Kaoru Endo, Hozumi Sano, Takayuki Fukuzumi, Jun Adachi, and Toshiyuki Aoki
Department of Dermatology, Habikino Hospital of Osaka Prefecture, Osaka, Japan.
K. Endo, Habikino Hospital of Osaka Prefecture, Department of Dermatology, Habikino 3-7-1, Habikino city, Osaka Prefecture, Japan. Fax: +81 729-58-3291
J Dermatol ScienceA22A54-61A1999B
@@@@We previously reported a simple and easy-to-use device, Scratch Monitor for evaluation of nocturnal scratching. In the present study, the effect of an antihistamine (azelastine hydrochloride ) on atopic dermatitis was investigated using this device.
@In 40 patients with atopic dermatitis, nocturnal scratching was measured by the monitor, when taking the drug and while off medication.
@Neither the "sleeping time" nor the "pre-asleep time" differed significantly, but there was a significant difference in ''scratch rate'', ''minute scratch records", "hourly awake number" and "awake rate", which indicated that this drug alleviated nocturnal scratching and sleep disturbance. The difference was most prominent especially in patients with a serum IgE 1000 IU/ml as well as in patients with mild symptoms and normal serum lactate dehydrogenase levels.
@The drug was more effective for nocturnal scratching in the early period, when the "sleeping time" was divided into three equal parts (early, mid and late periods) and each period was compared.
Key words: computer analysis, antihistamine, IgE, LDH.
@@@@In the treatment of atopic dermatitis, control of itching, especially at night, is very important. In general, various antihistamines are administered to control pruritus in patients with atopic dermatitis.
@However, patients often complain that itching does not improve when such drugs are taken.
@Conversely, some patients find these drugs very effective for itching.
@Accordingly, an objective method of measuring itching seems to be necessary.
@To study the antipruritic effect of drugs is very difficult.
@@@@Most of the studies done so far to evaluate the effect of drugs on pruritus have employed the double-blind method and self-assessment by the subjects, sometimes using the visual analogue scale (VAS) or Pain-Track@(1)(2)(3)(4)(5)(6)@(7).
@@@@According to Cormia et al. (8), the various factors which may influence the accuracy of studies can be considered under the following headings: 1) selection of case material, 2) control of associated factors, 3) placebo control, 4) administration of drug and placebo, 5) interpretation of treatment response, 6) reproducibility of results, and 7) elimination of chance variations. However, it is not easy to control all these factors.
@For instance, regarding the selection of case material, we may encounter various difficulties.
A clinical study should include reasonably intelligent patients with pruritic disorders who are able to recognize pruritus and its amelioration (9).
@Unfortunately, some patients lack enough comprehension or intelligence to evaluate itching objectively.
@They feel less itchy in the daytime, especially when treated with topical steroid ointments, which make the effect of antihistamines less clear.
@Pruritus is also influenced by the mental state.
@In fact, a double-blind randomized trial is likely to compensate for such problems. However, if it was possible to evaluate the utility of these drugs objectively by some method, the double-blind technique would not be necessary.
@Various methods of measuring nocturnal scratching have been reported, but many of them were too complex to apply clinically (10)(11)(12)(13)(14).
@@@@@In our previous paper, we reported a new, simple and ease-to-use device, the Scratch Monitor (SM), which can evaluate scratching at night (15).
@We showed that this monitor was useful for the evaluation of nocturnal scratching and sleep disturbance.
@@In the present study, in order to estimate the effect of an antihistamine, we measured and analyzed the nocturnal scratching of patients with atopic dermatitis using the monitor.
MATERIAL AND METHODS
Subjects
@@@@@We chose 40 inpatients with atopic dermatitis (28 males and 12 females, mean age: 24.1 years, range: 13 to 42 years) according to the criteria of Hanifin and Rajka(16).
@They were admitted to our hospital from December 1993 to June 1995. Before the start of the study, they had been in hospital more than two weeks.
@Their symptoms were stable and they had established a relationship with the attending physician.
@They had no complications of urticaria, skin infections, or other skin diseases. We excluded patients with severe insomnia.
@We also excluded subjects who had taken medicines that could influence itch, such as oral corticosteroids within one month before the study or antihistamines and hypnotics within one week before.
@Twelve patients were using topical corticosteroids and the treatment was not changed during this study.
Clinical severity
@@@@@The clinical severity of eczema was determined as follows: 1) more than 50 % of body surface (according to the rule of nines often used as a simple method of body surface) affected by active eczema was defined as severe, 2) 10 to 50 % was moderate, and 3) less than 10 % or localized eczema was mild.
Laboratory data
@@@@@We examined serum IgE levels by radioimmunoassay kit of Pharmacia and serum lactate dehydrogenase (LDH) levels by P¨L UV method at the start of the study.
@The normal ranges of IgE and LDH at our hospital were < 300 U/ml and 150 - 450 U/l, respectively.
@The clinical severity at the study was also assessed using serum LDH, which is a useful marker for evaluating eczema level in atopic dermatitis (17).
Methods
@@@@@We selected azelastine hydrochloride (2 mg tablets) as the antihistamine. It was taken twice a day, after breakfast and about nine o'clock at night.
@We conducted an irregular procedure of cross-over method without a placebo. The 40 patients were randomized into two groups.
@Group A (n=20) underwent monitoring after taking the drug for 3 days and after discontinuing it for the next 3 days (Fig.1).
@On the other hand, group B (n=20) was monitored before taking this drug and after taking it for 3 days.
@@@@@The monitors were installed under cotton gloves on the back of each hand and taped in place by a nurse at 21:30 just before the patient went to bed.
@A monitor was attached to each hand.
@As soon as the patient woke up, the monitors were removed by a nurse.
@Only data from the dominant arm were analyzed according to the method reported previously (TableT) (15).
@The "scratch rate" and the "minute scratch records" were used as indexes of nocturnal scratching.
@On the other hand, the "sound sleep rate", the "hourly awake number" and the "awake rate" were used as indexes of sleep disturbance.
@The study protocol was approved by the ethics committee of Habikino hospital in September 1993.
@After the study was fully explained, informed consent was obtained from all subjects.
Statistical analysis
@@@@@Statistical analysis was performed with Stat ViewR software (Abacus Concepts, Inc., Berkeley, CA, 1996).
@Group comparisons were done by Student's t-test and intergroup comparisons by the paired t-test.
@All p values were two-sided, and differences were considered significant at p<0.05.
RESULTS
Patients
@@@@@The 40 patients consisted of 3 with mild disease, 8 moderate disease, and 29 with severe disease.
@As there were few mild and moderate patients, we divided the subjects into two groups according to serum LDH level.
@The mild group had normal LDH levels (< 450 U/l) and included 18 patients, while the severe group had high LDH levels (450 U/l) and included 22 patients.
@The geometric mean of serum IgE level was 2289 IU/ml (range: 5 to 185500).
@Fourteen patients had serum IgE levels of less than 1000 IU/ml and 26 had serum IgE levels of 1000 IU/ml or more.
@@@@@Table U shows the patients and the laboratory data for groups A and B. There was no significant difference between both groups.
| Table U. Laboratory data of the subjects |
|||||||
| Number of patients | IgE (IU/ml) | LDH (U/l) | |||||
| total | male | female | <1000 | 1000 | <450 | 450 | |
| Group A | |||||||
| total | 20 | 13 | 7 | 9 | 11 | 10 | 10 |
| without steroid oint. | 14 | 8 | 6 | 6 | 8 | 8 | 6 |
| with steroid oint. | 6 | 5 | 1 | 3 | 3 | 2 | 4 |
| Group B | |||||||
| total | 20 | 15 | 5 | 5 | 15 | 8 | 12 |
| without steroid oint. | 14 | 10 | 4 | 3 | 11 | 6 | 8 |
| with steroid oint. | 6 | 5 | 1 | 2 | 4 | 2 | 2 |
| Total | 40 | 28 | 12 | 14 | 26 | 18 | 22 |
| Table V. Analysis of nocturnal scratching between group A and group B |
||||
| Group A | Group B | |||
| Azelastine | @(|) | @({) | @(|) | @({) |
| Sleeping time (min.) | 474.8}85.4 | 504.2}82.7 | 458.8}78.4 | 472.4}77.5 |
| Pre-asleep time (min.) | 84.2}82.5 | 63.8}78.2 * | 93.4}82.3 | 82.7}72.7 |
| Scratch rate | 0.262}0.136 | 0.218}0.104 * | 0.267}0.135 | 0.221}0.122 * |
| Minute scratch records (No./min.) | 8.81}7.71 | 6.41}4.46 * | 7.86}5.48 | 6.19}5.07 * |
| Sound sleep rate | 0.528}0.201 | 0.571}0.201 | 0.509}0.207 | 0.572}0.214 |
| Hourly awake number (No./h.) | 1.45}1.15 | 1.21}0.88 | 1.32}0.93 | 0.99}0.63 * |
| Awake rate | 0.172}0.148 | 0.126}0.102 * | 0.163}0.136 | 0.124}0.119 * |
| (|) : taking no drug, ({) : taking azelastine hydrochloride, mean}SD, * : p<0.05 | ||||
Analysis of nocturnal scratching
@@@@@Considering the possibility of the difference between group A and B by the order of monitoring, we indicated the results of both groups in Table V.
@These results showed no significant difference between group A and group B.
@The change by taking azelastine hydrochloride was also similar.
@We combined both data and analyzed them.
@The Scratch Monitor showed that neither "sleeping time" nor "pre-asleep time" differed significantly when taking azelastine hydrochloride (Table W).
@However, there was a significant difference in "scratch rate", "minute scratch records", "hourly awake number" and "awake rate" (not the "sound sleep rate"), which indicated that this drug alleviated nocturnal scratching and sleep disturbance.
@However, the improvement was only 20`25 % on average.
| Table W. Analysis of nocturnal scratching by Scratch Monitor |
||
| Azelastine | (|) | ({) |
| Sleeping time (min.) | 466.8}81.3 | 488.3}80.7 |
| Pre-asleep time (min.) | 88.8}81.4 | 73.2}75.1 |
| Scratch rate | 0.265}0.134 | 0.220}0.113 * |
| Minute scratch records (No./min.) | 8.34}6.63 | 6.30}4.71 ** |
| Sound sleep rate | 0.518}0.201 | 0.571}0.205 |
| Hourly awake number (No./h.) | 1.38}1.03 | 1.10}0.76 * |
| Awake rate | 0.167}0.140 | 0.125}0.109 * |
| mean}SD, * : p<0.05, ** : p<0.01 | ||
| Table X. Analysis of nocturnal scratching when the subjects were @@@@@@@sorted according to serum IgE |
||||
| IgE <1000 | IgE 1000 | |||
| Azelastine | (|) | ({) | (|) | ({) |
| Number of patients | 14 | 14 | 26 | 26 |
| Sleeping time (min.) | 462.4}96.4 | 503.6}99.6 | 469.1}73.9 | 480.0}69.3 |
| Pre-asleep time (min.) | 96.9}104.3 | 77.9}87.4 | 84.5}68.1 | 70.7}69.4 |
| Scratch rate | 0.239}0.131 | 0.233}0.103 | 0.279}0.136 | 0.212}0.117 ** |
| Minute scratch records (No./min.) | 6.56}4.76 | 5.68}3.56 | 9.29}7.34 | 6.74}5.26 ** |
| Sound sleep rate | 0.533}0.194 | 0.498}0.212 | 0.510}0.208 | 0.620}0.234 ** |
| Hourly awake number (No./h.) | 1.16}0.88 | 1.12}0.73 | 1.51}1.11 | 1.09}0.79 ** |
| Awake rate | 0.135}0.126 | 0.107}0.078 | 0.185}0.147 | 0.134}0.124 * |
| mean}SD, * : p<0.05, ** : p<0.01 | ||||
@@@@@Table X shows the results of the analysis of nocturnal scratching when the subjects were classified according to serum IgE level.
@The subjects with serum IgE levels of less than 1000 IU/ml showed no significant differences in all parameters between monitoring with and without drug treatment.
@In contrast, there was a significant difference in the "scratch rate", "minute scratch records", "sound sleep rate", "hourly awake number" and "awake rate" in the patients with a serum IgE level of 1000 IU/ml or more.
@The results obtained when the patients were divided according to serum LDH are shown in Table Y.
@There was a significant difference in "sleeping time", "scratch rate", "minute scratch records", "sound sleep rate", "hourly awake number" and "awake rate" in the patients with normal serum LDH levels.
| Table Y. Analysis of nocturnal scratching when the patients were @@@@@@@sorted according to serum LDH |
||||
| Azelastine | @(|) | ({) | @(|) | ({) |
| Number of patients | 18 | 18 | 22 | 22 |
| Sleeping time (min.) | 471.1}82.4 | 510.6}86.4 * | 463.2}82.2 | 470.0}72.6 |
| Pre-asleep time (min.) | 95.6}85.4 | 71.2}79.0 | 83.2}79.7 | 74.8}73.7 |
| Scratch rate | 0.266}0.142 | 0.180}0.099 ** | 0.263}0.130 | 0.252}0.113 |
| Minute scratch records (No./min.) | 7.40}5.14 | 4.43}2.99 ** | 9.10}7.67 | 7.82}5.35 |
| Sound sleep rate | 0.513}0.230 | 0.620}0.234 * | 0.523}0.180 | 0.532}0.174 |
| Hourly awake number (No./h.) | 1.34}1.14 | 0.86}0.71 * | 1.42}0.96 | 1.30}0.76 |
| Awake rate | 0.157}0.134 | 0.072}0.055 ** | 0.175}0.148 | 0.168}0.124 |
| mean}SD, * : p<0.05, ** : p<0.01 | ||||
| Table Z. Analysis of nocturnal scratching between patients with @@@@@@@steroid ointment and patients without steroid ointment |
||||
| @With steroid ointment | @Without steroid ointment | |||
| Azelastine | (|) | ({) | (|) | ({) |
| Number of patients | 12 | 12 | 28 | 28 |
| Sleeping time (min.) | 443.5}89.0 | 487.7}85.6 | 476.8}77.3 | 485.0}80.2 |
| Pre-asleep time (min.) | 93.9}105.9 | 80.4}83.6 | 86.6}70.7 | 70.1}72.6 |
| Scratch rate | 0.283}0.134 | 0.234}0.102 | 0.257}0.135 | 0.218}0.117 * |
| Minute scratch records (No./min.) | 10.1}9.02 | 6.79}4.20 * | 7.58}5.32 | 6.09}4.98 * |
| Sound sleep rate | 0.492}0.176 | 0.548}0.210 | 0.530}0.213 | 0.581}0.206 |
| Hourly awake number (No./h.) | 1.51}1.02 | 1.24}0.80 | 1.33}1.05 | 1.04}0.75 * |
| Awake rate | 0.198}0.146 | 0.139}0.101 | 0.154}0.138 | 0.119}0.114 * |
| mean}SD, * : p<0.05 | ||||
@@@@@Thus, azelastine hydrochloride had a good effect on nocturnal scratching and sleep disturbance in patients with atopic dermatitis, especially those who had high serum IgE levels or mild symptoms with normal serum LDH levels.
@@@@@@Table Z shows the results of the analysis of nocturnal scratching between 12 patients treated with seroid ointment and 28 patients treated without steroid ointment.
@Every group included fewer patients, therefore there was not enough statistical difference, especially in patients treated with steroid ointment.
@However, there was a significant difference (p<0.05) in "minute scratch records" in patients with seroid ointment and in "scratch rate", "minute scratch records", "sound sleep rate", "hourly awake number" and "awake rate" in patients without steroid ointment.
@@@@@@When we divided the "sleeping time" into three equal parts (early, mid, and late periods) and investigated the "minute scratch records" in each period, azelastine hydrochloride was more effective for nocturnal scratching in the early period (Fig. 2).
DISCUSSION
@@@@@@The stimuli that can elicit or augment pruritus consist of physical and chemical ones. Chemical stimuli reported in humans include nonspecific irritants such as acids or alkalis, inflammatory mediators such as histamine, kallikrein, bradykinin or prostaglandins, histamine-releasing substances such as compound 48/80 or protamine, peptidases such as papain or trypsin, neuropeptides such as substance P (SP), vasoactive intestinal polypeptide (VIP), neurotensin or secretin, opioids, serotonin, chloroquine, and IL-2.(18).
@Many of these may act indirectly by the degranulation of mast cells. Histamine seems to be regarded as one of the most important mediators.
@However, histamine is unlikely to be the only mediator involved in the skin, because antihistamines have often been demonstrated to be ineffective against itch.
@The antipruritic effect of antihistamines, especially in atopic dermatitis, is still controversial.
@@@@@As a matter of fact, previous experiments have often demonstrated that non-sedative antihistamines have no effect on the pruritus in atopic dermatitis.
@Several researchers have utilized various devices to evaluate the effect of antihistamines objectively.
@@@@@Savin et al. (19) reported the effects of trimeprazine and trimipramine on nocturnal scratching in patients with atopic eczema using electroencephalogram, electro-oculography, the submental electromyogram, and muscle potentials from both forearms.
@They also demonstrated no significant suppression of scratching by a H1-receptor antagonist, as measured by limb movement meters (20).
@Krauze et al. (21) demonstrated that two non-sedative H1 antihistamines had no effect on itch measured objectively as nocturnal scratching, while two sedative antipruritic drugs had an antipruritic effect as shown by VAS and nocturnal limb movement assessment with limb meters.
@Wahlgren et al. (22) reported that neither the mean clinical itch intensity nor the mean percentage of time awake without pruritus differed significantly between patients treated with terfenadine, clemastine, and placebo using the Pain-Track or VAS.
@@@@@Johnson et al. (23) reported increased concentrations of histamine levels in atopic skin and suggested that this mediator might play a role in this condition.
@Elevated plasma histamine levels are usually found in patients with severe eczema and high serum IgE levels (24).
@However, despite the increase of cutaneous or plasma histamine levels, most patients with atopic dermatitis show no wheals or other manifestation than itch.
@Hagermark et al. (25) reported that repeated histamine injection at the same site cause the triple response to decrease, i.e. tachyphylaxis develops, which makes it less likely as a mediator of chronic itching lasting for hours.
@Thus, the effect of antihistamines may be a placebo effect or due to sedation which relieves anxiety and helps the patient to sleep (25).
@However, clinical itching does not last for hours in our experience.
@In fact, itching in atopic dermatitis shows episodic occurrence, namely after taking a bath, in warm surroundings, after sweating, inhaling dust, touching pets or eating some foods.
@The itch is stronger at night in most patients, but it does not continue all night long.
@A patient sleeping in a bed with many house dust mites only feels itchy and does not develop wheals.
@Some part of this itch is caused by an allergic reaction in atopic dermatitis.
@@@@@@We found that azelastine hydrochloride was more effective for patients with mild symptoms or high serum IgE levels.
@This result shows that chemical mediators such as histamine released by IgE cause itch, which may be controlled by an antihistamine.
@On the other hand, it may be difficult to prove the effect of antihistamines due to a relatively low level of restraint, which also indicates that histamine does not play a major role, especially in patients with severe symptoms.
@None the less, if appropriate patients are selected, there is a possibility that antihistamines may be effective against atopic dermatitis.
@@@@@@Whether the decrease of nocturnal scratching resulted from a decrease of itching or the reduction of insomnia is a matter for argument.
@According to Savin et al. (19), the reduced time spent in stage 1 of sleep accounted for a modest reduction in the overall amount of scratching during the night.
@Azelastine hydrochloride is a non-sedative H1-antihistamine.
@Some patients may feel sleepy after taking this drug, because most antihistamines cross the blood-brain barrier and cause sleepiness as a side effect.
@However, the sleeping effect of azelastine hydrochloride is relatively lower than that of other drugs.
@@@@@@Azelastine hydrochloride is a phthalazinone derivative that is widely used for the management of urticaria, asthma, and atopic allergy.
@In addition to a non-sedative H1-antihistamine effect, it has been reported that this drug inhibits allergic and non-allergic release of chemical mediators, such as histamine, serotonin, and platelet-activating factor (PAF) from mast cells, eosinophils, and other cells (26)(27)(28).
It has also been shown to act as a functional antagonist of PAF and leukotrienes (27).
@The mechanism of itch is complicated and we cannot deny that the effect of azelastine hydrochloride may be related to other mediators in addition to histamine.
In conclusion, azelastine hydrochloride controls itching in atopic dermatitis, but further studies are needed to verify its role more carefully.
ACKNOWLEDGEMENT
@@@@@@This study was supported in part by a research grant for atopic dermatitis from Ministry of Health and Welfare.
@We thank Eisai Co. Ltd. (Tokyo, Japan) and Mr. Fumitaka Asano (Gram Corporation, Urawa, Japan) for devising the Scratch Monitor and the analysis system.
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Fig. 1 Method of the administration of the drug and the installment of Scratch@Monitor (SM)
The forty patients were randomized into two groups. Group A underwent monitoring after taking the drug for 3 days and after discontinuing it for the next 3 days. On the other hand, group B was monitored before taking this drug and after taking it for 3 days.
Fig.2 Change of "minute scratch records" by taking azelastine in each sleeping period
When we divided the "sleeping time" into three equal parts (early, mid, and late periods) and investigated the "minute scratch records" in each period, azelastine hydrochloride was more effective for nocturnal scratching in early period
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