J Am Board Fam Pract: first published as 10.3122/jabfm.5.2.137 on 1 March 1992. Downloaded from Treatment Of Atopic Dermatitis With Antihistamines: Lessons From A Single-Patient, Randomized Clinical Trial james Nuovo, M.D., Allan j. Ellsworth, Pharm.D., and Eric B. Larson, M.D., MPH.

Abstract: IJIIcllground: Single-padent randomized clinical tria1s (RC1S) can be utilized to maintain methodologic precision in the analysis of treatment effect in individual patients. We describe the results of a single-patient RCT in a patient with atopic dermatitis and review practical considerations regarding the use of antihistamines. Methods: Using double-blind, crossover techniques, the padent was randomly allocated to four 2-week treatment periods with the following regimens: chlorpheniramine, 8 mg twice daily; chIorpheniramine, 12 mg twice daily; terfenadine, 120 mg twice daily; and p1acebo (phase 1). The drug that produced superior results from phase 1 (chlorpheniramine, 8 mg) was subsequently compared with astemizole, 10 mgld, during phase 2, consisting of four 4-week, double-blind, crossover trial periods with random allocation of study drugs. Daily symptom scores, as well as end of treatment period summary impressions by padent and investigator, were analyzed. Results: In both phases, chlorpheniramine produced the most noticeable positive therapeutic effect on the padent's mild but most disturbing symptoms (pruritus and eye irritation) associated with atopic dermatitis. Drowsiness was reported with chlorpheniramine. Tolerance to this side effect, however, developed quickly. Conclusions: Asingle-patient RCT with different antihistamines in a patient with chronic atopic dermatitis was a useful tool in achieving a favorable balance among efficacy, toxicity, and cost of therapy. (J Am Board Fam Pract 1992; ;:137-42.)

Atopic dermatitis is a genetically conferred and subsequently less able to penetrate the hyperirritable skin disease manifested by vari­ blood-brain barrier} The antipruritic efficacy able degrees of xerosis, lichenification, pruritus, of these newer agents has not been proved su­ http://www.jabfm.org/ and white dermographism. Exacerbations occur perior to traditional antihistamines.4 Further­ throughout life, often resulting from physical or more, the newer agents are significantly more emotional stress. I Systemic antihistamines are expensive.S commonly prescribed for pruritic symptoms.l Before prescribing a daily course of these medi­ Traditional antihistamines (e.g., diphenhydra­ cations for atopic dermatitis, a prudent physician

mine, chlorpheniramine, and hydroxyzine), al­ may want to know the comparative efficacy for on 25 September 2021 by guest. Protected copyright. though potentially effective at relieving pruritus, these drugs, including potential for adVerse ef­ often produce bothersome sedative effects. 2 fects. Randomized clinical trials (RCIS) are usu­ Newer, more selective antihistamines (e.g., ter­ ally required to establish valid evidence of drug fenadine and astemizole) cause less sedation and efficacy. In some clinical situations, however, interference with cholinergic muscarinic re­ treatment decisions cannot be guided by such ceptors,l in part because they are less lipophilic trials. One obvious example is the treatment of a disease in which Refs have not been conducted. More commonly, even when an Ref has shown that a treatment is effective, the result of that Submitted, revised, 4 October 1991. From the Departments of Family Medicine, Phannacy Prac­ Ref may not apply to the individual patient. If tice, and Medicine, Schools of Medicine and Phannacy, Univer­ the patient does not meet the eligibility criteria, sity of Washington, Seattle. Address reprint request to James generalization may be unwarranted. Regardless of Nuovo, M.D., Department of Family Medicine, RF-30, Univer­ the overall trial results, some patients appear to sity of Washington, Seattle, WA 98195. This paper was supported by a grant (HS06006) from the benefit from the otherwise effective therapy and National Center for Health Services Research-OASH. some do not.6-8

Treaunent of Atopic Dennatitis 137 J Am Board Fam Pract: first published as 10.3122/jabfm.5.2.137 on 1 March 1992. Downloaded from To maintain the methodological precision pro­ Data Collection Form vided by RCIS and to avoid the disadvantages of End 01 Treatment ReconI large-sample multicenter studies, methods for ex­ IIANDOMtZED TRIAl IN INDIVIDUAL PATIENTS: Anti_I lor Atopic Dlrmatitil amination of the treatment effect in individual pa­ OatO:,__ _ TIme 01 day.: ____ tients have been developed.6-8 Single-patient RCIS _: are especially useful in assessing the efficacy oftreat­ An_, the "'\lowing questions racarding the walment period just completed. ment for chronic conditions. We report the results 1. W..... rnodication offective1 YES ( ) NO( 2. Did you experience any _ ,"acts? YES ( ) NO ( of a single-patient RCf and review practical con­ "YES. pIe_ explain: siderations regarding the use of antihistamines in

such a chronic disease as atopic dermatitis. 3. Do IOU feel thai yOIJ ....iYod active or placebo medica- ACTIVE ( lion during this treatment period? PLACEBO (

4. _ many pills ant \eft in the boHlo?' ___

case Report 5. lilt any other medications that you took during this A 32-year-old man had a lifelong complaint of treatment period. including over-the-counter medications. classic atopic dermatitis. His main manifestations were diffuse pruritus, a dry lichenified dermatitis 8. Comments: in the distribution of his hands and flexure creases Figure 2. Patient-directed end of treatment reoord for of elbows and knees, and red swollen eyelids. single-patient randomized clinical trial. Nondrug modalities and moderate strength topi­ cal corticosteroids effectively controlled the rash; however, pruritus and eye complaints persisted. corded in a daily symptoms log (Figure 1). M­ He had tried a variety of antihistamines without ter giving consent, the patient underwent an ini­ significant relie£ Diphenhydramine caused exces­ tial trial (phase 1) that included four 2-week pe­ sive sedation. Hydroxyzine caused a severe dys­ riods with the patient receiving the follOwing phoric reaction. He was taking terfenadine, 60 mg regimens: (1) chlorpheniramine, 8 mg twice daily; twice daily, with minimal relief. (2) chlorpheniramine, 12 mg twice daily; (3) ter­ fenadine, 120 mg twice daily; and (4) placebo, Methods twice daily. The order of treatment was deter­ Single-Patient Randomized Clinical TriIIl mined by random allocation. The patient and During an explanatory interview with the patient, investigators were blinded to the treatment se­

outcome variables were developed consistent with quence. A pharmacist prepared all study medica­ http://www.jabfm.org/ his most significant complaints and possible anti­ tions to appear identical as pink capsules and histamine adverse effects. These outcomes were maintained the drug code. The drug that pro­ scored by the patient using Likert scales and re- duced superior results from phase 1 was subse­ quendy compared with astemizole 10 mg/d dur­ ing a second trial (phase 2) consisting of four Daily Symptoms Log 4-week double-blind trial periods. In addition to on 25 September 2021 by guest. Protected copyright. 1lAN000000D TRIAl IN INDIVIDUAL PATIENTS: the daily log of symptoms, during both phases, the AnlilullalTli".. lor Atopic ~ patient also completed a report summarizing his Oate.:___ _ Timeolday.: ____ T..-period:.__ _ impressions about the trial period just completed _: IIogMIlng thec:urrenlWlllment Iorycurcondlioft. dido the _thal ___ ~ (Figure 2). you haw lett during the lui 2. _. The severity of symptoms and adverse effects 1. Rate the S8YIrity 01 itcIIing 2 3 5 e 7 thai IOU experienced today. of study medications measured on Likert scales 2. Rate ... S8YIrity 01 """ oyo -1 2 3 - 5 -7 were analyzed using Kruskal-Wallis one-way IymIItOmO (.-.- • • ing) thai you .xporieoood analysis ofvariance by ranks set up on CRUNCH, 1DdI¥. - - - 9 3. Rate tilt S8YIrity oi_ l 2 3 4 5 e 7 a statistical package for personal computers. Ex­ _youfe.-,. perience with the 7-point Likert scale in single­ 4. _mMJ_didyou - 2 3 -4 I • -7 1IIPIl'---...-,? patient ReI's indicates that an average difference I. Commtntt (Doocrtbe.., ...... ~_lOycur_noI of 0.5 points shows a clinically significant differ­ -_ ..... --- ence (personal communication with Dr. E.B. Lar­ Figure 1. Patient-d.irected daily symptoms log for son and with G. Guyatt, McMaster University, single-patient randomized clinical trial. Ontario, Canada, 1989).

138 JABFP March-April 1992 Vol. 5 No.2 J Am Board Fam Pract: first published as 10.3122/jabfm.5.2.137 on 1 March 1992. Downloaded from

13bIe 1. Results of Phase 1 of Single-Patient RaDdomized CliDiad 'D:ial.

Symptom Phase 1 Mean Scores p Placebo Terfenadine* Chlorpheniramine* 120mg Smg 12 mg Severity of itchingt 1.7 0.7 0.7 1.4 0.06 Severity of eye symptoms* 2.0 2.6 3.0 1.5 0.1 Severity of drowsiness* 2.6 1.9 2.7 3.1 0.3 Topical steroid use:j: O.S 0.9 0.3 OJ 0.06 Was medicine effective? No No Yes Yes Compliance (%) 100 100 100 100 Medication guess Placebo Placebo Active Active "Drugs were administered twice daily. t Likert scales: 0 .. none, 1 • mild, 7 = severe. :j:Number of applications per day. Results was not consistendy effective based on symp­ The results of phase 1 are shown in Table 1. tom scores and was not judged effective by the During this phase, the mean severity of symptoms patient. for all complaints never exceeded moderate, al­ Phase 2 results (ch1orpheniramine, 8 mg twice though the scores ranged from mild to severe. daily, versus astemizole, 10 mg once daily) are Itching seemed to be more severe during treat­ shown in Table 2. The mean severity of symp­ ment with placebo and chlorpheniramine, 12 toms for all complaints (itching, eyelid itching, mg. Severity of eye symptoms (redness and and swelling) never exceeded moderate. There swelling) was fairly consistent across all drug was lime difference between the two drugs regimens, with chlorpheniramine, 12 mg, yield­ when judged by their effect on itching, but ing the lowest mean score. Chlorpheniramine the severity of the eye complaints was much was also associated with less topical corticoster­ less during treatment with chlorpheniramine. oid use. With regard to pruritus, the patient There was a significant amount of drowsiness thought that only chlorpheniramine (either accompanying the relief of symptoms produced dose) was effective. There were no identifiable by chlorpheniramine. As seen in Figure 3, how­ http://www.jabfm.org/ trends in related adverse effects, although the ever, the severity of drowsiness decreased from patient was able to guess correcdy the active severe to mild the longer the patient remained on drug and placebo periods. Both the patient and chlorpheniramine. the clinician agreed that during this treatment Based on the results of both phases, chlorphen­ phase, chlorpheniramine produced the most iramine was recommended for symptomatic re­ noticeable positive therapeutic effect. Terfena­ lief except when sedation might be a liability. As dine, even at double the recommended dosage, of 15 months of follow-up care, the patient had on 25 September 2021 by guest. Protected copyright.

Table 2. Results of Phase 2 of Single-Patient Randomized CliDkaI 'D:ial.

Symptom Phase 2 Mean Scores P Astemiwle* Chlorpheniramine* 10mg Smg Severity of itchingt 3.3 3.0 O.S Severity of eye symptoms· 4.0 2.5 0.2 Severity of drowsiness" 1.4 4.6 om Topical steroid use:j: S.O 5.6 0.7 Was medicine effective? Yes Yes Compliance (%) >95 >95 Medication guess Unknown Active *Drugs were administered twice daily (astemizole, 10 mgld; chlorpheniramine, 16 mg/d). t Likert scales: 0 • none, 1 .. mild, 7 .. severe. ;Number of applications per day.

Treatment of Atopic Dermatitis 139 J Am Board Fam Pract: first published as 10.3122/jabfm.5.2.137 on 1 March 1992. Downloaded from

Drowsiness and Chlorpheniramine Therapy marketing of terfenadine with the accompanying 6.------, "no sedation" claims, the drug has become one of Severity scales the most popular antihistamines prescribed in this III 5 o. none Ql 1. mild c: 1. severe country. 10 Are the newer antihistamines worth the "~ 4 cost? Do they really offer significant advantage to -0 3 '0 justify a greater than to-fold increase in cost? ~ 2 The results of the single-patient ReT in this .~ patient indicate that the less expensive chlorphen­ ~ 1 iramine might be the better agent. This trial 2 3 4 5 6 7 8 9 10 11 also reinforces the conventional wisdom that Days of continuous therapy tolerance to the sedative side effects of tradi­ tional antihistamines develops quickly.10 Ter­ Figure 3. Severity of self-reported drowsiness (Ukert fenadine and the other nonsedating antihista­ scale) during cblorpbeniramine therapy. mines could have advantages for intermittent dosing when sedation is more likely to be prob­ been following this treatment with good relief of lem. Combination therapy using nonsedating symptoms. antihistamines during the day and traditional antihistamines at night could be the most eco­ Discussion nomical regimen. Single-patient ReTs can be useful to evaluate This study was not difficult to perform and, drug therapy when doubt (on the part of either with the assistance of a pharmacist, could be du­ the patient or the physician) exists about the effi­ plicated. Although it is not appropriate to gener­ cacy of the treatment. Doubt can occur when a alize from a single-patient RCT about treatment physician is uncertain of the nsk-to-benefit ratio effects for other patients with the same condition, of a new treatment as a result of limited literature there are other general conclusions: (1) for condi­ and available experience or when a patient with" a tions that require on-going daily administration chronic disease is doing poorly on a particular of antihistamines, a single-patient RCT can be a medication. Additionally, for patients with rare or useful therapeutic decision-making tool, particu­ unusual conditions, the single-patient ReT could larly when patients do not get substantial benefit http://www.jabfm.org/ not only benefit the patient but also add to knowl­ from the least expensive regimen; (2) single­ edge about management of unusual conditions. patient RCTs can help clarify issues of efficacy, Single-patient trials are usually of most value toxicity, and cost for a variety of comparative for patients with chronic problems requiring treatments; and (3) single-patient RCfs allow pa­ long-term treatment. Single-patient trials of tients a greater sense of participation in the man­ short-term treatments are less likely to have value agement of their disease. Further, trials can be for an individual patient unless the patient will individualized to patient-specific complaints. on 25 September 2021 by guest. Protected copyright. require the short-term treatment repeatedly. The Daily log entries can be made by allowing patients ideal treatment for single-patient RCfs has a to use their own words to emphasize their most rapid onset and offset. Thus, assessment of out­ significant symptoms or side effects. comes can be accomplished starting relatively A single-patient RCT with different antihista­ early in the trial, and there is little or no carry­ mines in a patient with chronic atopic dermatitis over between treatment periods. Single-patient was a useful tool in choosing an effective and trials are less likely to be useful for curative treat­ affordable therapeutic regimen. Further studies ments and for long-acting treatments. of this type can be done by primary care physi­ A disease with characteristics similar to atopic cians seeking assurance of a favorable balance dermatitis lends itself to this type of evaluation. among efficacy, toxicity, and cost of therapy for The literature on aritihistamines for pruritus in patients with chronic medical problems. atopic dermatitis does not clearly favor anyone 2 particular agent for treatment. Further, there are References substantial differences in costs and claims for side 1. Kaplan AP, Buckley RH, Mathews KP. Allergic skin effects for the different antihistamines.4 Since the disorders.JAMA 1987; 258:2900-9.

140 JABFP March-April 1992 Vol. 5 No.2 J Am Board Fam Pract: first published as 10.3122/jabfm.5.2.137 on 1 March 1992. Downloaded from

2. Rhodes AR. Treatment of atopic dermatitis: old and 7. Larson EB. N of 1 clinical trials. A technique for im­ new modalities. Clio Rev Allergy 1986; 4:87-99. proving medical therapeutics. West J Med 1990; 3. Krstenansky PM, Cluxton RJ Jr. Astemiwle: a long­ 152:52-6. acting nonsedating antihistamine. Drug Intell Clio 8. Guyatt GH, Keller JL, Jaeschke R, Rosenbloom Pharm 1987; 21:947-53. D, AdachiJD, Newhouse MT. The n-of-l random­ 4. Flowers FP, Araujo OE, Nieves CR. Antihistamines. ized controlled trial: clinical usefulness. Our IntJ Dermatol1986; 25:224-31. three-year experience. Ann Intern Med 1990; 5. Cardinale VA, editor. Drug topics red book 1989. 112:293-9. Oradell, NJ: Medical Economics, 1989. 9. Crunch interactive statistical package. Oakland, CA: 6. Guyatt G, Sackett D, Taylor DW, ChongJ, Roberts Crunch Software Corporation, 1987. R, Pugsley SO. Determining optimal therapy­ 10. Drouin MA. HI antihistamines: perspective on the randomized trials in individual patients. N Engl J use of the conventional and new agents. Ann Allergy Med 1986; 314:889-92. 1985; 55:747-52..

ABFP ANNOUNCEMENT

Sports Medicine Certificate of Added Qualification (CAQ) http://www.jabfm.org/

Applications will be available beginning September I, 1992. All applications must be returned to the Board office by January IS, 1993. A late fee will apply for applications received from January 16, 1993, through February IS, 1993.

DON'T WAIT RESERVE YOUR APPLICATION TODAY on 25 September 2021 by guest. Protected copyright.

SEND YOUR WRITTEN REQUEST FOR APPLICATION MATERIALS TO:

Sports Medicine CAQ American Board of Family Practice 2228 Young Drive Lexington, Kentucky 40505

YOUR MATERIALS WILL BE MAILED TO YOU AUTOMATICALLY

Treatment of Atopic Dermatitis 141