Suppression of histamine-induced pruritus by three anti~histaminicdrugs Robert B. Rhoades, and Heinz J. Wittig,
M.D., Kent N. Leifer, M.D., M.D. GainesviUe, PZXL
Robert
Cehan,
M.D.,
A double-bliruE crossover study of inhibition of histamtie-induced przlritlls by three commonly prescribed antihistamines was conduded on 6% normal subjects. Drugs used included dipheshy&amine HC1 (Benadryl), oyproheptadine (Periactin), hydroxyzine HCl (Atarax), and a lactose placebo in identical caps&s. lntradermal histamine dose-response thresholds of pruritus were obtained before and after pretreatment with the three antihistamines and placebo in each subject. Analysis of data revealed a fivefold increase above baseline of the histamine dose required to prWe pruritus following both qproheptadine and placebo. Thk compared to 0 tenfold increase following aiphenhyaramine and a 750-fold increase following hy&oEyzdne IlCl. The most common side effect was drowsiness, whkh occurred with all three drzlgs.
Despite the plethora of antihistaminic drugs, either as single medieations or in combination with other pharmaceutical agents, surprisingly few controlled studies of their effectiveness are to be found in clinical literature. Studies reporting the inhibitory action of antihistamine on skin testing are availablc.l-s The relative effectiveness of different antihistamines in terms of suppression of pruritus has been considered in several previous studies.‘-I8 h’one of these investigations has considered the commonly prescribed antipruritics in a double-blind study. This study was undertaken to determine comparative effectiveness of suppression of histamine-induced pruritus following oral administration of conventional doses of three commonly prescribed antipruritic drugs or a placebo in a doubleblind manner. STUDY
SUBJECTS
Twenty-eight healthy student volunteers, aged 18 to 35 years, were randomly selected. Individuals with a history of atopic diseasesor present systemic illness or dermatologic diseaseswere excluded. METHODS All 28 subjects were given intradermal injeetions of increasing doses o-f aqueous histamine phosphate in the volar aspect of the foresrm in order to establish their individual threshold
From the Department of Pediatrics, University of Florida College of Medieine. Supported in part by National Institutes of Health Grant No. T 01 AI00341. Received for publication March 11, 1974. Re rint requests to: Dr. Robert B. Rhoades, Department of Pediatrics, University e allege of Medicine, Gainesville, Fla. 32610. Vol.
55, No.
3, pp.
180-185
of Florida
VOLUME 55 NUMBER 3
Suppression
of pruritus
by drugs
181
TABLE 1. Itch suppression change
Drug No. 1 Hydroxyzine Hydroxyzine Hydroxyzine Hydroxyzine Diphenhydramine Diphenhydramine Cyproheptadine Cyproheptadine Diphenhydramine Placebo “Significance
was determined
Drug No. 2
1
3 z ; ; s > by the Wilcoxon
Significance*
Diphenhydramine Cyproheptadine Placebo Baseline Placebo Baseline Placebo Baseline Cyproheptadine Raseline Matched-Pairs
p p p p p p p p p p
< < < < < < < < >
0.05). Drowsiness was bothersome but was not found to be incapacitating in any of the cases studied. Only one subject reported more than one side effect (nausea and dizziness). Nausea was not included in the table since it occurred in only 1 patient. DISCUSSION
The experimental histamine intradermal challenge to induce prnritus has been used in more than 3,000 patients and has been found to be reliable and reproducible.18, BJAlthough individual thresholds vary, 75 per cent of individuals will have the same threshold levels when tested days to weeks apart.‘, 8sIQ*2u The work of Cormia and Dougherty9 pointed out the multiple difficulties in experimental design in testing efficacy of antipruritics. They listed the following factors influencing the accuracy of studies on these drugs: selection of case material; control of associated factors (other medications, environment, psychological status, unbiased staff) ; placebo control; administration of drug and placebo; interpretation of treatment response (itch thresholds may vary with time of day, temperature, emotional status) ; reproducibility of results; and elimination of chance variations. This study was designed to obviate these problcms: ( 1) it was of double-blind design; (2) test periods were on the same day of the week and at the same time of day; and (3) the magnitude of change in itch threshold was far greater than the magnitude of individual variation in itch threshold found by other investigators. In a review of the available literature we were unable to find previous studies utilizing the experimental histamine pruritus to evaluate efficacy of antipruritics in a double-blind, placebo-controlled manner. Cormia and KuykendalP utilized Sour antihistamines to alter the itch threshold induced by intradermal histamine. The drugs were not given double-blind. The antihistamines elevated the itch threshold in 30 to 60 per cent of the patients. Placebo elevated it in 17 per cent. Rajka, Korossy, and Gozonylo tested 35 drugs (including 14 antihistamines) for antipruritic effect in 662 patients with clinically pruritic dermatoses and with intradermal morphine-induced itching. The antihistamines were the most
184
Rhoades
et al.
J. ALLERGY CLIN. IMMJt’lQL. MARCH 1975
effective agents, acting favorably in 75 per cent of patients in reducing both spontaneous and morphine-induced itching. Rajkal’, l2 utilized intradermal trypsin to elicit itch threshold and duration in patients with pruritic dermatoses and then attempted suppression of the itching (i.e., elevation of threshold or shortened duration) by administering a single antihistamine and a placebo in a double-blind manner. The antihistamine elevated itch threshold and shortened duration in half of the patients. Joglekar, Balwani, and Mutalik18 tested the effect of ergotamine, trimeprazine, and placebo on the duration of itching induced by Mu.cun..a, prurielzs ointment (cowage) in 89 normal patients. This was double-blind. Both placebo and trimeprazine significantly (p < 0.01) shortened itch duration. Others’“-17 have tested single or multiple antihistamines, with or without placebo, on patients with spontaneously pruritic dermatoses in single-blind or poorly controlled situations with symptomatic evaluation as the measure of effect. Utilizing the intradermal histamine-induced itch threshold and its elevation following oral antihistamine administration, we concluded that hydroxyzine is the most effective antipruritic agent of the group we evaluated. It was significantly superior (p < 0.01) to both diphenhydramine and cyproheptadine in ant.ipruritic effect. Although, statistically, placebo was significantly superior compared with baseline (p < O.Ol), as were all other drugs, analysis of the effects on the largest single group of patients on each drug reveals the following: cyproheptadine and placebo increase the itch threshold concentration of histamine needed by only a factor of 5 (from 0.09 to 0.44 ,.g of histamine) ; test subjects receiving diphenhydramine required a ten fold increase of concentration (from 0.09 to 0.88 pg of histamine) whereas those on hydroxyzine required a 750-fold increase (from 0.09 to 68.8 pg) to elicit itching. RERMNCES 1 Schwartz, E,, and Wolf, J.: Histamine antagonista A comparative study of their effeat on histamine and allergic skin wheals, J. ALLEIUY 2Q: 32,194s. 2 Mosko, hi. N., and Marshall, R. B., Jr.: A study of the effect of various drugs on the wheeling reaction, 5. ALLERGY 21: 242, 1950. 3 Colliis, J, Dun&s, E., Edgar, II., and Toogood, J. H.: Graded response of experimental skin wheal, and its suppression by chlorpromaxine and antihistamine, J. ALLrmoY 3.X: 337, 1960. 4 Zippin, C., Oalant, 5. P., Bullock, J., and Crisp, J.: Antihistamine inhibition of the allergy skin test, J. ALLERGY CLIN. IM~JNOL. 47: 94, 1971. (Abst.) 5 Ualant, 8. P., Bullock, J., Wong, D., and Maibach, H. I.: Inhibitory effect of antiallergic drugs on allergen- and histamine-induced wheal and flare response, J. ALLESGY CLIN. IIdMUNOL. 49: 119,1972. (Abst.) 6 Cook, T. J., MaeQueen, D. M., Wit@, II. J., Thornby, J. I., Lantos, R. L., and Virtue, C. M.: Degree and duration of skin test suppres&on and side egecti with antihistamines. A double-blind controlled study with Ave ant%i&amines, J. ALLEEGIY&IN. Ihf&f~~o~. 6%: 71, 1973. 7 Cormia, F. E., and Kuykendall, V.: Experimental histamine pruritus. III. Influence of drugs on the itch threshold, Arch. Dermatol. Syphilol. 66: 206, 1954. 8 Shelley, W. B., and Melton, F. M.: Relative effect of local anesthetics on experimental his%Gnepruritua in man, J. Invest. Dermatol. 16: 299,19#. 9 Cormia, F. E., and Dougherty, J. W.: Clinical evaluation of antipruritic drugs, Con&eration of orally or parenterally administered age&s, Arch. Dermatol. 79: 172, f359.
VOLUME 55 NUMBER 3
Suppression
of pruritus
by drugs
185
Versuche mit Hautjucken 10 Rajka, V. E., Korossy, S., and Gozony, M.: Therapeutische beeinflussenden Arzneimitteln, Dermatologica 180: 113, 1965. 11 Rajka, G.: Itch duration in the involved skin of atopie dermatitis (prurigo besnier), Acta dermatol.-venereol. 47: 154, 1967. 12 Rajka, G.: Evaluation of drug intluence on the itch duration in the skin of patients with atopie dermatitis, various eczemas and psoriasis. I. Experiments in involved skin. Comparison with itch threshold technique, Arch. dermatol.-venereol. 48: 93, 1965. therapy for physiologic 13 Ayd, F. J., Jr., Bianco, E. A., and 2~110, L. M.: Trimeprazine and psychologic pruritis, 8. Med. J. 62: 1554, 1959. An adjuvant in the management of 14 Callaway, J. L., and Olansky, S.: Trimeprazine: itching dermatoses, N. C. Med. J. 18: 320, 1957. 15 Juhlin, L., and Skogh, M.: A double-blind investigation to test the antipruritic effect of some phenothiazine derivatives, Acta dermatol.-venereol. 69: 206, 1954. 16 London, I. D.: Trimeprazine, an oral antipruritic. A clinical and double-blind evaluation, J. Med. Assoc. Alabama 28: 342, 1959. 17 Smith, P., Jr., Cazort, A. G., Johnston, T. G., and Hefley, B. F.: Double-blind crossover study of antipruritic effect of chlorcyclizine hydrochloride, trimeprazine, and a placebo, South. Med. J. 55: 643, 1962. 18 Joglekar, G. V., Balwani, J. H., and Mutalik, 0. S.: Evaluation of antipruritic drugs in normal volunteers, CLIN. PHARMACOL. THER. 4: 197, 1963. 19 Cormia, F. E.: Experimental histamine pruritus. I. Influence of physical and psychological factors on threshold reactivity, J. Invest. Dermatol. 19: 21, 1952. 20 Cormia, F. E., and Kuykendall, V.: Experimental histamine pruritus. II. Nature; physical and environmental factors itiuencing development and severity, J. Invest. Dermatol. 20: 429, 1953.
Select the Foundation Question
ONE best cmswer for the of America Self-Assessment
following Program:
question
from
2. Diarrhea and vomiting after ingestion of specific caused by each of the following EXCEPT (A) (B) (C) (D) (E)
the
foods
Allergy
may
be
disaccharidase deficiency gluten-sensitive celiac disease alpha-l antitrypsin deficiency cystic fibrosis galactosemia
The correct answer this Journal.
and bibliographic
reference
will
be found
on page
194 of
M.D., Kent N. Leifer, M.D., M.D. GainesviUe, PZXL
Robert
Cehan,
M.D.,
A double-bliruE crossover study of inhibition of histamtie-induced przlritlls by three commonly prescribed antihistamines was conduded on 6% normal subjects. Drugs used included dipheshy&amine HC1 (Benadryl), oyproheptadine (Periactin), hydroxyzine HCl (Atarax), and a lactose placebo in identical caps&s. lntradermal histamine dose-response thresholds of pruritus were obtained before and after pretreatment with the three antihistamines and placebo in each subject. Analysis of data revealed a fivefold increase above baseline of the histamine dose required to prWe pruritus following both qproheptadine and placebo. Thk compared to 0 tenfold increase following aiphenhyaramine and a 750-fold increase following hy&oEyzdne IlCl. The most common side effect was drowsiness, whkh occurred with all three drzlgs.
Despite the plethora of antihistaminic drugs, either as single medieations or in combination with other pharmaceutical agents, surprisingly few controlled studies of their effectiveness are to be found in clinical literature. Studies reporting the inhibitory action of antihistamine on skin testing are availablc.l-s The relative effectiveness of different antihistamines in terms of suppression of pruritus has been considered in several previous studies.‘-I8 h’one of these investigations has considered the commonly prescribed antipruritics in a double-blind study. This study was undertaken to determine comparative effectiveness of suppression of histamine-induced pruritus following oral administration of conventional doses of three commonly prescribed antipruritic drugs or a placebo in a doubleblind manner. STUDY
SUBJECTS
Twenty-eight healthy student volunteers, aged 18 to 35 years, were randomly selected. Individuals with a history of atopic diseasesor present systemic illness or dermatologic diseaseswere excluded. METHODS All 28 subjects were given intradermal injeetions of increasing doses o-f aqueous histamine phosphate in the volar aspect of the foresrm in order to establish their individual threshold
From the Department of Pediatrics, University of Florida College of Medieine. Supported in part by National Institutes of Health Grant No. T 01 AI00341. Received for publication March 11, 1974. Re rint requests to: Dr. Robert B. Rhoades, Department of Pediatrics, University e allege of Medicine, Gainesville, Fla. 32610. Vol.
55, No.
3, pp.
180-185
of Florida
VOLUME 55 NUMBER 3
Suppression
of pruritus
by drugs
181
TABLE 1. Itch suppression change
Drug No. 1 Hydroxyzine Hydroxyzine Hydroxyzine Hydroxyzine Diphenhydramine Diphenhydramine Cyproheptadine Cyproheptadine Diphenhydramine Placebo “Significance
was determined
Drug No. 2
1
3 z ; ; s > by the Wilcoxon
Significance*
Diphenhydramine Cyproheptadine Placebo Baseline Placebo Baseline Placebo Baseline Cyproheptadine Raseline Matched-Pairs
p p p p p p p p p p
< < < < < < < < >
0.05). Drowsiness was bothersome but was not found to be incapacitating in any of the cases studied. Only one subject reported more than one side effect (nausea and dizziness). Nausea was not included in the table since it occurred in only 1 patient. DISCUSSION
The experimental histamine intradermal challenge to induce prnritus has been used in more than 3,000 patients and has been found to be reliable and reproducible.18, BJAlthough individual thresholds vary, 75 per cent of individuals will have the same threshold levels when tested days to weeks apart.‘, 8sIQ*2u The work of Cormia and Dougherty9 pointed out the multiple difficulties in experimental design in testing efficacy of antipruritics. They listed the following factors influencing the accuracy of studies on these drugs: selection of case material; control of associated factors (other medications, environment, psychological status, unbiased staff) ; placebo control; administration of drug and placebo; interpretation of treatment response (itch thresholds may vary with time of day, temperature, emotional status) ; reproducibility of results; and elimination of chance variations. This study was designed to obviate these problcms: ( 1) it was of double-blind design; (2) test periods were on the same day of the week and at the same time of day; and (3) the magnitude of change in itch threshold was far greater than the magnitude of individual variation in itch threshold found by other investigators. In a review of the available literature we were unable to find previous studies utilizing the experimental histamine pruritus to evaluate efficacy of antipruritics in a double-blind, placebo-controlled manner. Cormia and KuykendalP utilized Sour antihistamines to alter the itch threshold induced by intradermal histamine. The drugs were not given double-blind. The antihistamines elevated the itch threshold in 30 to 60 per cent of the patients. Placebo elevated it in 17 per cent. Rajka, Korossy, and Gozonylo tested 35 drugs (including 14 antihistamines) for antipruritic effect in 662 patients with clinically pruritic dermatoses and with intradermal morphine-induced itching. The antihistamines were the most
184
Rhoades
et al.
J. ALLERGY CLIN. IMMJt’lQL. MARCH 1975
effective agents, acting favorably in 75 per cent of patients in reducing both spontaneous and morphine-induced itching. Rajkal’, l2 utilized intradermal trypsin to elicit itch threshold and duration in patients with pruritic dermatoses and then attempted suppression of the itching (i.e., elevation of threshold or shortened duration) by administering a single antihistamine and a placebo in a double-blind manner. The antihistamine elevated itch threshold and shortened duration in half of the patients. Joglekar, Balwani, and Mutalik18 tested the effect of ergotamine, trimeprazine, and placebo on the duration of itching induced by Mu.cun..a, prurielzs ointment (cowage) in 89 normal patients. This was double-blind. Both placebo and trimeprazine significantly (p < 0.01) shortened itch duration. Others’“-17 have tested single or multiple antihistamines, with or without placebo, on patients with spontaneously pruritic dermatoses in single-blind or poorly controlled situations with symptomatic evaluation as the measure of effect. Utilizing the intradermal histamine-induced itch threshold and its elevation following oral antihistamine administration, we concluded that hydroxyzine is the most effective antipruritic agent of the group we evaluated. It was significantly superior (p < 0.01) to both diphenhydramine and cyproheptadine in ant.ipruritic effect. Although, statistically, placebo was significantly superior compared with baseline (p < O.Ol), as were all other drugs, analysis of the effects on the largest single group of patients on each drug reveals the following: cyproheptadine and placebo increase the itch threshold concentration of histamine needed by only a factor of 5 (from 0.09 to 0.44 ,.g of histamine) ; test subjects receiving diphenhydramine required a ten fold increase of concentration (from 0.09 to 0.88 pg of histamine) whereas those on hydroxyzine required a 750-fold increase (from 0.09 to 68.8 pg) to elicit itching. RERMNCES 1 Schwartz, E,, and Wolf, J.: Histamine antagonista A comparative study of their effeat on histamine and allergic skin wheals, J. ALLEIUY 2Q: 32,194s. 2 Mosko, hi. N., and Marshall, R. B., Jr.: A study of the effect of various drugs on the wheeling reaction, 5. ALLERGY 21: 242, 1950. 3 Colliis, J, Dun&s, E., Edgar, II., and Toogood, J. H.: Graded response of experimental skin wheal, and its suppression by chlorpromaxine and antihistamine, J. ALLrmoY 3.X: 337, 1960. 4 Zippin, C., Oalant, 5. P., Bullock, J., and Crisp, J.: Antihistamine inhibition of the allergy skin test, J. ALLERGY CLIN. IM~JNOL. 47: 94, 1971. (Abst.) 5 Ualant, 8. P., Bullock, J., Wong, D., and Maibach, H. I.: Inhibitory effect of antiallergic drugs on allergen- and histamine-induced wheal and flare response, J. ALLESGY CLIN. IIdMUNOL. 49: 119,1972. (Abst.) 6 Cook, T. J., MaeQueen, D. M., Wit@, II. J., Thornby, J. I., Lantos, R. L., and Virtue, C. M.: Degree and duration of skin test suppres&on and side egecti with antihistamines. A double-blind controlled study with Ave ant%i&amines, J. ALLEEGIY&IN. Ihf&f~~o~. 6%: 71, 1973. 7 Cormia, F. E., and Kuykendall, V.: Experimental histamine pruritus. III. Influence of drugs on the itch threshold, Arch. Dermatol. Syphilol. 66: 206, 1954. 8 Shelley, W. B., and Melton, F. M.: Relative effect of local anesthetics on experimental his%Gnepruritua in man, J. Invest. Dermatol. 16: 299,19#. 9 Cormia, F. E., and Dougherty, J. W.: Clinical evaluation of antipruritic drugs, Con&eration of orally or parenterally administered age&s, Arch. Dermatol. 79: 172, f359.
VOLUME 55 NUMBER 3
Suppression
of pruritus
by drugs
185
Versuche mit Hautjucken 10 Rajka, V. E., Korossy, S., and Gozony, M.: Therapeutische beeinflussenden Arzneimitteln, Dermatologica 180: 113, 1965. 11 Rajka, G.: Itch duration in the involved skin of atopie dermatitis (prurigo besnier), Acta dermatol.-venereol. 47: 154, 1967. 12 Rajka, G.: Evaluation of drug intluence on the itch duration in the skin of patients with atopie dermatitis, various eczemas and psoriasis. I. Experiments in involved skin. Comparison with itch threshold technique, Arch. dermatol.-venereol. 48: 93, 1965. therapy for physiologic 13 Ayd, F. J., Jr., Bianco, E. A., and 2~110, L. M.: Trimeprazine and psychologic pruritis, 8. Med. J. 62: 1554, 1959. An adjuvant in the management of 14 Callaway, J. L., and Olansky, S.: Trimeprazine: itching dermatoses, N. C. Med. J. 18: 320, 1957. 15 Juhlin, L., and Skogh, M.: A double-blind investigation to test the antipruritic effect of some phenothiazine derivatives, Acta dermatol.-venereol. 69: 206, 1954. 16 London, I. D.: Trimeprazine, an oral antipruritic. A clinical and double-blind evaluation, J. Med. Assoc. Alabama 28: 342, 1959. 17 Smith, P., Jr., Cazort, A. G., Johnston, T. G., and Hefley, B. F.: Double-blind crossover study of antipruritic effect of chlorcyclizine hydrochloride, trimeprazine, and a placebo, South. Med. J. 55: 643, 1962. 18 Joglekar, G. V., Balwani, J. H., and Mutalik, 0. S.: Evaluation of antipruritic drugs in normal volunteers, CLIN. PHARMACOL. THER. 4: 197, 1963. 19 Cormia, F. E.: Experimental histamine pruritus. I. Influence of physical and psychological factors on threshold reactivity, J. Invest. Dermatol. 19: 21, 1952. 20 Cormia, F. E., and Kuykendall, V.: Experimental histamine pruritus. II. Nature; physical and environmental factors itiuencing development and severity, J. Invest. Dermatol. 20: 429, 1953.
Select the Foundation Question
ONE best cmswer for the of America Self-Assessment
following Program:
question
from
2. Diarrhea and vomiting after ingestion of specific caused by each of the following EXCEPT (A) (B) (C) (D) (E)
the
foods
Allergy
may
be
disaccharidase deficiency gluten-sensitive celiac disease alpha-l antitrypsin deficiency cystic fibrosis galactosemia
The correct answer this Journal.
and bibliographic
reference
will
be found
on page
194 of
