Valerie A. Fadok, DVM, PhD, DACVD
Itch is one of the most frustrating clinical signs experienced by our pets, and a major reason for presentation for veterinary help. Chronic itch seriously reduces the quality of life for animals as well as for their owners. As veterinarians trying to manage itch, we too are frustrated and thus our quality of life is decreased. Our objectives will be to review briefly the new science of itch, discuss the known diseases that cause itch in companion animals, and review our approach to treating itch. For many years, itch was thought to be a variant of pain, mediated through the pain neural pathways. Recently scientists made a major breakthrough when they discovered a neural circuit just for itch.
Itch is now known to be transmitted to the brain through a dedicated subset of TRPV1 (transient receptor potential cation channel subfamily V member 1 aka capsaicin or vanilloid receptor 1) neurons that mediate itch, pain, heat, and cold. These nerves utilize several different neurotransmitters to transmit the signals. Scientists were able to generate mice that are resistant to itch by knocking out one of these neurotransmitters Nppb (natriuretic peptide B). The Nppb -/- mice demonstrated no response to any of the itch inducers including histamine and non-histaminic stimuli, but could still respond to other stimuli (pain, heat, cold, touch). A clear pathway of itch has now been described, in which itch triggers in the skin stimulate the nerves which send a signal to the cell bodies in the dorsal root ganglia. These cells release the Nppb which binds its receptor Npra and stimulates the interneuron in the dorsal horn of the spinal cord to release its transmitter GRP (gastrin releasing peptide) which binds its receptor GRPR to carry the signal to the brain. These findings are tremendously exciting, because they suggest we can isolate pruritus from pain and other sensations to target itch specifically. There are selective experimental antagonists for the Nppb receptor, and it will be interesting to see if any of these could be developed as safe and effective treatments for itch in future. Other investigators have data to support these findings and so itch research is booming! In fact, research shows that there are histamine responsive TRPV1 nerves and those that respond to other pruritogens, suggesting that specific subsets of itch nerves could be targeted. This approach could make itch control much more easy than trying to target the multiple different molecules that bind nerves within the skin.
In order to control itch we must make a short term and a long term plan. The short term plan is to control the itch quickly, and the approach will be determined by the individual patient's presentation (severity of itch, presence of ectoparasites, presence of infection, age, differential diagnoses for the underlying cause, physical trigger factors). Combining systemic and topical therapy will provide more relief than either alone.
For most itchy pets, we start with eliminating ectoparasites. For most dogs and cats, excellent flea control every 30 days throughout the year is important in flea-prone areas. In addition, we consider the possibility of sarcoptic mange whether we find mites on skin scrapings or not. Traditionally we have recommended ruling out scabies by treatment. Where available, ELISA testing can be helpful; while a positive result is not absolutely diagnostic, a negative result appears to rule the possibility out. Depending on geographic area we may need to consider other ectoparasites (mites, lice) that can cause itch in pets. The next consideration is whether infection (bacterial, yeast) is present. If so, then treatment to address those infections will be critical in the management of the itch. Once ectoparasites and infections are controlled, then we can consider allergic disease. For nonseasonal pruritus, most dermatologists advocate for a proper food trial prior to considering allergy testing for immunotherapy. Nonallergic causes of pruritus may need to be considered as well; these can include autoimmune diseases such as pemphigus foliaceus or neoplastic diseases such as epitheliotropic lymphoma. Whenever a disease is unusual biopsy for histopathology should be done.
Managing itch in the short term could and should combine topical therapy with appropriate systemic therapy. Bathing in tepid water is extremely helpful, and there are a number of therapeutic shampoos that can give substantial if temporary itch relief. These shampoos contain ingredients such as pramoxine, a topical anesthetic, and/or colloidal oatmeal with fatty acids in emollient soothing bases that moisturize the skin as they relieve itch. Many of these product lines offer cream rinses, sprays, and mousses as well. Residual leave-on products containing hydrocortisone can be very helpful too. If infection is present, then shampoos containing chlorhexidine and imidazoles can be used. These shampoos often have lipids to help with skin barrier repair as well. In some case, systemic antibiotics and antifungals can be used initially for a rapid response.
For atopic dermatitis, a chronic inflammatory disease, utilizing oral and topical fatty acids has been shown over time to reduce the inflammation and itch associated with this disease, and can have a steroid-sparing effect in some dogs. Likely these approaches are working because they help repair the skin barrier, and barrier repair is one of the pillars of multimodal therapy for dogs with atopic dermatitis.
Itch control in the short term usually involves the use of antihistamines and steroids. For most dogs with moderate to severe itch, antihistamines provide limited relief. In veterinary medicine, evidence for their use is poor as few quality trials have been published. No one H1 blocker has been shown superior to any other. Thus, these medications are used by trial and error. The older generation have significant sedating effects which may be exploited at night. Physicians using antihistamines to control itch often advocate for using 4 times the dose used for upper respiratory allergies. New antihistamines are less sedating, but there is no evidence that they have superior activity. Some of the antidepressant medications (amitriptyline, doxepin, mirtazapine) have been used as they have antihistaminic activity.
Oral or injectable glucocorticoids are often used for short term control of itch, and can be used long term, although their side effects make them less desirable. Glucocorticoids have a number of cellular and molecular targets which enable them to reduce itch and inflammation very effectively. Topical steroids can be helpful when itch is focal. Hydrocortisone aceponate (Cortavance, Virbac) or triamcinolone (Genesis, Virbac) are sprays that can be used initially twice daily then tapered to every other day. Topical creams such as betamethasone can also be used for 7–10 days, but should not be used for long periods of time as they can cause cutaneous atrophy and even systemic signs of hyperadrenocorticism.
For focal itch, topical tacrolimus (0.1%, Protopic, Astellas Pharma) can be helpful in some patients. It is a calcineurin inhibitor which is best used twice daily for the first week, then once daily or as needed. It does not work rapidly to reduce itch; it can cause irritation and itch in some patients.
Most of the time steroids are used systemically. Short term side effects can include polyuria, polydipsia, polyphagia, and behavior changes. When using prednisone or prednisolone, 0.5 mg/kg can be given every 12 h initially then tapered according to response. Methylprednisolone can be used to help reduce the polyuria and polydipsia associated with steroid use. Rarely, oral triamcinolone (0.2 mg/kg) or oral dexamethasone (0.1 mg/kg) can be used if animals have become refractory to prednisone. These steroids are potent and not recommended for long term use. Interestingly a recent publication showed that those dogs with suboptimal serum levels of vitamin D were less responsive to prednisolone. Some dermatologists supplement atopic dogs with oral vitamin D and believe it has benefit; these empirical findings require further testing. Often dermatologists will use an intravenous injection of dexamethasone sodium phosphate for quick relief which may last for up to 72 h in some patients.
For long term steroid use, we recommend utilizing the "safe steroid dose" calculation popularized by Dr. Candace Sousa. The body weight in kg is multiplied by 30 to give the annual dose of prednisone or prednisolone in mg. Thus a 10 kg dog would take 300 mg per year; if trimeprazine/prednisolone is used (Temaril-P, Zoetis, with 2 mg prednisolone per tablet), this is 150 tablets per year or about 1 tablet every other day. Many dogs can live on this dosing throughout the year with minimal long term steroid side effects (e.g., liver enzyme elevation, muscle wasting). Many clients object to behavioral side effects when they occur, and many dogs will still gain weight and have dry skin even with low dosing.
For long term management of atopic dermatitis in some dogs (failure to respond to immunotherapy, elderly), it is preferable to use cyclosporine (Atopica) as it has fewer side effects when used long term. It is a fungal metabolite that binds to a protein in the cell called cyclophilin; this complex inhibits the enzyme calcineurin which ultimately blocks the production of IL-2 and other upstream cytokines critical for lymphocyte proliferation and function. Calcineurin is a serine/threonine phosphatase that dephosphorylates the NFAT family of transcription factors which activate production of IL-2 and other cytokines. This medication revolutionized the treatment of atopic itch, as it allowed us to control atopic itch in dogs and cats in which glucocorticoids were no longer effective or in which glucocorticoids were contraindicated. It can be expensive for larger dogs and it does take 4–6 weeks to be fully effective, because of its mechanism of action. The drug is given initially at 5–7 mg/kg/day for 4–6 weeks, then decreased slowly to the frequency that controls the disease. Some animals may need daily therapy indefinitely. Short term side effects of nausea and vomiting are common, and can be prevented by using maropitant initially for 4 days (Cerenia, Zoetis) or by initially giving with food then transitioning to administration on an empty stomach. Long term side effects can include chronic loose stools, and the risk of opportunistic infections. Gingival hyperplasia, papillomas, lichenoid cutaneous reactions, hypertrichosis, and some unusual neurologic signs have also been seen. Because this dog is an immunomodulatory drug, it is best to avoid use in dogs and cats less than one year of age and in dogs with a previous history of malignant neoplasia.
Our newest and most innovative treatment for itch control in canine allergic skin disease is oclacitinib (APOQUEL, Zoetis). This drug, given orally, works very rapidly to stop itch and can therefore be used for short term and long term itch control. Oclacitinib is a Janus kinase inhibitor that is targeted to those cytokines utilizing JAK1 as their major signal transduction pathway. Its primary target for itch control in allergic disease is the T helper 2 cytokines IL-31. IL-31 is released as part of the skewed Type 2 lymphocyte response in allergic disease and it can bind directly to nerves to cause itch. In addition, the cytokine TSLP which is produced by keratinocytes, also binds directly to nerves to stimulate itch, and it too utilizes JAK1 as part of its signal transduction mechanism. Studies have shown that oclacitinib is effective in flea allergy, food allergy, atopic dermatitis, and contact allergy. It has provided excellent itch control in dogs with chronic atopic dermatitis who have failed immunotherapy and/or cyclosporine and in those dogs who can't tolerate glucocorticoids or who have become refractory to them. It is critical to remember than oclacitinib is meant for allergic itch. It will not control the itch associated with infection and thus it is important that infection and ectoparasite control be addressed if oclacitinib is to be used chronically. The most common side effects seen with oclacitinib (in less than 5% of dogs) were gastrointestinal. Complete information can be found on the product insert. Oclacitinib is given orally at 0.4 to 0.6 mg/kg every 12 h for up to 14 days, then once daily if used chronically. Some dogs will have a mild relapse of itch when the dose is dropped to once daily; I have found that giving the medication in the early evening works better. Other dogs have a more serious relapse and may need to take the medication twice daily for a longer period of time. Prolonged BID dosing is off-label, and these dogs should be monitored for changes in CBC. Some owners have found that splitting the once daily dose into a ½ dose twice daily works better for them.
In summary, effective management of itch requires a search for the underlying cause and an approach individualized to each patient, combining systemic and topical therapy to maximize efficacy and long term safety.
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