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Choice of Antihistamines for Urticaria
Brian S. Alper, MD
From the Center for Family Medicine Science, Department of Family and Community Medicine, University of Missouri, Columbia.
Arch Fam Med. 2000;9:748-751.
QUESTION
Are nonsedating antihistamines as effective as sedating antihistamines in treating generalized urticarial allergic reactions?
SOLUTION
SEARCH STRATEGY
MEDLINE was searched using PubMed on February 21, 2000, using the terms "urticaria/drug therapy and antihistamines" and limiting the set to human RCTs. Because chronic urticaria and acute urticaria may respond differently to treatment, literature reviews were conducted for each.
BACKGROUND
Urticaria and its response to treatment in an individual patient are affected by many variables such as the "strength" of the stimulus, the strength of the host response, and the speed of natural clearance. Differences in any of these variables can bias the results of comparisons of treatments for urticaria. Randomized controlled trials (RCTs) provide opportunities to evaluate treatments for urticaria while minimizing these biases.
Because the study populations in separate trials may vary widely, only head-to-head comparison trials of sedating and nonsedating antihistamines can accurately assess their comparable efficacy. Indirect comparison of medications based on separate placebo-controlled trials may be inaccurate because of differences in the underlying study populations.
RESULTS FOR CHRONIC URTICARIA
Eighty-nine references were identified of which 26 were comparisons of antihistamines. Twelve of these were comparisons of nonsedating (or less sedating) antihistamines with sedating antihistamines in patients with chronic idiopathic urticaria. These are described in Table 1.
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Nonsedating vs Sedating Oral Antihistamines for Chronic Urticaria*
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Ten trials1-10 with 18 to 203 patients each found sedating and nonsedating antihistamines equally effective (and to a clinically and statistically significant degree, more effective than placebo). Outcomes included the number of urticarial episodes, the severity of pruritus, individual and total symptom scores, and patient and physician ratings for the overall response to treatment. Statistical significance is important when evaluating a trial with positive results (ie, a trial demonstrating differences between treatment groups), and it represents our confidence that the finding is true. When evaluating trials with negative results (ie, no statistically significant differences found between treatment groups, concluding that treatments are equally efficacious), power is the measure that represents our confidence that the finding (of equality) is true. None of these reports addressed the issue of power, so we cannot immediately distinguish a true finding of equality for these treatments from a false finding of equality related to inadequate sample sizes (ie, larger trials might show differences in treatment efficacy).
One crossover trial11 found terfenadine more effective than clemastine, and both more effective than placebo in 60 patients. Outcomes evaluated were not described in detail. A figure displaying results of daytime itching symptom scores on a scale of 0 to 3 suggests that the differences between antihistamines and placebo vary from 0.5 to 1 while the differences between terfenadine and clemastine vary from 0 to 0.3. Although reported as statistically significant, it is not clear that the differences between antihistamines are clinically significant.
One trial published in German12 with 51 patients found azatadine more effective than terfenadine. Although clinically and statistically significant results were reported, the validity of this trial is potentially hampered by losses to follow-up, baseline differences in treatment groups, lack of a placebo control, and inconsistent reporting of results.
The preponderance of published evidence supports equivalence in the efficacy of sedating and nonsedating antihistamines for chronic urticaria.
RESULTS FOR ACUTE URTICARIA
The search identified only 4 RCTs involving patients with acute urticaria. One additional trial13 did not use randomization for treatment assignment, despite such a description in the abstract.
No trials comparing nonsedating antihistamines with sedating antihistamines were identified. In fact, no trials comparing antihistamines with placebo in patients with acute urticaria were identified, so it is not clear if antihistamines are effective in this population. The search criteria were expanded to include the text word "urticaria" and no additional trials were identified.
Three trials compared histamine1 antihistamines with histamine2 blockers and had inconsistent results. One trial14 with 33 patients found diphenhydramine more effective than famotidine or cromolyn sodium in terms of patient satisfaction, but results were based on only 20 patients and no intention-to-treat analysis was performed. One trial15 with 33 patients found a single intravenous dose of cimetidine more likely than a single intravenous dose of diphenhydramine to be associated with clinically significant relief (in 80% vs 46% of patients) but the sample size was inadequate to reach statistical significance (P = .18). In this trial, a significant difference (P = .03) was found when comparing the combination of cimetidine and diphenhydramine (92% patients with clinically significant relief) with diphenhydramine alone. A trial16 with 93 patients that compared a single intramuscular dose of diphenhydramine with a single intramuscular dose of cimetidine found no significant differences in their efficacy. Again, power was not discussed in the article. It is noted that nonsedating antihistamines are not available in injectable forms, a common consideration when treating acute urticaria.
One placebo-controlled trial17 of 43 patients found the addition of prednisone to antihistamine therapy to be effective compared with an antihistamine alone.
In the absence of RCTs that evaluate patients with acute urticaria, a search was undertaken for RCTs that evaluate subjects with experimental urticaria (ie, expanding the search to include the text word "wheal" and evaluating trials using healthy volunteers and histamine-induced skin reactions). Seven trials were found that compared sedating and nonsedating antihistamines. All but 1 evaluated histamine-induced skin reactions after ingestion of medication. One evaluated the ingestion of medication to reduce an ongoing histamine-induced skin reaction.18 Four trials using placebo controls18-21 found antihistamines effective in suppressing histamine-induced wheals. Four trials reported no significant differences between nonsedating antihistamines and either diphenhydramine18-19 or hydroxyzine.20, 22 Three trials found nonsedating antihistamines (terfenadine,23 cetirizine24 or higher doses of loratadine21) to be more effective than chlorpheniramine.
BOTTOM LINE
In patients with chronic urticaria, the current best evidence suggests that nonsedating antihistamines are as effective as sedating antihistamines. Drug selection can be based on issues of cost and adverse effects. In patients with acute urticaria, effectiveness of antihistamines has not been established with clinical trials, but may be warranted based on clinical experience and experimental evidence. It is reasonable to substitute nonsedating for sedating antihistamines based on conclusions derived from trials in chronic urticaria and experimental urticaria. Placebo-controlled trials of antihistamines (including histamine2 blockers) are needed to determine whether or not their use for acute urticaria is truly beneficial. Steroids may increase efficacy in selected cases of acute urticaria.
AUTHOR INFORMATION
I would like to acknowledge Bernard Ewigman, MD, MSPH, and Robert L. Blake, Jr, MD, for editorial advice; Rainer Kretschmer, MD, for translating the German article; and Susan Meadows, MLS, for retrieval and organization of references.
REFERENCES
1. Breneman DL. Cetirizine versus hydroxyzine and placebo in chronic idiopathic urticaria. Ann Pharmacother. 1996;30:1075-1079.
ABSTRACT
2. Monroe EW, Bernstein DI, Fox RW, et al. Relative efficacy and safety of loratadine, hydroxyzine, and placebo in chronic idiopathic urticaria. Arzneimittelforschung. 1992;42:1119-1121.
PUBMED
3. Monroe EW. Relative efficacy and safety of loratadine, hydroxyzine, and placebo in chronic idiopathic urticaria and atopic dermatitis. Clin Ther. 1992;14:17-21.
4. Sussman G, Jancelewicz Z. Controlled trial of H1 antagonists in the treatment of chronic idiopathic urticaria. Ann Allergy. 1991;67:433-439.
PUBMED
5. Boggs PB, Ellis CN, Grossman J, et al. Double-blind, placebo-controlled study of terfenadine and hydroxyzine in patients with chronic idiopathic urticaria. Ann Allergy. 1989;63:616-620.
PUBMED
6. Gale AE, Harvey SG, Calthrop JG, Gibson JR. A comparison of acrivastine versus chlorpheniramine in the treatment of chronic idiopathic urticaria. J Int Med Res. 1989;17:25B-27B.
7. Salo OP, Harvey SG, Calthrop JG, Gibson JR. A comparison of acrivastine versus hydroxyzine and placebo in the treatment of chronic idiopathic urticaria. J Int Med Res. 1989;17(suppl 2):18B-21B.
8. Grant JA, Bernstein DI, Buckley CE, et al. Double-blind comparison of terfenadine, chlorpheniramine, and placebo in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol. 1988;81:574-579.
PUBMED
9. Ormerod AD, Baker R, Watt J, White MI. Terfenadine and brompheniramine maleate in urticaria and dermographism Dermatologica. 1986;173(1):5-8.
10. Leyh F, Harvey SG, Gibson JR, Manna VK. A comparison of acrivastine versus clemastine and placebo in the treatment of patients with chronic idiopathic urticaria. J Int Med Res. 1989;17(Suppl 2):22B-24B.
11. Fredriksson T, Hersle K, Hjorth N, et al. Terfenadine in chronic urticaria: a comparison with clemastine and placebo. Cutis. 1986;38:128-130.
PUBMED
12. Neumann Y. Antihistaminic therapy of chronic urticaria. Results of a multicenter study with azatadine and terfenadine. [in German]. Fortschr Med. 1984;102:967-970.
PUBMED
13. Zuberbier T, Ifflander J, Semmler C, Henz BM. Acute urticaria: clinical aspects and therapeutic responsiveness. Acta Derm Venereol. 1996;76:295-297.
ISI
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14. Pontasch MJ, White LJ, Bradford JC. Oral agents in the management of urticaria: patient perception of effectiveness and level of satisfaction with treatment. Ann Pharmacother. 1993;27:730-731.
ABSTRACT
15. Runge JW, Martinez JC, Caravati EM, Williamson SG, Hartsell SC. Histamine antagonists in the treatment of acute allergic reactions. Ann Emerg Med. 1992;21:237-242.
FULL TEXT
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16. Moscati RM, Moore GP. Comparison of cimetidine and diphenhydramine in the treatment of acute urticaria. Ann Emerg Med. 1990;19:12-15.
FULL TEXT
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17. Pollack CV Jr, Romano TJ. Outpatient management of acute urticaria: the role of prednisone. Ann Emerg Med. 1995;26:547-551.
PUBMED
18. Bjerring P. Effect of antihistamines on argon laser-induced cutaneous sensory and pain thresholds and on histamine-induced wheal and flare. Skin Pharmacol. 1989;2:210-216.
PUBMED
19. Simons FE, Fraser TG, Reggin JD, Simons KJ. Comparison of the central nervous system effects produced by six H1-receptor antagonists. Clin Exp Allergy. 1996;26:1092-1097.
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20. Gengo FM, Dabronzo J, Yurchak A, Love S, Miller JK. The relative antihistaminic and psychomotor effects of hydroxyzine and cetirizine. Clin Pharmacol Ther. 1987;42:265-272.
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21. Roman IJ, Kassem N, Gural RP, Herron J. Suppression of histamine-induced wheal response by loratadine (SCH 29851) over 28 days in man. Ann Allergy. 1986;57:253-256.
PUBMED
22. Simons FE, Murray HE, Simons KJ. Quantitation of H1-receptor antagonists in skin and serum. J Allergy Clin Immunol. 1995;95:759-764.
PUBMED
23. Simons KJ, Martin TJ, Watson WT, Simons FE. Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly. J Allergy Clin Immunol. 1990;85:540-547.
PUBMED
24. Snyman JR, Sommers DK, Gregorowski MD, Boraine H. Effect of cetirizine, ketotifen and chlorpheniramine on the dynamics of the cutaneous hypersensitivity reaction: a comparative study. Eur J Clin Pharmacol. 1992;42:359-362.
PUBMED
SECTION EDITOR: M. LEE CHAMBLISS, MD, MSPH
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