Gene H. Nesbitt, DVM, MS, DACVD
Canine pruritus has many different etiologies and pathophysiologic mechanisms.
Canine pruritus has many different etiologies and pathophysiologic mechanisms. The most common causes of pruritus include allergic, parasitic, bacterial and fungal (Malassezia). Almost every dermatosis can have a pruritic component due to either the primary or secondary problems. Animals have a pruritic threshold mediated by both allergic and nonallergic factors that initiate pruritus. The success of symptomatic control of pruritus is directly related to minimizing the various etiologic factors. Parasitic infestations must be eliminated and prevented. Bacterial or Malassezia infection are diagnosed and treated concurrently with the antipruritic medications.
The clinician frequently encounters the need to symptomatically control the pruritus while pursuing the specific diagnosis or as part of the short-term or long-term management of the pruritic patient. There are multiple options of both topical and systemic drugs, each with their own indications and limitations.
Shampoos and conditioners are used routinely to help provide temporary relief of pruritus. There efficacy may be the result of 1) the removal or inactivation of pruritic mediators such as bacteria, yeast or aeroallergens, 2) substituting heat or cold for itching, 3) local anesthetic effects, 4) raising the pruritic threshold by cooling or moisturizing the skin and 5) by application of specific biochemical agents such as glucocorticoids or L-Rhamnose.
The most widely recommended topical antipruritic agent is colloidal oatmeal. It has both an emollient (softens, lubricates, soothes) and hydroscopic (incorporated into the stratum corneum and attracts water) activities. There are several oatmeal formulations which have incorporated 1% hydrocortisone, diphenhydramine or praxomine in the shampoo or conditioner. L-Rhamnose (Allermyl™, Virbac) inhibits TNFa proinflammatory cytokine. Newer technology using microvesicles (Novasomes®, Vetoquinol) or spherolites (Virbac) incorporates water or specific agents to provide a residual effect. Phytosphingosine (Douxo®, Sogeval) has recently been introduced. This agent reduces the secretion of the cytokine IL-1a.
The application of a topical mixture of Liquid HEET® or IcyHot® and bitter apple in a ratio of 1:2 has been very helpful in breaking the itch/lick cycle seen in dogs with acral lick granulomas when used concurrently with antibiotics. The most likely mode of action is a substitution of heat sensation for itching. It may be effective in up to 6o% to 70% of dogs with acral lick lesions.
Topical glucocorticoids including hydrocortisone or triamcinolone are indicated to help control pruritus of local or regional lesions. The more potent topical glucocorticoids include amcinonide 0.1% (Cyclocort®, Lederle), fluocinonide 0.05% (Lidex®), Dermik), betamethasone cream and triamcinolone solution 0.05% (Genesis®.Virbac). Hydrocortisone 1-2% cream is a commonly used mild antipruritic. Efforts should always be made to use the agent with the least anti-inflammatory effect that will control the symptoms. Continued application often lasting more than 10-14 days may result in hypothalamic-pituitary-adrenal axis suppression as well as local effects in the skin such as atrophy and alopecia. These adverse reactions may be the result of percutaneous absorption or ingestion.
Tacrolimus (Protopic®) is a topical calcineurin inhibitor. It has potent antiinflammatory activity which affects both humoral and cellular immune responses. Tacrolimus 0.03% can be used on milder local pruritic lesions daily until clinical response and then taper frequency. The 0.1% concentration is used on localized lesions associated with autoimmune disease such as pemphigus foliaceus. In a few dogs, there may be an irritant reaction causing more pruritus. Tacrolimus is more expensive than most topical antipruritic agents.
Glucocorticoids have many effects involving inflammatory and immunologic activities that help control pruritus. These activities may affect leukocyte kinetics, phagocytic defenses, cell-mediated or humoral activity and production of inflammatory mediators.
Since adverse reactions can occur with any form of glucocorticoid with a wide variation of dose and frequency, the overall goal is to use the least potent glucocorticoid at the lowest dosage for the shortest duration possible to control pruritic symptoms. Short-acting prednisone, prednisolone or methylprednisolone are most commonly used. The antiinflammatory dose of the short-acting glucocorticoids is 1-2.2 mg/kg q24h. There are minimal differences in clinical response if a once daily dose or divided daily dose is administered. Adverse effects can be significantly diminished if alternate day dosage is used. A general rule is if the pruritus is 100% controlled with glucocorticoids, the dosage is excessive!
Oral triamcinolone acetonide (Vetalog®, Ft. Dodge)) is a good substitute if an animal becomes less responsive to prednisone. The loading dose is 0.05-0.1 mg/kg q24h. The maintenance dose is 0.0125-0.025 mg/kg q48-72 hours. Methylprednisone is sometimes used as a replacement for prednisone or prednisolone if needed. The anti-inflammatory effect is approximate 20% stronger than prednisone. Methylprednisolone has less mineralcorticod effects often resulting in less polyuria and polydipsia.
Long-acting glucocorticoids (dexamethasone, betamethasone, flumethasone) should be limited to those conditions when a stronger antiinflammatory effect of expected short duration is needed such as with insect mites or urticaria. They are also used when there is an inadequate response to the short-acting glucocorticoids. The oral antiinflammatory dose of dexamethasone is 0.1-0.3 mg/kg q24-48 h. The indications for residual glucocorticoids are cases of acute pruritus of expected short duration in dogs that are difficult to administer oral medication. Injections of methylprednisolone acetate (Depo-Medrol®, Pharmacia & Upjohn) at a dose of 4-20 mg (small dog, 40 mg (medium dog) or up to 120 mg (large dog) IM. The suggested doses for betamethasone valerate is 0.2-0.4 mg/kg and flumethasone (Flucort®, Ft. Dodge) 0.06-0.25 mg/kg IM or SC.
Approximately 15% to 30% of the pruritic dogs will benefit from the administration of antihistamines. Since the antihistamines are only expected to partially control pruritus unless the intensity is mild, concurrent antipruritic medications such as fatty acids (Omega 3 and 6) or glucocorticoids are used. Antihistamines have minimal side effects. The major effect of overdosing is excessive sedation. The general rule is to find a dose that produces results of not too "sleepy" or too "itchy". The optimal dosage will be variable among dogs depending on the degree of pruritus and the primary and secondary problems contributing to the pruritus. Multiple antihistamines may be tried to find the most effective for the individual dog. There a few reports of maximum response being observed without excessive sedation when two different antihistamines are given concurrently at their recommended doses. Table 1 lists the various antihistamines used for symptomatic treatment of pruritus and their recommended doses.
Table 1. Antihistamines used for canine pruritus
An estimated 25% to 40% of pruritic dogs will have some benefit from fatty acid supplementation. Fatty acids exert a regulating effect in the arachidonic acid cycle which produces both proinflammatory and antiinflammatory leukotriene and prostaglandins. Omega 3 (n-3) fatty acids are found in marine fish oils. The primary component is eicosapentaenoic acid (EPA). Although the optimal dosage for EPA has not been determined, limited studies have shown a beneficial effect with 180 mg/4.55 kg q24 h. Several commercial supplements have both Omega 3 and Omega 6 (n-6) fatty acids. There is no definitive studies eliciting the optimal n-6:n-3 ratio for antipruritic effect. Most commercial dog foods are supplemented with both Omega 3 and Omega 6 fatty acids. The additional fatty acid supplement has not been associated with adverse reactions. A lag time of 45 to 60 days has been reported before maximum clinical improvement is observed. Fatty acids are thought to be synergistic with some antihistamines. Dogs with a predisposition for pancreatis, diarrhea or bleeding disorders may experience more problems.
Cyclosporine is a calcineurin inhibiting drug. Blocking the calcineurin activity prevents the induction of genes encoding for cytokines (IL 2 and 4) and their receptors, thus affecting both humoral and cellular immune responses. Both drugs inhibit the activation of many cells including mast cells, eosinophils, lymphocytes, Langerhans' cells and keratinocytes.
At a dosage of 5 mg/kg there have been a high percentage of dogs with a 50-80% decrease in pruritus within 3 to 6 weeks. Studies have shown a comparable antipruritic response between prednisone and cyclosporine.
There are two formulations of cyclosporine. An older formulation in a vegetable oil base (Sandimmune®, Novartis) is not absorbed as readily, resulting in lower serum levels. The emulsified formulation (Atopica®, Neoral®, Novartis) results in more reliable clinical response although it is more expensive. Drugs that inhibit cytochrome P-450 microsomal enzyme activity potentiate the increased absorption and utilization of cyclosporine by reducing cyclosporine clearance. The concurrent use of ketoconazole at a dosage of 5-10 mg/kg will increase the utilization of cyclosporine by 50% or more. In larger dogs this allows for a lower total dosage and less expense. Other drugs that inhibit cytochrome P-450 include itraconazole, fluconazole, erythromycin and methylprednisolone. If any of these medications are used concurrently with cyclosporine, the cyclosporine dosage should be reduced by 50%. Caution should be used if rifampin is being administered concurrently with cyclosporine. Liver enzymes may be induced by rifampin which may lower the cyclosporine serum concentrations through faster breakdown.
Studies have shown higher serum levels of cyclosporine if it is administered on an empty stomach. However, there is often minimal difference in clinical response whether given with or without food. Monitoring of cyclosporine blood levels is generally not indicated. If on concurrent ketoconazole, monitoring of liver function is indicated. Studies with dogs on cyclosporine for 5 years or more have not shown any significant side effects. No abnormalities in the blood and organ profiles have been detected. It has been determined that measuring cyclosporine serum levels is not necessary for most dogs. It may have some indication in dogs that are not responding to current dosages of medication.
The most common adverse reactions to cyclosporine are vomiting, diarrhea and anorexia. If gastrointestinal problems occur with the initiation of therapy, it is recommended to discontinue treatment for 1-2 days and retry. If problems do occur when administered on an empty stomach, try giving with a meal. Administering a stomach-coating medication concurrently may also help with gastrointestinal side effects. Most dogs become tolerant of the medication within one week. Other side effects rarely reported included weight loss, nephrotoxicity, gingival hyperplasia, papillomatosis, hirsutism and involuntary shaking.
Tricyclic antidepressants such as amitriptyline and doxepin inhibit the reuptake of serotonin and norepinephrine as well as functioning as an H1 blocker. Fluoxetine (Prozac®) is a serotonin-reuptake inhibitor. Fluoxetine has shown variable efficacy in dogs with allergic dermatitis and acral lick granulomas. Polydipsia, polyphagia, lethargy and wheals are reported adverse reactions. Recommended dosage for fluoxetine is 1 mg/kg q24h with a maximum of 40 mg total dose/day.
Endorphins are believed to play a role in inducing or perpetuating some pruritic behaviors such as self-destructive behaviors that occur with acral lick granulomas. Naltrexone (Depade®, Mallinckrodt) at a dosage of 2.2mg/kg q24h is reported to be beneficial in 70% of treated dogs. Adverse reactions are uncommon with rare increased pruritus reported. Naltrexone is an expensive drug.
Dextromethorphan is an opoid antagonist that has been beneficial in the treatment of cribbing in horses. The specific effect of dextromethorphan is to block NMDA (N-methyl-D-aspartic acid). The activation of the NMDA receptor is believed to help maintain repetitive behavior. In a blinded, cross-over pilot study there was a significant difference of the time spent scratching, licking or biting during the 2 week treatment with dextromethorphan compared to the placebo. Interestingly, there was no significant decrease in the clinical scores (lesions) between the two groups, although the trend was for improvement during the treatment period. All dogs in the study were bathed weekly with a colloidal oatmeal shampoo.
Therapy for concurrent or secondary problems
Malassezia infections are a common finding associated with pruritic lesions. Excessive licking and biting results in excessive moisture. If this occurs in the feet, skin folds, axillae or groin, there is often an overgrowth of Malassezia that increases the inflammation and pruritus. Increased sebum production as the result of pruritus also creates a favorable environment for yeast proliferation. Topical treatment for localized Malassezia infections (feet, folds, axillae) involves initially cleaning and degreasing if necessary. A mild dish detergent (Dawn or Ivory) may be used. The use of topical wipes (Malacetic wipes®, Dermapet) or pledgets (Malaseb pledgets®, Ivax) may be used daily or as needed to minimize surface yeast populations. Shampoos containing antifungal agents such as ketoconazole (KetoChlor®, Virbac), chlortrimazole (Malaseb®, Ivax) or chlorhexiderm 4% may be used once or twice weekly.
If the Malassezia infection is multifocal, generalized or severe, systemic ketoconazole (10 mg/kg) for 20-30 days is indicated while the pruritic symptoms are being controlled and further diagnostic testing is pursued. There is often a significant decrease in the pruritic symptoms when the secondary Malassezia infection is controlled.
Appropriate antibiotics are indicated if there is a secondary bacterial infection. These should be continued for at least 7 days after all of the pyoderma lesions are resolved. Topical therapy with antibacterial shampoos should be used every 4-7 days.
The successful management of the pruritic dog requires a multifaceted approach including: 1) identification of the primary and secondary etiologies of the pruritus, 2) treatment and/or prevention of parasitic infestations, bacterial and fungal infections and other specific treatment of disease when possible and 3) symptomatic treatment based on clinical signs. The symptomatic treatment is often a combination of both non-steroidal therapy such as non-steroidal shampoos and rinses, antihistamines, fatty acids or cyclosporine. At times glucocorticoids, either topically or systemically are needed. No therapy will be effective for controlling pruritus if there is a lack of compliance or inability to administer the therapy.