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Doxepin incorporated into a dermatologic cream: an assessment of both doxepin antipruritic action and doxepin action as an inhibitor of papules,

in allergen and histamine-caused pruritus

Keskin, G; Inal, A; Ali Sari, R; S engl, A; Sahin, M; Turgay, M; Next Document Allergol Immunopathol (Madr). 1999;27:265-70.

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Keywords: Histamina. Prick test. Ppulas. Prurito. Doxepina.

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Doxepin incorporated into a dermatologic cream: an assessment of both doxepin antipruritic action and doxepin action as an inhibitor of papules, in allergen and histamine-caused pruritus L. Greiding* and P. Moreno** *Head of the Department of Specialists in Allergy and Immunology, School of Medicine, Universidad de Buenos Aires (Federal University of Buenos Aires) and Asociacin Argentina de Alergia e Inmunologa (Argentine Association on Allergy and Immunology). Co-Chief Executive Officer of the Instituto Argentino de Alergia e Inmunologa (Argentine Institute on Allergy and Immunology). **Medical Doctor at the Department of Specialists in Allergy and Immunology at Asociacin Argentina de Alergia e Inmunologa, and School of Medicine, Universidad de Buenos Aires. Correspondence: Leonardo Greiding Sarmiento 592, 4 A 1878 Quilmes Buenos Aires Argentina E-mail:

SUMMARY "Doxederm", a 5% doxepin hydrochloride ("doxepin") cream, has been used for assessments on patients'' response to histamine and allergens by means of a prick test. Parameters selected papule diameters, and pruritus intensity. Doxederm was applied: (a) immediately before tests, (b) 10 minutes after tests, and (c) 72 hours before tests. All test reactions have been compared to similar tests that had been performed with a placebo cream. Tests yielded the following findings: (1) a remarkable remission of pruritus when doxederm was applied according to above mentioned (a), (b), and (c) schedules; (2) no inhibition of papule size --should either antigens or histamine be administered, could be observed when doxederm was applied immediately before tests or 10 minutes after tests had been performed (p > 0.10 vs placebo); (3) an evident remission of papules when doxederm had been applied 72 hours before tests were performed. No difference, however, could be detected with patients forearms placebo cream had been applied whereon (difference among previously observed papules, and papules observed 72 after doxederm application: p > 0.005. Difference between doxederm and placebo: p > 0.10). Pursuant to the above mentioned observations, it can be suggested that doxederm evidences a highly siwft response on pruritus. Doxederm local effect, however, does not alter histaminic responses. Responses, however, are likely to be altered after a doxederm percutaneous absorption. Key words: Histamine. Prick test. Papule. Pruritus. Doxepina.

INTRODUCTION Treatment of pruritus in patients suffering from any allergic dermatitis (ie atopic dermatitis, prurigo, urticaria) is, in many a case, rather difficult to manage. Pruritus can be triggered by a direct histamine action coupled to other phenomena such as erythema or edema, with a consequent formation of papules. Histamine, however, is not the only mediator of either pruritus or other expressions of allergic reactions. Other mediators are also likely to intervene, such as prostaglandins, leukotrienes, interleukins, PAF, acetylcholine, protease, tachykinins, and opioids (1). Usage of first generation antihistaminics (i.e. chlorpheniramine, diphenhydramine, etc.) has been reduced due to secondary effects, especially somnolence, and antimuscarinic effects. Second generation antihistaminics (ie cetirizine, loratadine, ebastine, etc.) have a good control on histaminic action when it comes to papule formation, and erythema. Control, however, is not so satisfactory on pruritus --an important factor whenever atopic dermatitis is to be dealth with (2). Tricyclic components are endowed with a powerful antihistaminic action (antiH1, and antiH2). Among tricyclic components, doxepin hydrochloride ("doxepin") is the more active component.

Doxepin affinity for histaminic receptor is 775 times higher than diphenhydramine affinity, and 56 times higher than hydroxyzine affinity. Doxepin is also an active H2 blocker (3). Owing to doxepin antihistaminic effect, and a role played by histamine in allergic inflammatory processes, and in pruritus as well, topically applied doxepin has been used as a topic to assess patientsresponse to histamine-caused pruritus: a significative increase in histamine threshold could be observed (4). In a double blind study wherein Drake et al could verify doxepin cream effectiveness for the treatment of patients suffering from atopic dermatitis (AD) (3). The present study has been aimed at comparing doxepin cream-caused pruritus local inhibition together with an inhibition of histamine-induced papules, and papules caused by a 6-allergen battery --such allergen being a frequent cause for and IgE response among atopic patients. MATERIALS AND METHODS Thirteen patients suffering from respiratory allergy (seven patients with allergic rhinitis, and six patients with rhinitis/asthma) have been assessed. Antihistaminic medication was interrupted for all patients concerned for no less a period than: (a) 60 days before trial (astemizol), and (b) 21 days before trial (loratadine, and cetirizine). Patients were allowed to use nasal vasoconstrictors, and beta2-agonists. Patients''average age was 23-year-old (ages ranging between 15-year-old, and 45-year-old). Eight patients were female patients, and five patients were male patients. Percutaneous tests were conducted with six allergens especially conditioned for Greer Laboratory prick tests, and 1 mg/ml histamine. All elements were 0.5% glycerine-coated. Dermoprick technique was resorted to allergens, and doses there of were as follows: 1. A mixture of household dust, 67 PNU. 2. A mixture of mites, 67 AU. 3. Dermatophagoides pteronnyssinus, 67 AU. 4. Dermatophagoides farinae, 67 AU. 5. Cat''s hair, 67 AU. 6. Alternaria, 422 PNU. 7. Histamine, 6.7 l out of a 1/100 glycerin suspension. For pruritus measurement, patient''s subjective appreciation was considered when each type of test was performed. To assess papules, bigger papule diameters were directly traced on tracing paper from each patient''s skin. Thereafter, an average papule diameter was taken as a millimeter index of response to each antigen, and histamine as well.

Doxederm cream with 5% doxepin, and a placebo cream (vehicle) with no doxepin whatsoever were used. In all applied on the right forearm anterior face of patients, and the left forearm anterior face of patients. Both creams centimeter large strip. Research was divided into the following phases:

containing cream base elements only cases, 1 g of Doxederm cream was 1 g of placebo cream was applied on covered a 3-centimeter wide by 5-

-- Phase 0. Patients were administered tests with allergens, and histamine. Papule sizes were measured. Results were considered as baseline results. -- Phase 1. A doxederm cream strip was applied on each patient''s right forearm anterior face, and a placebo cream similar strip was applied on the left forearm anterior face. Ten minutes later, tests were administered on both forearms with allergens, and histamine. Pruritus subjectivity was assessed with regard to both reactions. Allergen-caused papules, and histamine-caused papules were measured on both forearms, 20 minutes after doxederm cream, and placebo cream had been applied. Pruritus measurement was totally subjective: each patient was requested his or her opinion about pruritus level on both forearms. -- Phase 2. First, tests were administered on both forearms. A 10-minute lapse of time was allowed to elapse. Thereafter, doxepine cream was applied on each patient''s right forearm anterior face, and placebo cream was applied on each patient''s left forearm anterior face. Twenty minutes later, papule sizes were measured, and each patient was requested his or her opinion about pruritus level as previously pointed out. -- Phase 3. Seventy-two hours before trial, patients were instructred so that they were to apply doxepine cream on their right forearm anterior face, and placebo cream on their left forearm anterior face according to a daily, self-administered 3-dose schedule. Each dose was a 1-gram dose. In total, nine grams of doxederm cream --that is, a total of 450-milligram of doxepin (150 mg qd). Papules obtained were compared as follows: (a) papules on each patient''s right forearm were compared to papules appearing on patient''s left forearm; and (b) papules were compared to papules obtained during baseline Phase 0. Statistical calculation Tests administered during Phases 0, 1, 2, and 3 were statistically compared as regards both doxepin, and placebo. Student''s t test was used for coupled samples developed by means of a Quattro Pro for Microsoft Windows 6.0 schedule. Ninety-five per cent (p < 0.005) was considered a significative level. RESULTS

Individual evaluation for each tested antigen, and for histamine, comparing Phases 0, 1, 2, and 3, only yielded a significative differences regarding Phase 3 with regard to baseline tests and tests administered on each forearm antigens, and doxepin cream had been applied thereon, and each forearm antigens, and placebo cream had been applied thereon. No significant differences were found between each patient''s both forearms --that is, among antigens applied on places either doxepin cream of placebo cream had been applied onto (see table I).

Table I. Average papule sizes. Results obtained after he different phases of the present study Phase X antigens X histamine 0.72 mm

0 1.37 mm 1 20 min before application doxederm 1.28 placebo 1.27 2 10 min after test doxederm 1.29 placebo 1.26 3 After a 72 h application before test doxederm 0.51 placebo 0.58 Difference between Phase 0 and Phase 3: p < 0.005.

0.66 0.67

0.66 0.69

0.19 0.23

Considering determinations for each patient involved, as well as each patient''s average, statistical studies do not evidence differences among papules between doxepin-treated and placebo-treated papules in Phase 0 baseline trial, and Phases 1, and 2 trials (p < 0.10). Phase 3 trial, however, evidences a significative difference (p < 0.005) between baseline trial, and trials involving either doxepin or placebo for both tests involved --ie antigen administered tests, and histamine-- administered test (see figures 1, 2 and 3).

Figure 1.--Locally administered doxepin and placebo behavior.

Figure 2.--Locally administered doxepin and placebo behavior.

Figure 3.--Locally administered doxepin and placebo behavior. DISCUSSION Doxepin hydrochloride is a component of dibenzoxepin tricyclics which, originally, is used as a therapeutic psychoneurologic antidepressant. Doxepin hydrochloride has a great affinity for H1, and H2 receptors due to doxepin hydrochloride strong blocking action on both receptors (5). Doxepin hydrochloride use as an antiH1, and antiH2 has been indicated for the treatment of chronic urticarias inasmuch as doxepin hydrochloride inhibits both erythema and edema besides being a strong pruritus inhibitor (6). To allow a more focused treatment with doxepin, doxepin hydrochloride has been elaborated as a 5% cream. It has been observed elsewhere (2) that a topic application can act significantly on pruritus, with a 68% pruritus threshold increase --if compared to a 25% pruritus threshold increase observed among patients receiving only placebo, a fact that led to the use of doxepin in several pathologies such as atopic dermatitis (3, 4), prurigos, and neurodermatitis. Percutaneous absorption of doxepin cream as assessed in a 19-patient sample, eight days after doxepin cream application yielded values ranging between 0, and 47 ng/ml in plasma, with a mean of 10,8 ng/ml. Optimal concentrations for an antidepressant action of doxepin are to be found between 30, and 150 ng/ml (7). As far as local action is concerned, lower doxepin doses are required than doses required for doxepin application on CNS. Pruritus physiopathology is still unsatisfactorily determined: even though pruritus "accompanies" several pathologies no correlation could be discovered between the role inflammation mediatos play, and pruritus itself. In this connection, the blame was put on histamine in the first place as the most significative mediator, bradykinin, P substance, endopeptidases, leukotrienes, and IL-2 (1). Cell-released histamine acts upon two well individualized receptors, namely H1, and H2 located on vessels, and cells. Upon the skin, both receptors have a vasodilatation effect on capillaries thus causing erythema and edema to appear, and, probably due to either direct or indirect stimulations, thus favoring an activation of pruritus nervous receptors. It is Greaves'' contention (1) that skin response to histamine varies according to how deep has been histamine application. If histamine is superficially applied on skin, pruritus appears. If histamine application is deeper, both pain and heat are feeled. H3 histamine receptors, however, appear not to have any action at skin level - H3 histamine receptors are likely to act as histamine release regulators. Among patients suffering from some types of allergic reaction --patients with food allergy for example, an easier histamine release by means of circulating basophiles coupled to the action of histamine release factors originating in monocytic cells could be observed. Among patients with

AD, a greater tendency to histamine release --especially during exacerbation (8, 9) could be observed on the one hand. On the other hand, skin of patients with AD contains a greater number of cutaneous mast cells. Either some degranulation or some evidence that endocell contents have been released can be observed in many a mast cell (3). Hence, an erythema response plus the appearance of papules triggered by percutaneously or intradermally applied allergens are due to an histamine release insofar as a correlation between the released histamine levels, and the intensity of response involved can be observed (9). Antihistaminics. Two wide groups of antihistaminics are known: (a) the so-called first generation antihistaminics with H1 effects. Their action on CNS, however, causes somnolence. Such antihistaminics being endowed with anticholinergic effects, mucosa dryness, costiveness, and urinary dysfunction are likely to occur among other secondary effects: (b) the so-called second generation antihistaminics have also a blocking action on H1 receptors --inasmuch, however, as second generation antihistaminics do not cross the hematoencephalic barrier, neither somnolence is caused nor anticholinergic effects are observed. Generally speaking, antihistaminics are not very useful for the treatment of atopic dermatitis even though antihistaminics have been successfully used for the treatment of urticarias, and pruritus. Doxepin cream has been tested with more than 800 patients --among such patients, a 600-- patient sample participated in two multicenter studies (4). On the basis of such multicenter studies, it could be said that doxepin cream significantly reduces pruritus in atopic dermatitis, chronic simplex lichen, and other forms of eczema. Being AD one of the most frequent, and precoccious manifestations of the atopic illness, finding a local treatment likely to significantly reducing the most painful symptom of such a pathology -namely pruritus seems to be most appropriate forasmuch as pruritus not only accompanies but also exacerbates other aspects of eczema such as erythema, xerosis, vesiculation or impetiginization secondary to scratching. A worsening of pruritus --and AD in general can be due to several factors: (a) environmental factors such as allergens, skin dampness or skin dryness; (b) irritating factors such as detergent and/or soap components; (c) cutaneous infections, and (d) emotional factors. Forasmuch as AD patients tend to suffer from xerosis, emollients are applied to mitigate xerosis --however, emollients per se are insufficient to reduce pruritus. Usage of topic corticoids --and, in some cases systemic corticoids so that inflammatory aspects of AD are inhibited is quite positive as far as clinical evolution, and histopathology are concerned. However, corticoids cause some important secondary effects on skin such as a tendency to induce telangiectasias, atrophy, striae, and hypopigmentation, besides corticoid secondary effects on the function of the hypophysissuprarenal axis. Doxederm cream application is likely to induce secondary effects, namely cutaneous effects, and systemic effects as follows: 1. Cutaneous effects. Local irritation, and contact dermatitis. On a 97-patient sample Taylor (10) found out that, after an extensive use of doxepin cream 17 patient subsample, 13 patients had positive tests for contact dermatitis.

2. Systemic effects caused by absorption --in this connection, it is recommended that doxepin cream should not be used on more than 10% of body surface, according to a qid application qd, for eight days''time. Application may cause somnolence, and dizziness. Special precautions must be observed in glaucoma cases, or urinary retention cases. CONCLUSIONS The present study suggests as follows: a) Doxepin cream has an immediate effect on pruritus: it can be clearly seen that, once a few minutes have elapsed after doxepin cream has been applied, pruritus is significantly reduced on a patient''s forearm doxederm cream has been applied thereon, a fact unlikely to be observed on a patient''s forearm placebo cream has been applied thereon. b) To inhibit papules --caused by either histamine or allergens, determined by means of the prick test, doxederm cream needs to be absorbed. Inhibition could be observed after a 72 hours''time application on either a patient''s forearm placebo cream had been applied thereon or a patient''s forearm doxederm cream had been applied thereon. Reference must be made to a study by Sameh Karaz et al (11) whose trial evidences some characteristics skin to the present study: indeed, Sameh Karaz et al have found out that doxepin cream is to be applied over a 3-day lapse of time if a negative response is to be obtained regarding cutaneous trials carried on either a patient''s forearm doxepin cream had been applied thereon or a patient''s forearm placebo cream had been applied thereon. Among a great majority of patients under study, a negative response could be found out up to five days after trial. Studies conducted by E. F. Simons (12, 13) suggest that orally administered antihistaminics inhibit the appearance of papules for different time spans, according to each antihistaminic pharmacokynetic properties. So, chlorpheniramine inhibits papules during 24 hours''time; hydroxyzine inhibits papules during 1 to 36 hours''time; both cetirizine and loratadine inhibit papules during 24 hours''time; and astemizol inhibit papules during an 8-week lapse of time approximately. Orally administered doxepin is likely to extend its inhibitory action during a 4 to 8 week lapse of time after administration has been interrupted: hence persistence of doxepin cream inhibitory action should be taken into account when it comes to a time/dose application relationship. It is the contention of the authors of the present study that doxepin cream is very useful to counteract swiftly and persistently pruritus, especially among patients suffering from either AD or urticarias, hence sparing patients the use of either local or systemic corticoids. Conversely, however, a more extensive application period (72 hours''time, approximately) should be allowed so that doxepin cream application acts satisfactorily on either papules or vesicules. In other words, a combined use is suggested, namely and oral-cutaneous doxepin administration at the beginning of treatment, followed by a local application once the 72-hour lapse of time is over.

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