamol
NSAIDs
aspirin, ibuprofen
Moderate pain
Low efficacy opioid
dihydrocodeine
low efficacy opioid + NSAID dihydrocodeine + ibuprofen
Moderate efficacy
opioid + NSAID
meptazinol + ibuprofen
Severe pain
High efficacy opioids morphine
High efficacy opioids + NSAIDS
morphine + ibuprofen
Overwhelming pain
High efficacy opioid + anxiolytic
morphine + diazepam
and/or major tranquilliser morphine + chlorpromazine
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Analgesics
Non Opioid analgesics
Opioid analgesics
Drugs for neuropathic and functional pain
Antimigraine drugs
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Acetaminophen (APAP)
Mechanism of action unclear
No anti-inflammatory effects
Causes liver toxicity at high doses
Max dose: 4 gm/day, if no liver disease
Newest recommendation 2.6 gm/day
Decreases opioid requirements
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
NSAIDs
Efficacy is similar amongst NSAIDs
Differences in potency, time of onset, &
duration of action
Side effects:
GI bleeding
renal dysfunction
platelet dysfunction
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
For what conditions are NSAIDs
used?
Rheumatoid Arthritis
Osteoarthritis
Inflammatory arthritis,
psoriatic arthritis,
Reters syndrome
Acute gout
Metastatic bone pain
Dysmenorhea
Headache, migraine
Postoperative pain
Pyrexia ( fever)
Ileus
Renal colic
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Prostaglandin and Thromboxane
Biosynthesis
Membrane-bound phospholipids
Phospholipase A2
NSAIDs, ASA
Arachidonic acid
COX-1
O2
COX-2
PGG2
Coxibs
PGH2
Tissue-specific isomerases
PGD2
PGE2
PGF2
PGI2
TxA2
COX = cyclooxygenase; coxibs = COX-2 inhibitors; PG = prostaglandin; TxA2 = thromboxane A2;
NSAID = nonsteroidal anti-inflammatory drug; ASA = aspirin.
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Mechanism of Action of NSAIDs
CO2
H
Arachidonic acid
COX-1
Constitutive
Non-specific NSAIDs
COX-2
Inducible
COX-2 NSAIDs
GI Mucosa
Prostaglandins
GI mucosal
Protection
Platelet
Thromboxane
Hemostasis
Prostaglandins
Mediate pain,
inflammation, and fever
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Physiological stimulus
Macrophages/other cells
COX-1
constitutive
TXA2
PGI2
platelets stomach mucosa
endothelium
Inhibition of COX-1
causes G I damage
Inflammatory stimulus
COX-2
induced
PGE2 Proteases
kidney
PGs
Other
inflammatory
mediators
Inflammation
Inhibition of COX-2 is antiinflammatory
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Classification NSAID
Acetic acid derivatives
Arthrotec
(diclofenac/misoprostol)
Diclofenac
Ketorolac
Tolmetin
Etodolac
Indomethacin
Sulindac
Enolic acid derivatives
Meloxicam
Piroxicam
Tenoxicam
Napthylkanone derivatives
Nabumetone
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Classification NSAID
Propionic acid derivatives
Flurbiprofen
Ketoprofen
Oxaprozin
Ibuprofen
Naproxen
Carboxylic acid derivatives
Diflunisal
Salsalate
COX-2 inhibitor
Celecoxib
Rofecoxib
Valdecoxib
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
NSAIDs: COX-2 vs COX-1 Selectivity
6-MNA
COX-2 IC50 (M)
100.00
Naproxen
Acetaminophen
Ibuprofen
10.00
Meloxicam
Nimesulide
1.00 Indomethacin
Celecoxib
Rofecoxib
0.10
Diclofenac
0.01
0.01
0.10
1.00
10.00 100.00
COX-1 IC50 (M)
6-MNA = 6-methoxy-2-naphthylacetic acid;
IC50 = drug concentration at which the enzymatic activity is inhibited by 50%.
FitzGerald and Patrono. N Engl J Med. 2001;345:433.
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
CLASS Trial: Upper GI Complications
Alone and With Symptomatic Ulcers
= celecoxib
p = 0.02
= NSAIDs (ibuprofen + diclofenac)
All Patients
Patients Not Taking Aspirin
Patients Taking Aspirin
Annualized Incidence %
p = 0.09
11 / 1441
20 / 1384
49 / 1384
30 / 1441
p = 0.02
p = 0.04
5 / 1143
14 / 1101
32 / 1101
16 / 1143
p = 0.49
17 / 283
14/ 298
p = 0.92
6 / 298
6 / 283
Silverstein et al. JAMA 2000; 284:1247-1255
Ulcer Complications
Symptomatic Ulcers and
Ulcer Complications
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
CLASS Trial: Time to Complicated Ulcer
2
Log-rank P values:
(%) 1
Celecoxib vs NSAIDs
0.450
Celecoxib vs diclofenac
0.640
Celecoxib vs ibuprofen
0.414
Ibuprofen 800 mg TID
Diclofenac 75 mg BID
Celecoxib 400 mg BID
0
0
80
160 180
Days
240
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
320
Risk factors for upper GI bleeding
associated with NSAID use
Lanas A Rheumatology 2010;49:ii3-ii10
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Gastro protection:
Misoprostol (MUCOSA trial)
% of patients with serious upper GI complications at 6 months
p=0.049
40% reduction in GI
complications
Placebo + NSAID
(n=4439)
Misoprostol + NSAID
(n=4404)
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Silverstein et al.
Ann Intern Med
1995;123:241249
Gastro protection:
Proton Pump Inhibitors
% of patients with recurrent upper GI bleeding at 6 months
p=0.005
76% reduction in upper
GI bleeding
Chan et al. N Engl J
H. pylori eradication
Omeprazole + NSAID
Med 2001;344:967
+ NSAID
973
(n=75)
(n=75)
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Results of Case-Control and Cohort Studies Reporting
on Cardiovascular Risks With Nonselective NSAIDs.
McGettigan, P. et al. JAMA 2006;296:1633-1644
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Case-Control and Cohort Studies Reporting
on Cardiovascular Risks With Cyclooxygenase 2 Inhibitors.
McGettigan, P. et al. JAMA 2006;296:1633-1644
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
NSAIDs & Renal Effect
Coxibs
Arachidonic acid
NSAIDs
COX-1
COX-2
PGE2
Sodium retention
Peripheral edema
Blood pressure
CHF (rarely)
Brater. Am J Med. 1999;107:65S.
PGI2
Hyperkalemia
Acute renal
failure
Others : Nephrotic syndrome
interstitial nephritis
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
During pregnancy
NSAIDs are not recommended during pregnancy,
particularly during the third trimester.
While NSAIDs as a class are not direct teratogens, they
may cause premature closure of the fetal ductus arteriosus
and renal ADRs in the fetus. Additionally, they are linked
with premature birth.
In contrast, paracetamol (acetaminophen) is regarded as
being safe and well-tolerated during pregnancy.
Doses should be taken as prescribed, due to risk of
hepatotoxicity with overdoses
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Salicylates
Aspirin (ASA)
Effective as APAP for
acute pain at similar
doses
Worse side effect
profile than APAP
Salicylates Salts
Safer than ASA
No platelet effects
Examples:
Diflunisal (Dolobid)
Magnesium salicylates
(Doans)
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Aspirin (Acetyl salicylate)
Actions
Analgesic - central and peripheral action
Antipyretic - act in hypothalamus to lower the set
point of temperature control elevated by fever, also
causes sweating
anti-inflammatory - inhibition of peripheral
prostaglandin synthesis
respiratory stimulation - direct action on respiratory
centre, indirectly by CO2 production
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Aspirin (Acetyl salicylate)
Uricosuric effects
reduces renal tubular reabsorption of urate but treatment of
gout requires 5-8g/d, < 2g/d may cause retention of urate.
antagonises the uricosuric action of other drugs
Reduced platelet adhesion- irreversible inhibition of COX by
acetylation, prolongs bleeding time, useful in arterial
disease
Note: low doses are adequate for this purpose since the
platelet has no biosynthetic capacity and can not
regenerate the enzyme
Hypothrombinaemia : occurs with large doses ie >5g/day
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Aspirin (Acetyl salicylate)
OVERDOSAGE
Ingestion of > 10 g can cause moderate/severe
poisoning in an adult
Clinical features - salicylism
tremor, tinnitus, hyperventilation, nausea,
vomiting, sweating
Management- mainly supportive
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Daily Aspirin Dose and
Admission for Ulcer Bleeding
Aspirin Dose
Odds Ratio (95% Cl)
75 mg (n=27)
2.3 (1.2-4.4)
150 mg (n=22)
3.2 (1.7-6.5)
300 mg (n=62)
3.9 (2.5-6.3)
Weil J et al. BMJ. 1995;310:827-830.
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Risk of UGI bleeding with Different Formulations of
Low-Dose Aspirin (< 325mg)
Relative Risk
3.2
Plain ASA
3.6
2.6
Coated ASA
2.6
2.4
2.6
Buffered ASA
550 cases of UGIB
admitted to hospital
with melena or
confirmed
hematemesis
Gastric bleeding
Duodenal bleeding
Kelley et al, Lancet 1996; 348; 1413
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Risk of Combining Low-Dose Aspirin
with NSAIDs
National cohort study in Denmark
27,694 people on aspirin 100-150 mg qd
Treatment regimen
Low-dose aspirin
Low-dose aspirin + NSAIDs
Increased incidence
over general
population
95% CI
2.6
2.2 - 2.9
5.6
4.4 - 7.0
Sorensen et al, Am J Gastroenterol 2000; 95; 2218
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioids
Originally derived from
poppies
Body possesses
endogenous opioids
enkephalins
endorphins
Opiate Receptors
mu ( )
delta ( )
kappa ( )
sigma ( )
Papaver somniferum
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Pharmacology of Opioids
1: inhibit transmission of pain
2: respiratory depression, euphoria,
constipation, physical dependence
: inhibit transmission of pain
: inhibit transmission of pain
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Pharmacology of Opioids
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy in Pain Related to
Medical Illness
Opioid therapy is the mainstay approach for
Acute pain
Cancer pain
AIDS pain
Pain in advanced illnesses
But undertreatment is a major problem
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy in Chronic
Nonmalignant Pain
Supporting evidence
>1000 patients reported in case series and
surveys
Small number of RCTs
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Common Side Effects of Opioids
Constipation
very common, tolerance is unlikely
stool softeners + stimulant +/metoclopramide
Nausea/Vomiting
tolerance usually develops
pretreat with prochlorperazine
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Common Side Effects of Opioids
Urticaria/Pruritis
due to histamine release
treat with antihistamine
Sedation
tolerance usually develops
Delirium
rare in patients with normal renal function
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Side Effects of Opioids
Respiratory Depression
preceded by somnolence
tolerance develops
use caution in patients with underlying
pulmonary dysfunction
if RR <8 bpm, consider naloxone (Narcan)
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy: Prescribing Principles
Prescribing principles
Drug selection
Dosing to optimize effects
Treating side effects
Managing the poorly responsive patient
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy: Drug Selection
Immediate-release preparations
Used mainly
For acute pain
For dose finding during initial treatment of chronic pain
For rescue dosing
Can be used for long-term management in select
patients
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy: Drug Selection
Immediate-release preparations
Combination products
Acetaminophen, aspirin, or ibuprofen combined with
codeine, hydrocodone, dihydrocodeine
Single-entity drugs, eg, morphine
Tramadol
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy: Drug Selection
Extended-release preparations
Preferred because of improved treatment
adherence and the likelihood of reduced risk in
those with addictive disease
Morphine, oxycodone, fentanyl,
hydromorphone, codeine, tramadol,
buprenorphine
Adjust dose every 23 days
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Selection:
Poor Choices for Chronic Pain
Meperidine
Poor absorption and toxic metabolite
Propoxyphene
Poor efficacy and toxic metabolite
Mixed agonist-antagonists (pentazocine,
butorphanol, nalbuphine, dezocine)
Compete with agonists withdrawal
Analgesic ceiling effect
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy: Routes of Administration
Oral and transdermalpreferred
Oral transmucosalavailable for fentanyl
and used for breakthrough pain
Rectal routelimited use
ParenteralSC and IV preferred and feasible
for long-term therapy
Intraspinalintrathecal generally preferred for
long-term use
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy: Side Effects
Common
Constipation
Somnolence, mental clouding
Less common
Nausea
Sweating
Myoclonus
Amenorrhea
Itch
Sexual dysfunction
Urinary retention
Headache
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy and Chemical Dependency
Physical dependence
Tolerance
Addiction
Pseudoaddiction
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Opioid Therapy: Monitoring Outcomes
Critical outcomes
Pain relief
Side effects
Functionphysical and psychosocial
Drug-related behaviors
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Adjuvant Pain Medications
drugs that are used
primarily for treating
conditions other than
pain, but may be
analgesic in selected
circumstances
-AMA
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Common Adjuvant Medications
Antidepressants
Anticonvulsants
Corticosteroids
Topical Anesthetics
Calcitonin
Bisphosphonates
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
