British Journal of Dermatology C1990) 122, 545-551.
The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis C-F.WAHLGREN, O.HAGERMARK AND R.BERGSTROM* Department of Dermatology, Karolinska sjukhuset, Stockholm and * Department of Statistics, Uppsata University, Uppsala, Sweden Accepted for publication 20 September 1989
SUMMARY
A double-blind, randomized, cross-over study was carried out on the efFcct of a sedative and a non-sedative antihistamine on 25 adults with atopic dermatitis. Intensity of itch was recorded using a computerized tnethod for self-assessment (Pain-Track') and using conventional visual analogue scales. The antipruritic effect of 3 days of treatment with the non-sedative H, antagonist terfenadine (60 mg b.i.d.) and with the sedative antihistamine, clemastine (2 mg b.i.d.) did not differ from that found with the placebo. Our findings support the view that histamine is not of importance in the pathogencsis of itch in atopic dermatitis.
Although itching is a major feature in atopic dermatitis (AD),' its pathogenesis remains unknown. The traditional H,-receptor antagonists are widely prescribed as antipruritics in various non-wealing dermatoses, including eczema. In an open trial of 23 patients with 'eczematous dermatosis' or psoriasis it was concluded that the antipruritic effect of antihistamines was due to a central, sedative-related effect and not to peripheral Hj antagonism.^ In a placebo-controlled cross-over study of 10 adults with chronic AD, a new potent non-sedative HI antagonist LN 2974 failed to reduce itching and scratching."^ However, an antipruritic effect was found after 10 days' treatment with either acrivastine or terfenadine, non-sedative antihistamines, when compared with placebo in a double-blind, but parallel, study in 44 adults with AD.* Thus, contradictory results have been reported concerning the antipruritic effect of non-sedative antihistamines. The aim of this study was to use one of the new non-sedative antihistamines to determine the role of histamine in the pathogenesis of pruritus in AD. The effects of the non-sedative Hj-receptor antagonist terfenadine were compared with those of the sedative antihistamine clemastine and placebo. Correspondence: Dr C-F.Wahlgren, Deparimeni of Dermatology, Karolinska sjukhusei, S-104 01 Stockholm, Sweden.
545
546
C-F. Wahlgren et at. METHODS
Subjects Twenty-five adults (nine males and i6 females; median age 24 years, age range 17-42 years) with persistent AD according to the criteria of Hanifin and Rajka' participated in the study, having given informed consent. At the initial clinical examination they were asked about their symptoms. All had chronic pruritus for at least the previous year, and had attended our department over the previous 6 months. Patients with AD limited to the face or hands were excluded. Other exclusion criteria were the taking of any drug, pregnancy or lactation, skin infections, and the presence of urticaria or other skin diseases. The study was performed by the same investigators in the period December-Marchj and was approved by our Ethics Committee. Experimental design The course of treatment was terfenadine 60 mg b.i.d., clemastine 2 mg b.i.d. and placebo each for 3 days and with intervening washout periods of 4 days and according to a randomized, double-blind, 'double-dummy', cross-over protocol. Thus, each patient received three courses in random order: (i) terfenadine active + clemastine placebo, (ii) terfenadine placebo + clemastine active and (iii) terfenadine placebo -I- clemastine placebo. The subjects were not allowed any other oral medication or alcohol, and were instructed not to apply any topical corticosteroid more potent than i",, hydrocortisonc in the week before and during the whole study. None of the patients had ultraviolet light therapy during the previous month. The use of emollients, however, was permitted. On days without oral treatment, a hydrocortisone cream was permitted and the amount used was determined. On the third day of each course of medication, tests for histamine-induced skin flare and itch reactions were performed. Experimentalflareand itch An experimental flare and itch was induced 5-75 h after the ingestion of the morning tablet. Histamine solution {o-oi ml) (100 ^ig/ml) and a similar amount of buffered saline as control were injected intradermally in duplicate on rhc outer aspect of the upper arm. The injection sites were gradually changed to avoid tachyphylaxis to histamine.^ The flare reaction 5 min after injection was outlined and traced onto clear plastic film and the area measured planimetrically (mm^). The intensity of the histamine-induced itch was recorded over a period of 15 min by the subjects, using an indicator sliding along a loo-nim visual analogue scale (VAS). One end of the scale represented 'no itch' and the other 'maximal itch'. The indicator was attached to a potentiometer connected to a plotter out of sight of the patient. The recordings allowed the calculation of itch duration (ID, s), peak valueof itch(Imax, o-ioonim)anda 'total itch index' (Tii = area under the curve, nim^) as described elsewhere." Clinical itch and sedation On the last day of each treatment period the patients rated the total intensity of itch and sedation for that time using ioo-mm VAS on sheets of paper. The results were collected before the experimental skin test and sealed immediately. During the 24 h before and in the period of 17 days of the study the itch intensity was monitored continuously using the Pain-Track* computerized method.^
Antipruritic effect of antihistamines in AD
547
Pain-Track'*' Pain-Track* (Autenta AB, Uppsala, Sweden) is a system for the self-recording of subjective symptoms.'''^ It consists of portable data-loggers for patients' use, a terminal unit and a software package for storage, analysis and presentation of data. The logger has a switch for indicating awake/asleep, a button for marking the patient's presence, and a knob for rating itch intensity on afixed-pointnon-verbal scale (FPNVS) from o (*no itch') to 6 ('maximal itch'). When the switch is in the 'awake' position a buzz every 60 min requests the subject to press the marker button and to rate the intensity of pruritus at that moment. The knob can also be turned at any time, and during the night the switch is turned to the 'sleep' position to cut out the hourly buzz. The setting of the controls is recorded by the computer at sampling intervals of 10 min. Compliance is calculated as the percentage of the patient's responses to the buzzer. All days with a compliance of less than 70" 0 were excluded. The results from days 2 to 3 were used, as a pilot study showed that a steady-state for the inhibition of histamine-induced skin flare had been reached during these days. The 'itch variables' analysed were the median and average itch intensity based on samples every 10 min and the percentage of time awake without itch. The 'itch profile' was based on samples every hour. Siaiistical analysis For the experimental skin test results the non-parametric Wilcoxon signed-rank test was used, as normal distribution of these data was considered doubtful. For clinical itch, sedation and hydrocortisone consumption, analysis of variance was used, as the assumptions of interval-scale basis and normal distribution were considered reasonable for these variables. Paired follow-up analyses were performed using the standard t-test as the number of comparisons was small. As a check on the assumptions, non-parametric tests were also performed. The test used was one based on w-rankings with Wilcoxon scores, applicable to unbalanced factorial designs, which in balanced situations reduces to the Friedman non-parametric test. A test was carried out on the 'itch profile' using an analysis of variance model with the factors treatment, time and subject. The pattern of itch within the day was further analysed using an orthogonal polynomial decomposition. RESULTS
Data from introductory patient interviews In 13/25 patients C52",,) the AD started before i year of age (range 6 weeks to 37 years). The median duration of eczema with itching was 20 years (range 2-39 years). The majority, 20/25 (80*^;,), also had a history of asthma/hay fever, but no one was on any treatment for these conditions. In 21/25 (84"i,), the most pruritic period was generally in the evenings or at night and only 3/25 (12",,) reported the worst itching in the morning. Itch disturbed the sleep of 22/25 (88",i) in the last 3 months. Eighty per cent (20/25) had tried one or more types of antihistamine, often clemastine, hydroxyzine and levomepromazine. Of these, 9/20 (45*^*0) had a moderate or good effect. Compliance All patients completed the study and none were excluded because of an acute exacerbation or an intercurrent skin infection. One patient could not attend for one of her experimental skin tests and in another case, a 7 days' Pain-Track recording was lost, because of a defective batter>'. In total, 443 days and nights were recorded with the Pain-Track system. The subjects' average compliance was 92-2±5-4*''o (range 82-99",,). Nine patients had one or more days with a
548
C-F.Wahlgren et al.
compliance less than 70%, meaning that a total of 17/443 days (38",,) had to be excluded. A compliance of 100";, was shown on 198/443 days (44 7'),,). All VAS forms were completed. Experimental flare and itch
Both terfenadine and clemastine reduced histamine-induced flare and itch significantly (P
The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis C-F.WAHLGREN, O.HAGERMARK AND R.BERGSTROM* Department of Dermatology, Karolinska sjukhuset, Stockholm and * Department of Statistics, Uppsata University, Uppsala, Sweden Accepted for publication 20 September 1989
SUMMARY
A double-blind, randomized, cross-over study was carried out on the efFcct of a sedative and a non-sedative antihistamine on 25 adults with atopic dermatitis. Intensity of itch was recorded using a computerized tnethod for self-assessment (Pain-Track') and using conventional visual analogue scales. The antipruritic effect of 3 days of treatment with the non-sedative H, antagonist terfenadine (60 mg b.i.d.) and with the sedative antihistamine, clemastine (2 mg b.i.d.) did not differ from that found with the placebo. Our findings support the view that histamine is not of importance in the pathogencsis of itch in atopic dermatitis.
Although itching is a major feature in atopic dermatitis (AD),' its pathogenesis remains unknown. The traditional H,-receptor antagonists are widely prescribed as antipruritics in various non-wealing dermatoses, including eczema. In an open trial of 23 patients with 'eczematous dermatosis' or psoriasis it was concluded that the antipruritic effect of antihistamines was due to a central, sedative-related effect and not to peripheral Hj antagonism.^ In a placebo-controlled cross-over study of 10 adults with chronic AD, a new potent non-sedative HI antagonist LN 2974 failed to reduce itching and scratching."^ However, an antipruritic effect was found after 10 days' treatment with either acrivastine or terfenadine, non-sedative antihistamines, when compared with placebo in a double-blind, but parallel, study in 44 adults with AD.* Thus, contradictory results have been reported concerning the antipruritic effect of non-sedative antihistamines. The aim of this study was to use one of the new non-sedative antihistamines to determine the role of histamine in the pathogenesis of pruritus in AD. The effects of the non-sedative Hj-receptor antagonist terfenadine were compared with those of the sedative antihistamine clemastine and placebo. Correspondence: Dr C-F.Wahlgren, Deparimeni of Dermatology, Karolinska sjukhusei, S-104 01 Stockholm, Sweden.
545
546
C-F. Wahlgren et at. METHODS
Subjects Twenty-five adults (nine males and i6 females; median age 24 years, age range 17-42 years) with persistent AD according to the criteria of Hanifin and Rajka' participated in the study, having given informed consent. At the initial clinical examination they were asked about their symptoms. All had chronic pruritus for at least the previous year, and had attended our department over the previous 6 months. Patients with AD limited to the face or hands were excluded. Other exclusion criteria were the taking of any drug, pregnancy or lactation, skin infections, and the presence of urticaria or other skin diseases. The study was performed by the same investigators in the period December-Marchj and was approved by our Ethics Committee. Experimental design The course of treatment was terfenadine 60 mg b.i.d., clemastine 2 mg b.i.d. and placebo each for 3 days and with intervening washout periods of 4 days and according to a randomized, double-blind, 'double-dummy', cross-over protocol. Thus, each patient received three courses in random order: (i) terfenadine active + clemastine placebo, (ii) terfenadine placebo + clemastine active and (iii) terfenadine placebo -I- clemastine placebo. The subjects were not allowed any other oral medication or alcohol, and were instructed not to apply any topical corticosteroid more potent than i",, hydrocortisonc in the week before and during the whole study. None of the patients had ultraviolet light therapy during the previous month. The use of emollients, however, was permitted. On days without oral treatment, a hydrocortisone cream was permitted and the amount used was determined. On the third day of each course of medication, tests for histamine-induced skin flare and itch reactions were performed. Experimentalflareand itch An experimental flare and itch was induced 5-75 h after the ingestion of the morning tablet. Histamine solution {o-oi ml) (100 ^ig/ml) and a similar amount of buffered saline as control were injected intradermally in duplicate on rhc outer aspect of the upper arm. The injection sites were gradually changed to avoid tachyphylaxis to histamine.^ The flare reaction 5 min after injection was outlined and traced onto clear plastic film and the area measured planimetrically (mm^). The intensity of the histamine-induced itch was recorded over a period of 15 min by the subjects, using an indicator sliding along a loo-nim visual analogue scale (VAS). One end of the scale represented 'no itch' and the other 'maximal itch'. The indicator was attached to a potentiometer connected to a plotter out of sight of the patient. The recordings allowed the calculation of itch duration (ID, s), peak valueof itch(Imax, o-ioonim)anda 'total itch index' (Tii = area under the curve, nim^) as described elsewhere." Clinical itch and sedation On the last day of each treatment period the patients rated the total intensity of itch and sedation for that time using ioo-mm VAS on sheets of paper. The results were collected before the experimental skin test and sealed immediately. During the 24 h before and in the period of 17 days of the study the itch intensity was monitored continuously using the Pain-Track* computerized method.^
Antipruritic effect of antihistamines in AD
547
Pain-Track'*' Pain-Track* (Autenta AB, Uppsala, Sweden) is a system for the self-recording of subjective symptoms.'''^ It consists of portable data-loggers for patients' use, a terminal unit and a software package for storage, analysis and presentation of data. The logger has a switch for indicating awake/asleep, a button for marking the patient's presence, and a knob for rating itch intensity on afixed-pointnon-verbal scale (FPNVS) from o (*no itch') to 6 ('maximal itch'). When the switch is in the 'awake' position a buzz every 60 min requests the subject to press the marker button and to rate the intensity of pruritus at that moment. The knob can also be turned at any time, and during the night the switch is turned to the 'sleep' position to cut out the hourly buzz. The setting of the controls is recorded by the computer at sampling intervals of 10 min. Compliance is calculated as the percentage of the patient's responses to the buzzer. All days with a compliance of less than 70" 0 were excluded. The results from days 2 to 3 were used, as a pilot study showed that a steady-state for the inhibition of histamine-induced skin flare had been reached during these days. The 'itch variables' analysed were the median and average itch intensity based on samples every 10 min and the percentage of time awake without itch. The 'itch profile' was based on samples every hour. Siaiistical analysis For the experimental skin test results the non-parametric Wilcoxon signed-rank test was used, as normal distribution of these data was considered doubtful. For clinical itch, sedation and hydrocortisone consumption, analysis of variance was used, as the assumptions of interval-scale basis and normal distribution were considered reasonable for these variables. Paired follow-up analyses were performed using the standard t-test as the number of comparisons was small. As a check on the assumptions, non-parametric tests were also performed. The test used was one based on w-rankings with Wilcoxon scores, applicable to unbalanced factorial designs, which in balanced situations reduces to the Friedman non-parametric test. A test was carried out on the 'itch profile' using an analysis of variance model with the factors treatment, time and subject. The pattern of itch within the day was further analysed using an orthogonal polynomial decomposition. RESULTS
Data from introductory patient interviews In 13/25 patients C52",,) the AD started before i year of age (range 6 weeks to 37 years). The median duration of eczema with itching was 20 years (range 2-39 years). The majority, 20/25 (80*^;,), also had a history of asthma/hay fever, but no one was on any treatment for these conditions. In 21/25 (84"i,), the most pruritic period was generally in the evenings or at night and only 3/25 (12",,) reported the worst itching in the morning. Itch disturbed the sleep of 22/25 (88",i) in the last 3 months. Eighty per cent (20/25) had tried one or more types of antihistamine, often clemastine, hydroxyzine and levomepromazine. Of these, 9/20 (45*^*0) had a moderate or good effect. Compliance All patients completed the study and none were excluded because of an acute exacerbation or an intercurrent skin infection. One patient could not attend for one of her experimental skin tests and in another case, a 7 days' Pain-Track recording was lost, because of a defective batter>'. In total, 443 days and nights were recorded with the Pain-Track system. The subjects' average compliance was 92-2±5-4*''o (range 82-99",,). Nine patients had one or more days with a
548
C-F.Wahlgren et al.
compliance less than 70%, meaning that a total of 17/443 days (38",,) had to be excluded. A compliance of 100";, was shown on 198/443 days (44 7'),,). All VAS forms were completed. Experimental flare and itch
Both terfenadine and clemastine reduced histamine-induced flare and itch significantly (P
