Diphenhydramine versus nonsedating antihistamines for

acute allergic reactions: A literature review

Aleena Banerji, M.D.,* Aidan A. Long, M.D.,* and Carlos A. Camargo, Jr., M.D., Dr.P.H.#

ABSTRACT
First-generation antihistamines can have adverse effects on the central nervous system and thereby complicate discharge
planning from the emergency department (ED). Newer antihistamines are potentially safer, causing less sedation with similar
efficacy. The aim of this study was to review the literature to better define which antihistamines are good options for the
treatment of acute allergic reactions. A Medline search was conducted to identify English language articles published between
January 1975 and March 2006 on antihistamines, sedation, and acute allergic reactions. Bibliographies from included studies
were further investigated. We focused on sedative potential, effect on cognitive function, efficacy, onset of clinical activity, and
cost of antihistamines. Diphenhydramine impairs psychomotor performance and cognitive function. Loratadine and deslora-
tadine are nonsedating but less efficacious than cetirizine or fexofenadine. The incidence of sedation with cetirizine is less than
that of first-generation antihistamines but is greater than placebo. Cetirizine has the fastest onset of action among the newer
antihistamines. Fexofenadine does not impair psychomotor or cognitive skills and shows no dose-related increase in sedation
but has a slower onset of action than diphenhydramine and cetirizine. Newer antihistamines cost ⬃$0.52–2.39 more per dose
than diphenhydramine ($0.37). Newer antihistamines provide similar efficacy as first-generation antihistamines but with less
sedation. We believe this benefit outweighs the small increase in cost and that newer antihistamines should be considered in
the management of acute allergic reactions. Although comparative ED-based trials are not available, newer antihistamines are
an option for management of acute allergic reactions when sedation is a concern.
(Allergy Asthma Proc 28:418 –426, 2007; doi: 10.2500/aap.2007.28.3015)
Key words: Acute allergic reaction, anaphylaxis, antihistamines, cognitive function, cost, diphenhydramine,
impairment, psychomotor performance, sedation, urticaria

A cute allergic reactions, ranging from simple urti-

caria to anaphylaxis, account for ⬃1 million
emergency department (ED) visits each year.1 The life-
Despite the known sedative effects, diphenhydra-
mine remains the most commonly used antihistamine
in the ED for the treatment for acute allergic reac-
time prevalence of anaphylaxis, the most severe aller- tions.6,7 In a recent multicenter study of food-related
gic reaction, is ⬃1% in the United States or almost 3 allergic reactions in the ED, 72% of patients received
million Americans at risk of experiencing an episode of antihistamines, with 90% receiving diphenhydramine.6
anaphylaxis during their lives.2 Although the diagno- In a similar study of insect sting–related allergic reac-
sis and classification of acute allergic reactions is not tions, 57% of ED patients received antihistamines, with
simple, empiric therapy includes epinephrine, cortico- 90% receiving diphenhydramine.7 Treatment with an-
steroids, and antihistamines, in addition to supportive tihistamines improves outcomes8 and therefore is
therapy with volume replacement and bronchodila- necessary. Although there are many effective first-
tors. Antihistamines are an integral part of initial ther- generation antihistamines, we focus this review on
apy for the spectrum of acute allergic reactions, but the
diphenhydramine not only because it is the most com-
risk of sedation from this class of medication is signif-
monly used antihistamine in the ED but also because
icant.3,4 Additionally, in children, although first-gener-
diphenhydramine has been Food and Drug Adminis-
ation antihistamines often are administered without
tration (FDA) approved for use as an adjunct to epi-
apparent harm, data suggest that central nervous sys-
tem (CNS) impairment occurs far more often than is nephrine and corticosteroids in the treatment of acute
generally recognized.5 allergic reactions.
Although recognizing that epinephrine is the most
important initial treatment for anaphylaxis, we sought
From the *Division of Rheumatology, Allergy, and Immunology, and #Department of to determine if nonsedating, newer antihistamines of-
Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, fer a reasonable alternative to diphenhydramine in
Boston, Massachusetts
Address correspondence reprint requests to Aleena Banerji, M.D., Massachusetts treatment of the spectrum of acute allergic reactions—
General Hospital, 100 Blossom Street, Cox 201, Boston, MA 02114 from simple urticaria to anaphylaxis. Sedation is re-
E-mail address: abanerji@partners.org
ported to be significantly decreased with the newer
Copyright © 2007, OceanSide Publications, Inc., U.S.A.
class of H1-receptor blockers.4,9 The newer antihista-

418 July–August 2007, Vol. 28, No. 4

mines differ in their chemical structures and are be- widely between individual drivers. BRT can be vari-
lieved to generally lack CNS effects because of, in large able depending on driver characteristics such as atti-
part, their inability to cross the blood– brain barrier.10,11 tude, level of fatigue, and experience.
We reviewed the current literature regarding various
H1-blockers to better define which antihistamines are Cognitive and Psychomotor Performance Tests. These
the best options for the treatment of acute allergic tests simulate real-world activities and include simple
reactions with efficacy similar to diphenhydramine but reaction time, mathematical processing, backward
without impairment of cognitive function. digit span, digit symbol substitution scores, divided
attention test, dual task test, tracking, and vigilance
MATERIALS AND METHODS tasks.
Inclusion and Exclusion Criteria
Mood and Sedation Scales. These tests include visual
A literature review was conducted using the Medline analog scales, Stanford sleepiness scale, and mood
database. To qualify, studies satisfied the following scale.
criteria1: an English language journal from January
1975 through March 20062; key words antihistamines, Evaluation of Efficacy
sedation, or acute allergic reactions3; human studies
Articles comparing the efficacy of antihistamines,
and4 diphenhydramine, loratadine, desloratadine, ce-
individually or in comparison with one another, for the
tirizine, or fexofenadine as one of the drugs evaluated.
reduction of symptoms of allergic disorders (e.g., aller-
We focused on antihistamines available in the United
gic rhinitis and chronic idiopathic urticaria) were re-
States. Bibliographies from included articles were fur-
viewed. Unfortunately, data on the efficacy of newer
ther investigated. In addition to articles found on Med-
antihistamines in the treatment of acute allergic reac-
line, package inserts for each drug,12–15 the Physician’s
tions are lacking.
Desk Reference,16,17 and Lexi-Comp18 were reviewed
to determine the onset of clinical activity. Lexi-Comp is
Evaluation of Cost
the official drug reference guide for the American
Pharmacists Association. Data regarding the sedative Three different sources were evaluated to compare
potential, effect on cognitive function, efficacy, onset of the cost of diphenhydramine to the newer anti-
clinical activity, and cost of diphenhydramine and histamines: www.drugstore.com, www.cvs.com, and
newer antihistamines were considered. The most com- www.walgreens.com. The data from each source were
mon reason for article exclusion was presentation of combined to determine the average cost per dose of
anecdotal evidence without actual performance or se- medication.
dation measures.
RESULTS
Sedative Potential and Cognitive Function Reported The Medline search combining the words acute al-
Outcomes lergic reactions, sedation, and antihistamines limited to
the English language, humans, and published after
The effects of antihistamines on driving are difficult
1975 identified a total of 146 articles. Another 40 arti-
to measure; therefore, surrogates such as a driving
cles identified from the bibliographies of these initial
simulator and brake reaction time (BRT) in a laboratory
articles were reviewed also. Table 1 provides an over-
setting can be used. Cognitive and psychomotor tests
view of diphenhydramine and the newer antihista-
selected to simulate real-world activities along with
mines available in the United States.
mood and sedation scales can be used to assess the
effects of antihistamines on the CNS.
Diphenhydramine
Driving Simulation and BRT. The Iowa Driving Sim- Overview. Diphenhydramine has been available in
ulator19 allows collection of data on driving perfor- the United States since 1945, and its potential adverse
mance measures in a manner not available with on- effects were reported as early as 1947.20 In 1981, di-
street driving. The simulator consists of a domed phenhydramine was first sold over the counter (OTC)
enclosure mounted on a hexapod motion platform. The and within 20 years diphenhydramine was the top-
inner walls of the dome act as a screen on which selling OTC antihistamine with 40% market share.21
correlated images are projected. The experimental Diphenhydramine is a first-generation H1-receptor an-
drive is conducted in varying weather and traffic con- tagonist. This antagonism also can produce anticholin-
ditions. ergic effects and antiemetic effects.
BRT is the amount of time that elapses between the
recognition of an object or hazard in the roadway and Sedative Potential and Cognitive Function. Studies
the application of the brakes. The length of BRT varies show impairment of psychomotor performance and

Allergy and Asthma Proceedings 419

420
Table 1 Diphenhydramine vs newer-generation antihistamines
Diphenhydramine Loratadine Desloratadine Cetirizine Fexofenadine
Common trade Benadryl Claritin, Alavert Clarinex Zyrtec Allegra
name
OTC vs Rx OTC (1981) OTC (2002) Rx Rx Rx
Generic available Yes Yes No No Yes
Onset of action* 15–60 min 1–3 hr 1–3 hr 15–30 min 60 min
Duration of action* 4–7 hr ⱖ24 hr ⱖ24 hr ⱖ24 hr ⱖ24 hr
Half-life* 2–8 hr 12–15 hr 27 hr 8 hr 14.4 hr
Excretion* Urine Urine and feces Urine and feces Mainly urine Mainly feces
Adult dose 25–50 mg as needed 10 mg daily 5 mg daily 10 mg daily 60 mg b.i.d.,
180 mg daily
Pediatric dose 6.25–25 mg as needed 5–10 mg daily 1–5 mg daily 2.5–10 mg daily 30–60 mg daily
Dose adjustments Elderly patients Liver and renal Liver and renal Liver and renal Renal disease
disease disease disease
Supplied Chewable tab, dissolvable tab, Dissolvable tab, Dissolvable tab, Syrup, chewable tab, Pill
suspension, cream, elixir, pill, and syrup pill, and syrup and pill
gel, and pill
Approved age 2 yr 2 yr 6 mon 6 mon 12 yr
Pregnancy category B B C B C
FDA-approved AR, CIU, insomnia, AR and CIU AR and CIU AR and CIU AR and CIU
indications Parkinsonism, motion
sickness, and anaphylaxis
*Lexi-drugs.18
Rx ⫽ prescription; AR ⫽ allergic rhinitis; CIU ⫽ chronic idiopathic urticaria.

July–August 2007, Vol. 28, No. 4

 Figure 1. Average cost of one dose of antihistamine.

cognitive function after 50 mg of diphenhydramine, a for 50 mg p.o., and 50 mg i.v. is $0.81/dose at our
standard dose used in acute allergic reactions. Using institution. (Fig. 1).
an automobile driving simulator and digit symbol sub-
stitution scores, mental impairment was apparent for 2
hours after 50 mg p.o. of diphenhydramine, while sig- Overview of Newer Antihistamines
nificant feelings of drowsiness were present for up to 6 Drowsiness caused by first-generation antihista-
hours.3 Diphenhydramine has been shown to have a mines has been attributed to the blockade of central
greater impact on the complex task of operating an histaminergic receptors and antagonism of other brain
automobile than alcohol.4 receptors (i.e., serotonergic, cholinergic, and central
The effects of diphenhydramine on tasks that would ␣-adrenergic).11 The newer antihistamines are typically
mimic the demands of the modern workplace were
large, lipophobic molecules with a charged side chain
evaluated.22 This investigation suggested that a 50 mg
and are extensively bound to albumin, therefore limit-
p.o. of diphenhydramine increased the risk of errors
ing transfer across the blood– brain barrier. Loratadine,
when performing psychomotor tasks and decreased
desloratadine, cetirizine, and fexofenadine have excel-
motivation that is likely to translate into decreased
lent safety records. Their safety has been established in
productivity. The suggestion that nurses in intensive
care units or operators of heavy machinery taking di- drug-interaction studies, elevated-dose studies, and
phenhydramine may be at risk for significant errors clinical trials.31 These antihistamines also have proven
leading to potential hazards and decreased work pro- safe in special subpopulations, including children and
ductivity is more disturbing.23 elderly patients.31

Efficacy and Cost. Diphenhydramine is effective in the Loratadine and Desloratadine. Loratadine was first sold
treatment of acute allergic reactions with a very rapid in the United States in 1993 and has been available
onset of action.8 Oral diphenhydramine appears in OTC since 2002. Desloratadine has been available as a
plasma within 15 minutes with peak plasma concen- prescription medication in the United States since 2002.
trations within 1– 4 hours.24 –27 Intravenous diphenhy- Loratadine is a long-acting tricyclic antihistamine with
dramine maximally suppresses the wheal and flare selective peripheral histamine H1-receptor antagonistic
response induced by intradermal histamine at 1–3 activity. Loratadine is racemic mixture of active and
hours.25 Similarly, diphenhydramine acts rapidly in inactive isomers, and desloratadine is a metabolite of
the treatment of allergic rhinitis28,29 and chronic idio- loratadine made up only of the therapeutically active
pathic urticaria symptoms.28,30 The cost is low, ⬃$0.37 isomer.

Allergy and Asthma Proceedings 421

 Cetirizine. Cetirizine has been available in the United Fexofenadine. Fexofenadine is a highly specific, H1-
States as a prescription medication since 1996. Cetiriz- receptor antagonist with a safety profile similar to pla-
ine is a major metabolite of hydroxyzine, a first-gener- cebo.4,9,43 Unlike loratadine or cetirizine, fexofenadine
ation antihistamine. As with other antihistamines the is truly nonsedating, showing no dose-related increase
principal effects of cetirizine are mediated by selective in sedation, even at doses as high as 360 mg/day.47,48
inhibition of peripheral H1 receptors. The effects of fexofenadine at doses of 120, 180, and 240
mg were evaluated in six patients. Results showed no
Fexofenadine. Fexofenadine tablets were first intro- changes in performance or sleepiness with any dose of
duced in the United States in 1996. In the United States, fexofenadine at any time point.47 BRT with and with-
fexofenadine is now available in the generic form but out cellular phone usage as well as driving simulations
still requires a prescription. Fexofenadine, the major in fexofenadine-treated subjects did not differ from
active metabolite of terfenadine, has selective periph- placebo.49,50 Cognitive testing with fexofenadine was
eral H1-receptor antagonist activity and does not cross similar to placebo.51
the blood– brain barrier.
Efficacy of Newer Antihistamines
Sedative Potential and Changes in Cognitive The newer antihistamines have shown similar effi-
Function with Newer Antihistamines cacy in the treatment of allergic rhinitis and chronic
In terms of CNS safety, meta-analyses32,33 have urticaria to first-generation antihistamines.52–54 We are
shown, in comparison with diphenhydramine, much not aware of any studies directly comparing the effec-
less impairment with loratadine and cetirizine and al- tiveness of first-generation versus newer antihista-
most no impairment with fexofenadine. Similarly, mines for acute allergic reactions.
positron emission tomography imaging studies show Although loratadine has been shown in multiple
77% of H1-receptor occupation by a first-generation studies to be nonsedating, there is concern that it is less
antihistamine (chlorpheniramine, 2 mg p.o.) and 20 mg effective than other newer antihistamines in reducing
p.o. of cetirizine occupied 20 –50% of the H1-receptors symptoms associated with environmental allergies.55
and 120 mg p.o. of fexofenadine occupied ⬍1% of the Several studies56 –58 suggest that the effectiveness of
H1-receptors.34 cetirizine is greater than loratadine. Two double-blind,
randomized, placebo-controlled studies compared ce-
Loratadine and Desloratadine. There is no difference tirizine, 10 mg daily, with loratadine, 10 mg daily, in
between loratadine, 10 mg p.o., and placebo for any patients with seasonal allergic rhinitis.56,57 These stud-
measure of cognitive or psychomotor test performance, ies both found greater benefit from cetirizine using
mood, or sedation.23 Other studies also have shown symptom complex scores and patient assessments. A
that loratadine, 10 mg p.o., does not interfere with third study,58 among children aged 2– 6 years, found
visuomotor coordination, digit symbol substitution, histamine wheal response to be decreased more signif-
short-term memory, the ability to operate aircraft sim- icantly with cetirizine compared with loratadine while
ulators, or performance in driving tasks.35–37 Similarly, eosinophil counts and investigator and patient global
desloratadine is safe and nonsedating.38 Psychomotor symptoms scores were similar between the two
performance, BRT, and driving performance were not groups. Fexofenadine was superior to loratadine in
impaired by desloratadine.39,40 terms of improving itchy eyes, nasal congestion, and
quality of life in patients with seasonal allergic rhini-
Cetirizine. A double-blind, placebo-controlled, ran- tis.59 Using total symptoms scores for evaluation of
domized study in children, aged 7–14 years, showed patients with seasonal allergic rhinitis, cetirizine, 10 mg
cetirizine to have sedative properties.41 Cetirizine also daily; fexofenadine, 120 mg daily; and fexofenadine,
was reported to have a mild detrimental effect on 180 mg daily, were similar in efficacy.60
driving ability42 and sedative effects by visual analog In chronic urticaria, numerous studies have shown
scale and psychomotor activity.31,43,44 Sedation has equal if not improved effectiveness with newer anti-
been reported in up to 14% of those taking cetirizine, 10 histamines when compared with first-generation anti-
mg/day. Conversely, some reports show no impair- histamines.28,61,62 Cetirizine has shown better efficacy
ment in driving tests, cognitive and psychometric tests, in comparison with fexofenadine63 and loratadine.64
and specific questionnaires after 10 mg p.o. of cetiriz- Despite these data, some physicians prefer antihista-
ine.45 In comparison with loratadine, cetirizine has mines such as desloratadine and fexofenadine because
been shown to be associated with increased somno- they are less sedating and this becomes more impor-
lence and less motivation to perform activities during tant when patients need antihistamines daily.65
the workday.46 In psychomotor testing and sedation
scales, cetirizine was more impairing that fexofena- Onset of Action. Onset of action of the newer antihis-
dine.43 tamines has been shown to be rapid in after pollen

422 July–August 2007, Vol. 28, No. 4

challenge in subjects with seasonal allergic rhini- phenhydramine, should be considered. This would
tis.66 – 68 Other studies show that loratadine and deslo- be in addition to the prescription for self-injectable
ratadine exhibit their antihistaminic effect within 1–3 epinephrine in appropriate populations (e.g., ana-
hours and that this effect can last over 24 hours.14,15,18 phylaxis).6,7
Cetirizine is rapidly absorbed with maximum concen- In comparing the newer antihistamines (Table 1),
tration within 1 hour of oral administration.18,69 Fexo- both loratadine and cetirizine are safe in pregnancy but
fenadine has an onset of action of ⬃60 minutes.12,18 require dose adjustment in the presence of hepatic or
renal impairment. Fexofenadine is FDA approved
Cost of Newer Antihistamines down to age 6 years, and loratadine and cetirizine can
be used after age 2 years and 6 months, respectively.
Loratadine is OTC and offers the cheapest available
Loratadine is the only newer antihistamine available
“nonsedating” antihistamine whereas cetirizine and
without a prescription. The newer antihistamines are
fexofenadine require prescriptions and are more ex-
not available in i.v. forms and although no data exist,
pensive as shown in Fig. 1. The average cost per usual
oral dissolvable or liquid syrup forms of loratadine and
adult single dose of loratadine (10 mg), desloratadine
desloratadine may offer an easier method of treating
(5 mg), cetirizine (10 mg), generic fexofenadine (180
patients with acute allergic reactions without needing
mg), and fexofenadine (180 mg) is $0.88, $2.75, $2.32,
i.v. access. Similarly, cetirizine is available as both a
$2.15 and $2.43, respectively. Diphenhydramine (50
chewable tablet and liquid syrup.
mg) remains the least expensive antihistamine at $0.37.
Although loratadine seems less efficacious and fexo-
In the context of the cost of a typical ED visit being
fenadine appears to have the least sedation, the data
$383–560,70,71 these cost differences are minimal.
regarding cetirizine are less clear. Some studies report
cetirizine to be sedating41,46 and others do not.45 How-
DISCUSSION ever, to summarize a 1998 national task force, the in-
Diphenhydramine is the most frequently used med- cidence of sedation is less that that seen with first-
ication in the treatment of acute allergic reactions in the generation antihistamines but is greater that that seen
ED.6,7 Unfortunately, first-generation antihistamines, with placebo.76 Furthermore, use of a larger dose of
such as diphenhydramine, can be highly sedating and loratadine (40 mg/day) or cetirizine (20 mg/day) is
introduce hazard for activities such as driving cars, clearly linked with an increased incidence of seda-
flying planes, or using heavy machinery or for nurses tion.3,37,77,78 Loratadine, desloratadine, and fexofena-
administering medications to patients in the hospi- dine at the recommended doses are classified by the
tal.9,23,72 Our review suggests that newer antihista- FDA as nonsedating antihistamines and are approved
mines (such as loratadine, desloratadine, cetirizine, for use by airline pilots by the Federal Aviation Ad-
and fexofenadine) may offer equal efficacy with less ministration, unlike cetirizine.51,79 – 81
sedation43 than diphenhydramine. Therefore, the Approximately 5–20% of individuals with anaphy-
newer antihistamines provide an attractive option for laxis have an unusual pattern of symptoms, viz., either
either the acute care setting or prescription on dis- biphasic anaphylaxis or protracted anaphylaxis.82,83 Bi-
charge from the ED. phasic anaphylaxis refers to anaphylaxis that resolves
The sedative potential is not trivial. For example, but then recurs 1– 8 hours later. Protracted anaphylaxis
driving performance was worse in patients treated refers to anaphylaxis that persists for up to 48 hours
with diphenhydramine than in patients drinking alco- despite treatment. These two patterns are especially
hol. A single dose of diphenhydramine is equivalent to common among subjects who develop symptoms ⬎30
a blood-alcohol content of 0.1— higher than the 0.08 minutes after exposure and subjects who are exposed
level that makes a driver legally drunk.4 Despite this to an allergen by the oral route. Although we recognize
potential for psychomotor impairment and laws en- that epinephrine is a crucial part of initial manage-
acted in 37 states and the District of Columbia against ment, many patients also will (and should) receive
driving after taking OTC first-generation antihista- antihistamines.6,7 In such cases, the longer-acting
mines,22,73 many individuals continue to drive and newer antihistamines may provide benefit with less
prosecutions are rare. The Allergic Rhinitis and Its frequent dosing, leading to improved patient compli-
Impact on Asthma guidelines, along with other ex- ance after ED discharge. Diphenhydramine needs to be
perts, already suggest using the newer antihistamines taken every 4 – 6 hours to maintain benefit whereas the
for allergic rhinitis because of favorable efficacy and newer antihistamines can be taken once a day.
excellent safety profiles.74,75 Despite the lack of data in The main limitation of our review arises from the
the ED setting, we believe that this could be extended lack of evidence regarding the effectiveness of newer
to the management of acute allergic reactions. On dis- antihistamines for the specific treatment of acute aller-
charge from the ED after an acute allergic reaction, gic reactions. Similar efficacy might be expected based
prescription of newer antihistamines, rather than di- on their effectiveness in blocking histamine in allergic

Allergy and Asthma Proceedings 423

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