Treatment of canine atopic dermatitis with cetirizine, a second generation antihistamine: A single-blinded, placebo-controlled study

Abstract

Cetirizine and placebo were administered orally as individual agents to 23 dogs with atopic dermatitis. The pruritus was satisfactorily reduced in 4/22 (18%) dogs that completed the trial with cetirizine. Two dogs vomited after administration of the active drug.

Introduction

Atopic dermatitis is reported to be the second most common cause of hypersensitive (allergic) skin diseases in dogs (1). Canine atopic dermatitis (CAD) is estimated to affect 15% to 30% of the canine population (2). The exact pathogenesis of CAD is not yet completely established, but it is thought to involve immunoglobulin (Ig)E-mediated immediate and late-phase hypersensitivity reactions to environmental allergens (1). The importance of mast cell degranulation in hypersensitivity disease, such as CAD, is well established, particularly regarding the release of preformed mediators, such as histamine (1,3,4).

Canine atopic dermatitis is, in most cases, a life-long disease. As with many other chronic afflictions, the management of CAD is often frustrating for both owners and veterinarians. Standard therapeutic protocols include the use of glucocorticoids, antihistamines, omega-6/omega-3 fatty acid supplements, allergen-specific immunotherapy (“hyposensitization”), topical antipruritic agents, and combinations thereof (1). Expense can be considerable, and many dogs require long-term glucocorticoid therapy for adequate control of the associated pruritus. Some patients are never satisfactorily controlled with medical therapy alone.

The prime indication for antihistamine therapy in CAD is the treatment of pruritus mediated by histamine-activated H₁ receptors (1). Due to the risk and side effects of chronic glucocorticoid therapy, antihistamines are often used by veterinarians to avoid or reduce the necessary doses of glucocorticoids (1). The advent of a group of “second generation,” or nonsedating, antihistamines has stimulated much interest in the application of these new drugs for therapy of several different human disorders (5). Unfortunately, second generation antihistamines have not been successful in reducing CAD-associated pruritus to date (1,6).

Cetirizine hydrochloride, a metabolite of hydroxyzine, is a second generation antihistamine with demonstrated efficacy in the treatment of human disorders involving urticaria and pruritus (7,8). Studies have shown cetirizine to be effective in significantly reducing histamine-, bradykinin-, and allergen-induced wheal and flare reactions; decreasing monocyte and T-lymphocyte chemotaxis; reducing eosinophil responses; and decreasing intercellular adhesion molecule (ICAM)-1 expression on epithelial cells (9–17). The most significant clinical side effect reported in humans is somnolence (8).

Pharmacokinetic data regarding the use of cetirizine in dogs is limited (18,19). Cetirizine (1 mg/kg bodyweight [BW], PO) inhibited in vivo immediate hypersensitivity reactions to histamine and Ascaris antigen in dogs (18). Anecdotal reports (20–23) indicate that cetirizine is useful for the management of pruritus in CAD. To our knowledge, however, no clinical trial to evaluate cetirizine for the management of CAD has been published to date.

The purpose of this study was to evaluate the efficacy of cetirizine in controlling the pruritus in dogs affected with CAD.

Materials and methods

Twenty-three dogs examined at the Cornell University Hospital for Animals were randomly selected to participate in this study. All dogs had classical historical and clinical features of CAD (1) but otherwise were healthy. Various purebred dogs and mongrels were represented, including 11 males and 12 females (Table 1). Their ages ranged from 1.5 y to 9.5 y, and they weighed between 6.8 kg and 52.7 kg. The duration of clinical signs related to CAD ranged from 1 y to 7.5 y. Twenty-one dogs had nonseasonal pruritus, and 7 of these had seasonal exacerbations of pruritus (5 in summer and 2 in winter). Two animals had seasonal pruritus in the summer. All dogs had multiple positive reactions with intradermal testing (5 dogs), allergen-specific IgE serology (8 dogs), or both (10 dogs). Eighteen dogs with nonseasonal pruritus had completed 1 or more novel protein diet trials for at least 4 wk (ranges from 4 wk to 12 wk). Ten dogs had been fed a commercial novel protein diet, 2 dogs had been fed home-cooked novel protein diets, and 6 dogs had completed trials with both commercial and home-cooked diets. Two dogs with seasonal pruritus and 2 dogs with seasonal pruritus that progressed to nonseasonal pruritus had not undergone a dietary trial. One dog (case 18) with nonseasonal pruritus and a seasonal exacerbation in the summer failed to complete a home-cooked dietary trial when it was diagnosed with diabetes mellitus during the trial. No decrease in pruritus was seen in any of the 18 animals that completed dietary trials. Seventeen of the dogs received between 1 and 3 different antihistamines resulting in inadequate reduction of pruritus in all cases. Twelve dogs had received fatty acid supplements, either through direct supplementation or through their commercial diets, with no response. The pruritus of all dogs was known to respond completely to antiinflammatory doses of glucocorticoids (1).

Table 1.

Clinical data on 23 atopic dogs treated with cetirizine

Case	Breed	Age (y)	Sex	Weight (kg)	Duration of disease (y)
1	German shepherd	6	MC	40.9	3.5
2	Mixed	5	FS	26.4	4
3	Golden retriever	7.5	M	51	6.5
4	German shepherd	6.5	MC	46.4	5
5	Irish setter	9	FS	33	7
6a	Labrador retriever	1.5	MC	40	1
7	Labrador retriever	6	MC	34.6	5
8	German shorthaired pointer	7	FS	25.5	2
9a	Mixed	5	FS	17.7	1
10	Boxer	4	MC	36.4	3
11	West Highland white terrier	3	F	6.8	2.5
12	Labrador retriever	8.5	MC	33	1.5
13	Border collie	8	FS	26.4	1.5
14	Mixed	5.5	FS	25	2.5
15	Lhasa apso	4.5	FS	9.1	4
16	Golden retriever	3	M	43.2	2
17	English springer spaniel	7	FS	23.2	1.5
18	Miniature schnauzer	6	MC	9.6	3
19	German shepherd	3.5	FS	29.5	2.5
20a	Mixed	9.5	FS	24.8	7.5
21	Golden retriever	8	FS	25.5	7
22a	Bichon fries	6.5	MC	8.5	7
23	Labrador retriever	4	M	52.7	1.5

MC — castrated male; FS — spayed female; M — intact male; F — intact female

^aCases had reduced pruritus when receiving cetirizine (see results section)

Any animal with concurrent bacterial pyoderma, Malassezia dermatitis, or ectoparasite infestation was treated appropriately prior to beginning the trial (1). All dogs included in the trial had moderate to severe generalized pruritus. Eleven of the dogs did not receive glucocorticoids or other antihistamines during the trial. Twelve animals were maintained on low doses of glucocorticoids during the trial because of severe discomfort. In these animals, the glucocorticoid doses were reduced until clinically evident pruritus (scratching, chewing, licking) was present prior to beginning the trial. Glucocorticoid doses were then maintained at this level throughout the trial.

The dogs were treated with cetirizine hydrochloride (Zyrtec, 10 mg tablets; Pfizer Laboratories, New York City, New York, USA) during the first 2 wk of the trial, followed by a placebo (5 g tablet; B&L Sales, Worcester, Massachusetts, USA) for the second 2 wk. The dosage of cetirizine was 1 mg/kg BW, q24h, given PO with or without food. The placebo dosage was 1 tablet/10 kg BW, q24h, given PO. The owners were blinded to treatment, the researchers were not. The owners evaluated response to treatment, the researchers did not. The owners were asked to monitor and record any reduction of the dog’s pruritus after week 2 and again after week 4. Responses to the medication were scored by the owners as reduction of pruritus (scratching, licking, chewing): poor (0% to 25% reduction), fair (26% to 50%), good (51% to 75%), and excellent (76% to 100%). If either the cetirizine or the placebo received a score of fair, good, or excellent during the first 4 wk (stage 1), the owners were asked to readminister that product for an additional 30-day period (stage 2) to document a repeatable and sustained response.

Results

Twenty-two dogs completed the study. One dog (case 23) was removed due to poor owner compliance. Four dogs (cases 6, 9, 20, and 22) included in the study had a repeatable and sustained response to cetirizine throughout both stages of the trial. All 4 of these dogs had a nonseasonal pruritus and had undergone at least 1 dietary trial with no response. Two of the 4 dogs (cases 9 and 20) had “excellent” responses in both stages of the trial. One of these 2 dogs (case 20) received a low dose of glucocorticoid (prednisone [Prednisone Tablets, 20 mg tablets; Roxane Laboratories, Columbus, Ohio, USA] 0.1 mg/kg BW, PO, q48h) prior to and throughout stage 1 and during the first 2 wk of stage 2. Glucocorticoid therapy was stopped altogether for the last 2 wk of stage 2. A third dog (case 22) had a “fair” response throughout both stages of the trial. This animal was also maintained on a low dose of glucocorticoid (methylprednisolone [Methylprednisolone Tablets, 4 mg tablets; Barr Laboratories, Pomona, New York, USA] 0.5 mg/kg BW, PO, q48h) throughout the trial. The fourth dog (case 6) had a “fair” response during stage 1, and an “excellent” response during stage 2. All other dogs received no benefit from either cetirizine or the placebo.

Two dogs experienced side effects while receiving cetirizine. One dog (case 9) vomited several times 12 h to 24 h after receiving cetirizine during the first 2 d of stage 2. The drug was discontinued for 2 d until the vomiting resolved, at which point the trial was resumed and no further vomiting noticed. In this animal, a mild increase in salivation was reported during the few hours following administration of the drug for the rest of the 30-day period. No vomiting or increase in salivation was noticed in stage 1. Another dog (case 18) vomited shortly after the first dose of cetirizine, and the trial was discontinued. The vomiting continued and the animal was reevaluated at our hospital. A diagnosis of diabetes mellitus was made. The animal was treated appropriately, and the cetirizine trial was restarted a few months later with no further complications.

Discussion

The primary clinical symptom of CAD is pruritus. After the identification of pertinent allergens with the use of allergen-specific IgE serology or intradermal testing, many of these dogs benefit from allergen-specific immuno therapy (1). Even in these animals, however, medical intervention is often required to adequately control the pruritus (1). Glucocorticoids have traditionally been used in these cases. Antihistamines are commonly used, both as single agents, and as synergistic medications used to reduce required dosages of glucocorticoids.

While the role of histamine-regulated responses in CAD is well-established, antihistamines are not as effective as glucocorticoids in the management of the pruritus in atopic dogs (1). Results of previously published, placebo-controlled studies in which antihistamines were used for the management of pruritus in CAD are presented in Table 2. It can be seen that these antihistamines provided satisfactory control of pruritus in 0% to 30% of the dogs, and produced side effects in 0% to 25% of the dogs (24–28).

Table 2.

Results of published placebo-controlled studies on the efficacy of antihistamines for the control of pruritus in canine atopic dermatitis (CAD)

Drug	Satisfactory control (% of dogs)	Side effects (% of dogs)	Reference number
Astemizole	3.3	0	26
Brompheniramine	10	0	28
Clemastine	30	0	26
Cyproheptadine	0	25	25
Doxepin	0	13.3	26
Loratadine	0	0	27
Terfenadine	0	17	24
Trimeprazine	3.3	3.3	26
Tripelennamine	0	0	28

Cetirizine, a second general antihistamine, has given good results in the management of atopic dermatitis in humans (7,8,10,11,15,29,30), with the associated side effects being, in general, far less common or severe than those seen with the use of first generation (sedating) antihistamines. Although anecdotal reports suggest that cetirizine is useful for the management of CAD (20–23), the authors are not aware of any published studies that would provide details.

Anecdotal reports provide cetirizine protocols that vary considerably; from 2.5 to 10 mg/dog, q24h, to 1.1 mg/kg BW, q12h (20–23). The cetirizine protocol used in our study was adopted from a previous study in dogs (19). In that study, cetirizine was administered at 1 mg/kg BW, PO, q24h, and produced an 80% reduction of immediate hypersensitivity reactions to intradermally-injected histamine and Ascaris antigen. In our study, cetirizine provided satisfactory control of pruritus in 18% of the dogs evaluated, a success rate exceeded only by clemastine in previously controlled studies of antihistamines in CAD (see Table 2).

The responses to antihistamines in dogs with CAD are notoriously individualized and unpredictable (1,28). The efficacy of antihistamines is also unpredictable from the results of in vivo and in vitro laboratory studies. For instance, although terfenadine markedly inhibited allergen-induced wheal formation in the skin of Ascaris-hypersensitive dogs, the same or a higher dose of the drug was ineffective for the treatment of pruritus in atopic dogs (24). Similarly, although chlorpheniramine and clemastine failed to inhibit allergen-induced wheal formation in the skin of Ascaris-hypersensitive dogs, -both drugs are effective for the control of pruritus in a percentage of dogs with CAD (28). Loratadine markedly inhibited degranulation of dispersed canine mast cells (31), but it was ineffective for the management of pruritus in CAD (27). Although cetirizine did not block histamine release from dispersed canine mast cells (31), it provided satisfactory control of pruritus in 18% of the dogs with CAD in our study.

Cetirizine was well tolerated by most dogs in this trial, with only 2 dogs (9%) experiencing mild and transient side effects. This compares very favorably with results with other antihistamines (see Table 2). Neither clinical nor electrocardiographic abnormalities were seen in laboratory dogs given cetirizine (18,19).

Based on the results of this study, cetirizine is a useful and well-tolerated addition to the clinician’s armamentarium of antihistamines for use in CAD. The once daily treatment is particularly attractive to owners. CVJ