Suppression of seasonal allergic rhinitis symptoms with daily hydroxyzine Larry Schaaf, M.S. (Pharmacy), Leslie Hendeles, Miles Weinberger, M.D. Iowa City, lowa
Pharm.D.,
and
The effectiveness qf hydroxyzine in the suppression of allergic rhinitis symptoms was evaluated using a douhltp-blind, parallel study design during the 1977 ragweed season. Forty-three subjects with positive ragweed skin tests and a history of an exacerbation of symptoms during August and September of the previous hco years bvere randomly assigned to receive either hydroxyzine or placebo. Subjects scored the severity and duration of symptoms in a daily diary and adverse effects were evaluated from a structured interview at two-week intervals. Although drowsiness and dry mouth were frequent initially among the hydroxyzine-treated patients, these minor side effects rapidly disappeared as the dose was slowly increased, and all but one subject toleruted 150 mglday. Subsequently, during the period of the highest ragweed pollen counts, the hydroxyzine-treated group spent signi’cantly more days ,free of symptoms or with only mild sneezing, rhinorrhea, and eye symptoms than subjects who took placebo (p < 0.05). Thus, hydroxyzine appeared to be well tolerated on a continuous daily basis and was effective in suppressing most of the symptoms of seasonal allergic rhinitis. Comparison qf hydroxyzine with antihistamines more traditionally used,for allergic rhinitis appears warranted.
Hydroxyzine is commonly identified as a minor tranquilizer with antiemetic and antihistaminic effects . ’ Recent studies, however, have demonstrated that it suppresses the wheal-and-flare response to allergen and histamine administered intradermally to the greatest extent and for the longest duration when compared to other commonly used antihistamines .*, ’ Experimentally4 and clinically,” hydroxyzine has appeared to be the most potent antihistamine in alleviating IgE-mediated pruritus and urticaria. While it is frequently prescribed for the treatment of urticaria, hydroxyzine previously has not been recommended or commonly used for seasonal allergic rhinitis. Thus, the present study was undertaken to evaluate the efficacy of hydroxyzine in suppressing the symptoms of ragweed-allergic rhinitis. From the College of Pharmacy, the Pediatric Allergy and Pulmonary Division, the Iowa City Veterans Administration Hospital, and the Clinical Research Center, The University of Iowa. Supported in part by Grant RR-59 from the General Clinical Research Center’s Program, Division of Research Resources, National Institutes of Health, and in part by funds provided by the College of Pharmacy, University of Iowa. Received for publication July 13, 1978. Accepted for publication Oct. 1 I, 1978. Reprint requests to: Dr. Leslie Hendeles, College of Pharmacy. University of Iowa, Iowa City, IA 52242.
TABLE I. Symptom
scoring
criteria
Severity Symptom did not occur during the previous 12-hr 0 period 1 Mild symptom-the symptom was clearly present but was not annoying 2 Moderate symptom-the symptom was annoying but did not interfere with daily activities 3 Severe symptom-the symptom caused some interference with sleep or daily activities Duration 0 Symptom period 1 Symptom 2 Symptom 3 Symptom
did not occur during the previous 12-hr lasted for less than 2 hr lasted for 2 to 6 hr lasted for 6 to 12 hr
METHODOLOGY Subject selection Twenty-five men and 18 women 19 to 34 yr of age (mean, 24.5 yr) were selected for participation in the study after appropriate screening, including a history, physical examination, and skin testing. Criteria for acceptance into the study included
the following:
(I)
16 yr of age or older;
(2) ragweed hay fever symptoms, e.g., rhinitis from midAugust through September, for at least two consecutive seasons prior to the study; (3) a positive skin test to ragweed
Vol. 63, No. 2, pp. 129-133
130 Schaaf, Hendeles, and Weinberger
TABLE
II. Number
of patients
J. ALLERGY
with potential Period
adverse
1 (Aug. I-Aug.
CLIN. IMMUNOL. FEBRUARY 1979
effects from the antihistamine 15)
Periods
2-4 (Aug. 16-Sept. 26)
Adverse effect
H (n = 19)
P (n = 23)
H (n = 19)
P (n = 23)
Drowsiness* Dry mouth Irritability Dizziness
17 12 7 3
6 4 4 0
2 1 0 0
0 4 1 0
H: hydroxyzine; P: placebo. *Other adverse effects evaluated included headache,diarrhea, blurred vision, nervousness,nausea, and insomnia; these were all infrequent and did not differ significantly between the two groups during any of the periods. pollen antigen consisting of a wheal at least 7 mm in diameter within 15 min after a puncture test with 1: 20 w/v glycerinated extract or intradermal injection of 0.02 ml of 1: 500 w/v aqueous ragweed extract; (4) no immunotherapy for at least one year prior to the study; (5) residence within a 25-mile radius of Iowa City and not expected to be absent from the area for more than two days during the study; (6) no other diseases, e.g., hypertension, or chronic use of medication; (7) no asthma or eczema. Subjects were asked to assess the severity during the previous season of sneezing, rhinorrhea, itchy nose, nasal congestion, and conjunctivitis using a scoring system designed to reflect the degree of discomfort and/or disability. The amount of time spent in air-conditioned buildings was also estimated. Since the season for Alrernaria overlapped with ragweed, the presence of reaginic antibody to this inhalant allergen was determined in all patients.
Medication Subjects were randomly assigned in a double-blind manner to one of two groups receiving either hydroxyzine 25 mg as the pamoate salt or lactose placebo in capsules of identical appearance. To minimize problems from drowsiness, the first 25-mg dose was administered at bedtime, and the number of capsules taken daily was then progressively increased over a IO-day period as tolerated until six capsules daily (50 mg three times daily) was reached. A decongestant, 60 mg pseudoephedrine tablets (Sudafed), was provided to both groups of subjects to be taken on an “as-needed” basis for acute rhinitis symptoms. Seven subjects who complained of insomnia from pseudoephedrine received 25 mg phenylpropanolamine tablets or capsules instead; all tolerated this substitute oral decongestant.
Data collection Treatment began prior to the 1977 ragweed season (August 1) and was continued for eight weeks (August 1 to September 28). Four two-week study periods were identified for data tabulation and subsequent analysis. Throughout the eight weeks of the study, subjects recorded their symptoms and medication intake twice daily. Symptoms were scored by the severity and duration of sneezing, runny nose, stuffy nose, itchy nose, and itchy, red, watery eyes for 12-hr periods (Table I).
Subjects were interviewed at two-week intervals throughout the ragweed season; symptom score cards were reviewed, compliance was estimated by tablet counts, and blood pressure was measured in the sitting position. In addition, all subjects underwent a structured questioning period every two weeks regarding 16 specified symptoms. These included classical antihistamine side effects such as drowsiness and dry mouth as well as others included essentially as “placebo” questions. Lastly, at the end of the 8-week double-blind treatment period, subjects were asked whether rhinitis symptoms had been less intense, the same, or more intense than in the past season. Pollen counts were obtained daily throughout the study with a Durham gravity sampler.6
Data analysis A repeated measures analysis of variance design7 was used to determine the statistical significance of differences in symptom scores between the two groups for each twoweek study period. Differences in the use of decongestant tablets and side effects were evaluated by using the twosample t test and chi-square analysis, respectively. Random assignment resulted in 20 subjects in the hydroxyzine group and 23 in the placebo group. No significant differences between the groups were observed in age and sex ratios, the assessment of previous symptoms, the estimated time spent in air conditioning, or the frequency of positive skin tests to Ahrnaria.
RESULTS Data related to outcome were analyzed from 42 of the 43 subjects initially selected for the study; one subject in the hydroxyzine group dropped out after two days because he developed acute sinusitis. Incomplete data were available from four other subjects. One from the hydroxyzine group took the pseudoephedrine tablets inappropriately and his decongestant tablet count was therefore not considered. Due to an error in instruction, this subject also failed to complete the last two study periods. One placebo subject completed only the first two weeks of the study because of an unexpected absence from the area. Two placebo and no hydroxyzine subjects
VOLUME NUMBER
63 2
FIG. 1. Mean (+I SD) daily pollen count from the Durham Gravity Sampler Method for each 2-wk period from Aug. 1, 1977, to Sept. 28, 1977.
dropped out of the study because of severe rhinitis symptoms; this occurred during the second study period in both cases. A significantly (p < 0.005) higher percentage of the hydroxyzine group reported transient drowsiness and dry mouth during the dose titration period (August 1 to August IO) when compared to the placebo group (Table II). However, only one subject was unable to tolerate the full dose of 150 mg/day without adverse effects by the second period of the study; this individual tolerated a reduced dose of 125 mg/day. During the subsequent three periods, the percentage of subjects reporting side effects was small and did not differ significantly among the hydroxyzine and placebo groups. Elevation in diastolic blood pressure (>90 mm Hg) was not seen in subjects taking decongestant tabliets. The ragweed pollen count followed a typical pattern, reaching a peak during the second two-week period of the study, August 16 to August 3 1 (Fig. 1). As the pollen counts increased, a marked increase in the mean severity and duration of nasal symptoms, including sneezing, rhinorrhea, and itchy nose, was seen among the 23 subjects in the placebo group (Fig. 2). In contrast, the mean symptom scores remained relatively constant throughout the study in the hydroxyzine group (n = 19) without a marked exacerbation as pollen counts increased (p < 0.05 for sneezing and rhinorrhea; 0.05 < p < 0.1 for nasal itching). Eye symptoms (Fig. 3) followed a similar trend (0.05 < p < 0.1). When the frequency of more severe or prolonged symptoms was examined for the period of highest pollen counts (S/ 16-8/3 I), the hydroxyzine-treated
Hydroxyzine
treatment
of hay fever
131
FIG. 2. Sneezing scores (mean t SEMI derived from the product of severity and duration scores for each 2-wk period. Rhinorrhea and itchy nose scores paralleled these data.
FIG. 3. Eye symptom scores (mean + SEMI derived from the product of severity and duration scores for each 2-wk period.
group had significantly fewer days with symptoms that were annoying or interfered with daily activities (Fig. 4). In addition, the treated group experienced fewer days during which symptoms lasted two hours or more (p < 0.05). Nasal congestion did not follow the pattern of the other symptoms of allergic rhinitis. Congestion w&h was annoying or interfered with daily activities occurred on 40% of patient-days during treatment with hydroxyzine and 24% of patient-days during placebo therapy. These data, however, are heavily weighted by almost continuous nasal congestion among five subjects in the hydroxyzine group and two subjects in the placebo group. As a result of the intragroup variability in frequency of nasal congestion, the apparent difference in the frequency of nasal congestion was not significant (p > 0.1). During the peak pollen period, subjects in the
132
Schaaf,
Hendeles,
J. ALLERGY
and Weinberger
CLIN. IMMUNOL. FEBRUARY 1979
Hydroxyzine
Frequency of Symptom Scores 22 (annoying or disabling symptoms)
Frequency of Symptom Duration22 hours
FIG. 4. Mean frequency of symptoms that were judged by the subject to be annoying or disabling, i.e., sufficient to interfere with activities, and lasting a duration of at least 2 hr during the period from August 16 to August 31.
placebo group ingested 1.9 5 0.3 (mean + SEM) decongestant tablets per day while those in the hydroxyzine group took 1.1 -+ 0.2 (p = 0.08). Questionnaires at the end of the trial indicated that the hydroxyzine-treated subjects reported less intense symptoms compared with the previous year than subjects in the placebo group (p < 0.05).
DISCUSSION The present study demonstrates the ability of a potent antihistamine to suppress the symptoms of seasonal allergic rhinitis when administered on a continuous daily basis. Although subjects in the hydroxyzine group experienced some degree of symptoms, they generally did not have the marked exacerbation during the peak of the ragweed pollen season that was seen among the placebo group. Subjects taking hydroxyzine spent significantly more days during the peak of the ragweed season with little or no symptoms than subjects who took a placebo. Nasal obstruction was not similarly affected and may even have been somewhat less among the placebo subjects who took more pseudoephedrine or phenylpropanolamine. This is compatible with previous reports suggesting that psuedoephedrine relieves nasal congestion, 8, g thus providing a rationale for the traditional use of oral decongestants in conjunction with antihistamines. The low frequency of sustained side effects in the present study was compatible with previous reports that tolerance to the sedative effect of antihistamines often develops.10-12 The slow titration allowed the achievement of maximal dosage with only transient minor side effects.
The intriguing data of Cook and co-workers3 demonstrated that hydroxyzine has greater potency and duration of action than other antihistamines using a skin test for a bioassay of effect. The results of the current study support the need for further data comparing hydroxyzine with other antihistamines. This might allow evaluation of the validity of the skin test as a method for comparing the relative clinical efficacy of various antihistamines. The rather striking degree of efficacy and acceptance of the medication seen among these subjects also suggests that evaluation of other modes of therapy proposed for allergic rhinitis, e.g., injection therapy with allergenic extracts, intranasal cromolyn, or topical steroids, might include an antihistamine control group so that therapeutic perspective could be provided. We gratefully acknowledgethe Clinical ResearchCenter Nursing Staff, Miles Bextine of Burroughs Wellcome who provided Sudafedtablets, and JamesGillilland, D.O., and David Richards, B.A., of the Allergy Section, Immunology Division, Departmentof Internal Medicine, who performed the daily pollen counts. The statistical analysis was performed by Barbara Broffitt, M.S., and reviewed by P. A. Lachenbruch, Ph.D., Professorof Preventive Medicine and Environmental Health, University of Iowa. REFERENCES
I. AMA Department of Drugs:Antianxietyagents,in AMA Drug evaluations,ed3, Littleton,Mass.,1977,PublishingSciences Group,Inc., pp. 416-417. 2. Dundas E, ToogoodJH, WanklinJ: Inhibition of experimental skin whealby someataracticand antihistaminic drugs, J ALLERGY
3.
32:1, 1971.
CookTJ, MacQueen DM, Wittig HH, et al: Degree and duration of skin test suppression and side effectswith antihis-
VOLUME63 NUMBER2
4.
5.
6.
7.
Hydroxyzine
tarnines. A double-blind controlled study with five antihistamines, J ALLERGY CLIN IMMUNOL5S:71, 1973. Rhoades !RB, Leifer KN, Cohan R, et al: Suppression of histamine- induced pruritus by three antihistaminic drugs. J ALLERGY CLIN IMMUNOL55~180, 1975. Baraf CS: Treatment of pruritus in allergic dermatoses: An evaluation of the relative efficacy of cyproheptadine and hydroxyzine, Curr Ther Res 19:32, 1976. Durham 0C: The volumetric incidence of atmospheric allergens. IV. A proposed standard method of gravity sampling, counting, and volumetric interpretation of results, J AI.LERGY 1279, 1946. Winer BJ: Statistical principles of experimental design, New
York, I97 I. McGraw-Hill Book Co. 8. Benson MK: Maximum nasal inspiratory
flow rate: Its use in
9.
IO.
1I
12.
treatment
of hay fever
133
assessing the effect of pseudoephedrine in vasomotor rhinitis, Eur J Clin Pharmacol 3: 182, 197 I. Empey DW, Bye C, Hodder M, et al: A double-blind crossover trial of pseudoephedrine and triprolidine, alone and in combination, for the treatment of allergic rhinitis. Ann Allergy 3441, 1975. Ratner B: An evaluation of benadryl, pyribenzamine. and other so-called antihistaminic drugs in the treatment of allergy, J Pediatr 30~583, 1947. Weiss WI, Howard RM: Antihistamine drugs in hay fever. A comparative study with other therapeutic methods, J ALLERGY 19:271, 1948. Arbesman CE: The pharmacology, physiology, and clinical evaluation of the new antihistaminic drugs (pyribenzamine and benadryl). NY State J Med 47~1775. 1947.
Pharm.D.,
and
The effectiveness qf hydroxyzine in the suppression of allergic rhinitis symptoms was evaluated using a douhltp-blind, parallel study design during the 1977 ragweed season. Forty-three subjects with positive ragweed skin tests and a history of an exacerbation of symptoms during August and September of the previous hco years bvere randomly assigned to receive either hydroxyzine or placebo. Subjects scored the severity and duration of symptoms in a daily diary and adverse effects were evaluated from a structured interview at two-week intervals. Although drowsiness and dry mouth were frequent initially among the hydroxyzine-treated patients, these minor side effects rapidly disappeared as the dose was slowly increased, and all but one subject toleruted 150 mglday. Subsequently, during the period of the highest ragweed pollen counts, the hydroxyzine-treated group spent signi’cantly more days ,free of symptoms or with only mild sneezing, rhinorrhea, and eye symptoms than subjects who took placebo (p < 0.05). Thus, hydroxyzine appeared to be well tolerated on a continuous daily basis and was effective in suppressing most of the symptoms of seasonal allergic rhinitis. Comparison qf hydroxyzine with antihistamines more traditionally used,for allergic rhinitis appears warranted.
Hydroxyzine is commonly identified as a minor tranquilizer with antiemetic and antihistaminic effects . ’ Recent studies, however, have demonstrated that it suppresses the wheal-and-flare response to allergen and histamine administered intradermally to the greatest extent and for the longest duration when compared to other commonly used antihistamines .*, ’ Experimentally4 and clinically,” hydroxyzine has appeared to be the most potent antihistamine in alleviating IgE-mediated pruritus and urticaria. While it is frequently prescribed for the treatment of urticaria, hydroxyzine previously has not been recommended or commonly used for seasonal allergic rhinitis. Thus, the present study was undertaken to evaluate the efficacy of hydroxyzine in suppressing the symptoms of ragweed-allergic rhinitis. From the College of Pharmacy, the Pediatric Allergy and Pulmonary Division, the Iowa City Veterans Administration Hospital, and the Clinical Research Center, The University of Iowa. Supported in part by Grant RR-59 from the General Clinical Research Center’s Program, Division of Research Resources, National Institutes of Health, and in part by funds provided by the College of Pharmacy, University of Iowa. Received for publication July 13, 1978. Accepted for publication Oct. 1 I, 1978. Reprint requests to: Dr. Leslie Hendeles, College of Pharmacy. University of Iowa, Iowa City, IA 52242.
TABLE I. Symptom
scoring
criteria
Severity Symptom did not occur during the previous 12-hr 0 period 1 Mild symptom-the symptom was clearly present but was not annoying 2 Moderate symptom-the symptom was annoying but did not interfere with daily activities 3 Severe symptom-the symptom caused some interference with sleep or daily activities Duration 0 Symptom period 1 Symptom 2 Symptom 3 Symptom
did not occur during the previous 12-hr lasted for less than 2 hr lasted for 2 to 6 hr lasted for 6 to 12 hr
METHODOLOGY Subject selection Twenty-five men and 18 women 19 to 34 yr of age (mean, 24.5 yr) were selected for participation in the study after appropriate screening, including a history, physical examination, and skin testing. Criteria for acceptance into the study included
the following:
(I)
16 yr of age or older;
(2) ragweed hay fever symptoms, e.g., rhinitis from midAugust through September, for at least two consecutive seasons prior to the study; (3) a positive skin test to ragweed
Vol. 63, No. 2, pp. 129-133
130 Schaaf, Hendeles, and Weinberger
TABLE
II. Number
of patients
J. ALLERGY
with potential Period
adverse
1 (Aug. I-Aug.
CLIN. IMMUNOL. FEBRUARY 1979
effects from the antihistamine 15)
Periods
2-4 (Aug. 16-Sept. 26)
Adverse effect
H (n = 19)
P (n = 23)
H (n = 19)
P (n = 23)
Drowsiness* Dry mouth Irritability Dizziness
17 12 7 3
6 4 4 0
2 1 0 0
0 4 1 0
H: hydroxyzine; P: placebo. *Other adverse effects evaluated included headache,diarrhea, blurred vision, nervousness,nausea, and insomnia; these were all infrequent and did not differ significantly between the two groups during any of the periods. pollen antigen consisting of a wheal at least 7 mm in diameter within 15 min after a puncture test with 1: 20 w/v glycerinated extract or intradermal injection of 0.02 ml of 1: 500 w/v aqueous ragweed extract; (4) no immunotherapy for at least one year prior to the study; (5) residence within a 25-mile radius of Iowa City and not expected to be absent from the area for more than two days during the study; (6) no other diseases, e.g., hypertension, or chronic use of medication; (7) no asthma or eczema. Subjects were asked to assess the severity during the previous season of sneezing, rhinorrhea, itchy nose, nasal congestion, and conjunctivitis using a scoring system designed to reflect the degree of discomfort and/or disability. The amount of time spent in air-conditioned buildings was also estimated. Since the season for Alrernaria overlapped with ragweed, the presence of reaginic antibody to this inhalant allergen was determined in all patients.
Medication Subjects were randomly assigned in a double-blind manner to one of two groups receiving either hydroxyzine 25 mg as the pamoate salt or lactose placebo in capsules of identical appearance. To minimize problems from drowsiness, the first 25-mg dose was administered at bedtime, and the number of capsules taken daily was then progressively increased over a IO-day period as tolerated until six capsules daily (50 mg three times daily) was reached. A decongestant, 60 mg pseudoephedrine tablets (Sudafed), was provided to both groups of subjects to be taken on an “as-needed” basis for acute rhinitis symptoms. Seven subjects who complained of insomnia from pseudoephedrine received 25 mg phenylpropanolamine tablets or capsules instead; all tolerated this substitute oral decongestant.
Data collection Treatment began prior to the 1977 ragweed season (August 1) and was continued for eight weeks (August 1 to September 28). Four two-week study periods were identified for data tabulation and subsequent analysis. Throughout the eight weeks of the study, subjects recorded their symptoms and medication intake twice daily. Symptoms were scored by the severity and duration of sneezing, runny nose, stuffy nose, itchy nose, and itchy, red, watery eyes for 12-hr periods (Table I).
Subjects were interviewed at two-week intervals throughout the ragweed season; symptom score cards were reviewed, compliance was estimated by tablet counts, and blood pressure was measured in the sitting position. In addition, all subjects underwent a structured questioning period every two weeks regarding 16 specified symptoms. These included classical antihistamine side effects such as drowsiness and dry mouth as well as others included essentially as “placebo” questions. Lastly, at the end of the 8-week double-blind treatment period, subjects were asked whether rhinitis symptoms had been less intense, the same, or more intense than in the past season. Pollen counts were obtained daily throughout the study with a Durham gravity sampler.6
Data analysis A repeated measures analysis of variance design7 was used to determine the statistical significance of differences in symptom scores between the two groups for each twoweek study period. Differences in the use of decongestant tablets and side effects were evaluated by using the twosample t test and chi-square analysis, respectively. Random assignment resulted in 20 subjects in the hydroxyzine group and 23 in the placebo group. No significant differences between the groups were observed in age and sex ratios, the assessment of previous symptoms, the estimated time spent in air conditioning, or the frequency of positive skin tests to Ahrnaria.
RESULTS Data related to outcome were analyzed from 42 of the 43 subjects initially selected for the study; one subject in the hydroxyzine group dropped out after two days because he developed acute sinusitis. Incomplete data were available from four other subjects. One from the hydroxyzine group took the pseudoephedrine tablets inappropriately and his decongestant tablet count was therefore not considered. Due to an error in instruction, this subject also failed to complete the last two study periods. One placebo subject completed only the first two weeks of the study because of an unexpected absence from the area. Two placebo and no hydroxyzine subjects
VOLUME NUMBER
63 2
FIG. 1. Mean (+I SD) daily pollen count from the Durham Gravity Sampler Method for each 2-wk period from Aug. 1, 1977, to Sept. 28, 1977.
dropped out of the study because of severe rhinitis symptoms; this occurred during the second study period in both cases. A significantly (p < 0.005) higher percentage of the hydroxyzine group reported transient drowsiness and dry mouth during the dose titration period (August 1 to August IO) when compared to the placebo group (Table II). However, only one subject was unable to tolerate the full dose of 150 mg/day without adverse effects by the second period of the study; this individual tolerated a reduced dose of 125 mg/day. During the subsequent three periods, the percentage of subjects reporting side effects was small and did not differ significantly among the hydroxyzine and placebo groups. Elevation in diastolic blood pressure (>90 mm Hg) was not seen in subjects taking decongestant tabliets. The ragweed pollen count followed a typical pattern, reaching a peak during the second two-week period of the study, August 16 to August 3 1 (Fig. 1). As the pollen counts increased, a marked increase in the mean severity and duration of nasal symptoms, including sneezing, rhinorrhea, and itchy nose, was seen among the 23 subjects in the placebo group (Fig. 2). In contrast, the mean symptom scores remained relatively constant throughout the study in the hydroxyzine group (n = 19) without a marked exacerbation as pollen counts increased (p < 0.05 for sneezing and rhinorrhea; 0.05 < p < 0.1 for nasal itching). Eye symptoms (Fig. 3) followed a similar trend (0.05 < p < 0.1). When the frequency of more severe or prolonged symptoms was examined for the period of highest pollen counts (S/ 16-8/3 I), the hydroxyzine-treated
Hydroxyzine
treatment
of hay fever
131
FIG. 2. Sneezing scores (mean t SEMI derived from the product of severity and duration scores for each 2-wk period. Rhinorrhea and itchy nose scores paralleled these data.
FIG. 3. Eye symptom scores (mean + SEMI derived from the product of severity and duration scores for each 2-wk period.
group had significantly fewer days with symptoms that were annoying or interfered with daily activities (Fig. 4). In addition, the treated group experienced fewer days during which symptoms lasted two hours or more (p < 0.05). Nasal congestion did not follow the pattern of the other symptoms of allergic rhinitis. Congestion w&h was annoying or interfered with daily activities occurred on 40% of patient-days during treatment with hydroxyzine and 24% of patient-days during placebo therapy. These data, however, are heavily weighted by almost continuous nasal congestion among five subjects in the hydroxyzine group and two subjects in the placebo group. As a result of the intragroup variability in frequency of nasal congestion, the apparent difference in the frequency of nasal congestion was not significant (p > 0.1). During the peak pollen period, subjects in the
132
Schaaf,
Hendeles,
J. ALLERGY
and Weinberger
CLIN. IMMUNOL. FEBRUARY 1979
Hydroxyzine
Frequency of Symptom Scores 22 (annoying or disabling symptoms)
Frequency of Symptom Duration22 hours
FIG. 4. Mean frequency of symptoms that were judged by the subject to be annoying or disabling, i.e., sufficient to interfere with activities, and lasting a duration of at least 2 hr during the period from August 16 to August 31.
placebo group ingested 1.9 5 0.3 (mean + SEM) decongestant tablets per day while those in the hydroxyzine group took 1.1 -+ 0.2 (p = 0.08). Questionnaires at the end of the trial indicated that the hydroxyzine-treated subjects reported less intense symptoms compared with the previous year than subjects in the placebo group (p < 0.05).
DISCUSSION The present study demonstrates the ability of a potent antihistamine to suppress the symptoms of seasonal allergic rhinitis when administered on a continuous daily basis. Although subjects in the hydroxyzine group experienced some degree of symptoms, they generally did not have the marked exacerbation during the peak of the ragweed pollen season that was seen among the placebo group. Subjects taking hydroxyzine spent significantly more days during the peak of the ragweed season with little or no symptoms than subjects who took a placebo. Nasal obstruction was not similarly affected and may even have been somewhat less among the placebo subjects who took more pseudoephedrine or phenylpropanolamine. This is compatible with previous reports suggesting that psuedoephedrine relieves nasal congestion, 8, g thus providing a rationale for the traditional use of oral decongestants in conjunction with antihistamines. The low frequency of sustained side effects in the present study was compatible with previous reports that tolerance to the sedative effect of antihistamines often develops.10-12 The slow titration allowed the achievement of maximal dosage with only transient minor side effects.
The intriguing data of Cook and co-workers3 demonstrated that hydroxyzine has greater potency and duration of action than other antihistamines using a skin test for a bioassay of effect. The results of the current study support the need for further data comparing hydroxyzine with other antihistamines. This might allow evaluation of the validity of the skin test as a method for comparing the relative clinical efficacy of various antihistamines. The rather striking degree of efficacy and acceptance of the medication seen among these subjects also suggests that evaluation of other modes of therapy proposed for allergic rhinitis, e.g., injection therapy with allergenic extracts, intranasal cromolyn, or topical steroids, might include an antihistamine control group so that therapeutic perspective could be provided. We gratefully acknowledgethe Clinical ResearchCenter Nursing Staff, Miles Bextine of Burroughs Wellcome who provided Sudafedtablets, and JamesGillilland, D.O., and David Richards, B.A., of the Allergy Section, Immunology Division, Departmentof Internal Medicine, who performed the daily pollen counts. The statistical analysis was performed by Barbara Broffitt, M.S., and reviewed by P. A. Lachenbruch, Ph.D., Professorof Preventive Medicine and Environmental Health, University of Iowa. REFERENCES
I. AMA Department of Drugs:Antianxietyagents,in AMA Drug evaluations,ed3, Littleton,Mass.,1977,PublishingSciences Group,Inc., pp. 416-417. 2. Dundas E, ToogoodJH, WanklinJ: Inhibition of experimental skin whealby someataracticand antihistaminic drugs, J ALLERGY
3.
32:1, 1971.
CookTJ, MacQueen DM, Wittig HH, et al: Degree and duration of skin test suppression and side effectswith antihis-
VOLUME63 NUMBER2
4.
5.
6.
7.
Hydroxyzine
tarnines. A double-blind controlled study with five antihistamines, J ALLERGY CLIN IMMUNOL5S:71, 1973. Rhoades !RB, Leifer KN, Cohan R, et al: Suppression of histamine- induced pruritus by three antihistaminic drugs. J ALLERGY CLIN IMMUNOL55~180, 1975. Baraf CS: Treatment of pruritus in allergic dermatoses: An evaluation of the relative efficacy of cyproheptadine and hydroxyzine, Curr Ther Res 19:32, 1976. Durham 0C: The volumetric incidence of atmospheric allergens. IV. A proposed standard method of gravity sampling, counting, and volumetric interpretation of results, J AI.LERGY 1279, 1946. Winer BJ: Statistical principles of experimental design, New
York, I97 I. McGraw-Hill Book Co. 8. Benson MK: Maximum nasal inspiratory
flow rate: Its use in
9.
IO.
1I
12.
treatment
of hay fever
133
assessing the effect of pseudoephedrine in vasomotor rhinitis, Eur J Clin Pharmacol 3: 182, 197 I. Empey DW, Bye C, Hodder M, et al: A double-blind crossover trial of pseudoephedrine and triprolidine, alone and in combination, for the treatment of allergic rhinitis. Ann Allergy 3441, 1975. Ratner B: An evaluation of benadryl, pyribenzamine. and other so-called antihistaminic drugs in the treatment of allergy, J Pediatr 30~583, 1947. Weiss WI, Howard RM: Antihistamine drugs in hay fever. A comparative study with other therapeutic methods, J ALLERGY 19:271, 1948. Arbesman CE: The pharmacology, physiology, and clinical evaluation of the new antihistaminic drugs (pyribenzamine and benadryl). NY State J Med 47~1775. 1947.
