Canine pruritus: causes and therapies

Introduction – what is pruritus?

Pruritus or itching is defined as “an unpleasant sensation provoking a reflex, which in animals can take the form of scratching, biting or sucking, rubbing against surfaces or excessive licking” 1,2. Sometimes the signs of pruritus can be subtle and simply cause hair loss (self-inflicted alopecia, but it can also lead to skin lesions 3. This behavior is the animal’s way of protecting itself against external irritants (such as insects, chemical agents or poisonous plants 1,2,4), but it can negatively affect the pet’s quality of life and that of its owners if the condition is chronic 5.

Pruritus is one of the main complaints encountered in small animal dermatology 2. In human medicine, it is classified according to its type (acute, chronic, neuropathic, pruriceptive or psychogenic) or its clinical presentation (dermatological, systemic, neurological, psychogenic, mixed or other) 1,6,7. There is no clear categorization of pruritus for animals, although dermatological (Figure 1), psychogenic (Figure 2) and neuropathic (Figure 3) etiologies have been described 2,3. More commonly associated with a dermatological etiology, the exact sensation experienced by the animal cannot be precisely defined 3. Indeed, there are various sensations, which are better described in humans, such as burning, tingling, stinging or numbness 1, that could cause an animal to scratch or bite 3.

The signs of pruritus are the physiological result of a motor response caused by stimulation of the thalamus. Activation of the thalamus varies depending on the neurons that are stimulated, which may be either histaminergic or non-histaminergic 1,2,8. Although there are several mediators involved in pruritus, there are two predominant neurophysiological pathways routing the pruritus signal from the skin to the thalamus. The first is a histamine-stimulated pathway involving primary afferents that are unresponsive to mechanical stimuli, and the second is a histamine-independent pathway induced by the activation of cutaneous nociceptors 1,2,9. Pruriceptors will be present in the skin, but it is not clear if these receptors would truly be distinct from nociceptors 9,10.

When an irritating substance causes a sudden (acute) cutaneous reaction, the pruriceptors are activated, causing local cells to release a myriad of pruritogenic substances. The skin cells most effective in releasing these substances (histamine, cytokines, proteases and chemokines) are keratinocytes, mast cells and basophils. The key molecule in relation to acute pruritus is histamine, binding to H1 and H4 receptors on free histaminergic nerve endings 2,7,8. If the pruritus and inflammation resulting from a trigger is successful in suppressing the aggressor, then the pruritus should not persist more than a few days 7.

However, chronic pruritus, unlike acute pruritus, is usually induced by non-histaminergic chemical or mechanical stimuli, caused by a systemic condition or skin disease. It involves a series of complex events leading to a constant release of pruritogenic mediators 1,4. Chronic exposure to pruritogenic substances can potentially lead to peripheral or even central sensitization 1,8. This phenomenon of sensitization, defined as increased sensitivity to low-pruritic or non-pruritic stimuli 1, has not been well-described in relation to either canine or feline species. Nevertheless, peripheral or central sensitization could be significant following chronic exposure to inflammatory mediators, as it could modify the pruritus threshold, particularly with respect to allergies. At the peripheral level, this threshold may be altered by various mechanisms, such as an intraepidermal increase in pruriceptors or an increase in the number of mast cells 1,8,9,10,11. At the central level, sustained pruritus could modify the transmission of the pruritus signal along the spinal cord and the spinothalamic pathway and alter the functions and structure of the brain 8,10,11.

This brief review of the pathophysiology of pruritus may help understand why many animals do not respond to antihistamines in cases of chronic pruritus caused by, say, an allergy, or why the concurrent administration of several antipruritics is sometimes required.

Overall approach to pruritus 

When presented with a case of pruritus, the first step should be to compile a complete case history, which can include a standard dermatology-related questionnaire (Figure 4) and information concerning other systems (for example, if a dog is excessively licking one of its limbs, this could be an indication of pain secondary to (say) osteoarthritis, rather than pruritus). The use of a visual analogue scale¹ (Figure 5), whereby the owner assesses the degree of pruritus by marking on a line how severe they perceive the itch to be, can be very helpful for both the initial exam and for follow-ups. Background information, such as the age at which clinical signs first appeared and the breed, can sometimes help aid the diagnosis. For example, lateral phantom scratching around the cervical region in a Cavalier King Charles Spaniel is highly suggestive of primary secretory otitis media, which is often associated with syringomyelia 12. Similarly, flank sucking in a young Doberman Pinscher may suggest a behavioral disorder 3,13.

¹ https://www.cavd.ca/images/CAVD_ITCH_SCALE.pdf

The second step should be to identify any skin lesions and how they are distributed. For example, lumbosacral lesions could suggest flea allergy dermatitis, while pruritus around the ventral region and face might indicate atopic dermatitis (Figure 6) 14.

Once the examination is complete, the most common causes should be ruled out; these include skin infections (bacterial and fungal), ectoparasites, and skin hypersensitivities associated with food or environmental allergens 14,15. This requires a rigorous approach, following a series of logical steps, which makes it possible to confirm or rule out a skin infection or parasitic infestation before then addressing food and environmental allergies. If pustules, collarettes or crusted, eroded or ulcerated lesions are present, a simple cytological examination (Figure 7) of the lesions will be essential. This will make it possible to identify a bacterial (e.g., Staphylococcus) or fungal (e.g., Malassezia, Candida) infection or overgrowth that may either cause the pruritus or at least be a contributing factor 2,14,15. Where erythema is present, regardless of whether it is associated with papules, areas of alopecia, comedones, or crusty or scaly lesions, a search for ectoparasites using skin scrapings, a flea comb, a tape-test or an oil smear (for the ears) is recommended 2,14,15. Sometimes a search will be unsuccessful, and the only way to confirm or rule out this hypothetical diagnosis will be a trial course of treatment with a broad-spectrum antiparasitic 14.

Figure 7. Different sampling techniques for cytological examination ((a) swab; (b) impression smear; (c) adhesive tape). The chosen technique should take into consideration the type of lesion (crusts, ulcers, fistulas, etc.) in order to obtain maximum cytological findings. 
© Frédéric Sauvé

Other potentially useful diagnostic tests include a ultraviolet (Wood’s) lamp, a fungal culture test, or a polymerase chain reaction (PCR) test for dermatophytes, bacterial culture, and skin biopsies 2,15. However, skin biopsies are rarely useful for the etiological diagnosis of a pruritic skin condition. These should be reserved for atypical clinical cases or cases where the animal does not respond to antimicrobial or antiparasitic treatments and it is not possible to demonstrate skin hypersensitivity. Biopsies are recommended for skin conditions that are suspected to be caused by an autoimmune condition (such as pemphigus foliaceus) (Figure 8) or a tumor (such as cutaneous epitheliotropic lymphoma) 2,15.

Once any skin infections and infestations have cleared, any potential hypersensitivity can be investigated by way of an 8-week elimination diet. This should consist of a veterinary diet containing a source of hydrolyzed protein (ideally a novel one for the animal). Alternatively, a diet containing a new source of protein for the individual animal can be used, but bear in mind that many cross-reactions have been demonstrated between different sources of animal protein. An allergy test (whether intradermal or serological) should be the last step in the investigation process if pruritus persists despite an elimination diet. It should be noted that the diagnosis of atopic dermatitis relies on background information, the case history and a clinical picture compatible with hypersensitivity in the absence of infection, infestation or adverse food reactions. Allergy testing only serves to identify potential environmental allergens in order to then begin allergen immunotherapy 14,15.

Managing pruritus: general concepts

The main causes of pruritus can be grouped into four major categories: parasites, inflammatory skin conditions (infectious, irritants and autoimmune or immune-mediated conditions), allergies and neuropathies/neoplasms 2,15. These categories are not mutually exclusive, and it is possible for pruritus to be caused by two separate conditions simultaneously. The best way of controlling pruritus is to remove the causative agent from the environment. Identifying and removing an irritant (contact with a poisonous plant or chemical; a foreign body; recent use of shampoo, sunscreen, insecticide spray or powder; flea collar; etc.) may cure the condition. Similarly, antimicrobials and antiparasitics will be the best antipruritic treatments if there is a skin infection and/or ectoparasites are present. In the case of skin allergies, including flea bite allergies, atopic dermatitis and adverse food reactions, avoiding the allergen, if possible, will cure the condition 16. Aggressive flea management in the case of flea allergy dermatitis, and diet control in the case of adverse food reactions, will help control pruritus, but where environmental allergens are involved avoidance is rarely possible. Here, other long-term strategies should be implemented, including allergen immunotherapy, steroidal or non-steroidal antipruritics, and biological therapies 16. Potential causes of skin allergies include drug hypersensitivity and allergic contact dermatitis, and in these cases withdrawal of the drug or removal of the substance or object responsible should put an end to the pruritus. Finally, in suspected cases of psychogenic or neurogenic conditions, preferred treatments include behavioral therapies (such as tricyclic antidepressants or selective serotonin reuptake inhibitors 2,8), or treatments targeting peripheral or central neurological pathways (such as gabapentin or pregabalin) 2,8,9.

Antipruritic treatments

Acute pruritus

Antipruritic drugs can be useful in the short term to quickly ease the discomfort for the animal while an attempt is made to identify and control the causal agent. Here the most effective treatments will often be topical or systemic glucocorticoids (at an anti-inflammatory dose) due to their powerful anti-inflammatory effect and the fact that they are fast-acting. Since they act on various aspects of the inflammatory cascade and pruritus pathways, they are particularly effective in cases of pruritic inflammatory dermatosis if used diligently 2,16,17,18. However, glucocorticoids (both topical and systemic) have many side effects (Table 1), particularly when used over a prolonged period of time (Figure 9).

Table 1. Reported side effects following systemic and topical administration of glucocorticoids.

Chronic pruritus

There is no single solution that can effectively control all types of pruritus. The majority of studies published researching antipruritic treatments have focused on allergic dermatitis, and have looked at various therapeutic targets. Cytokines with the potential to induce pruritus in canine atopic dermatitis include interleukins (IL)-4, IL-13, IL-31 and IL-33, and thymic stromal lymphopoietin (TSLP) 1,7,16,19. The latter is linked to a type-2 immunological response (type 2 T helper lymphocytes) (whereas in cats, which have been studied less, histamine, IL-4 and IL-31 are potential candidates as mediators of pruritus 16,20).

In chronic pruritus caused by an allergy, while topical treatments such as glucocorticoids and tacrolimus 0.1% can be effective, their application is often limited by the animal’s fur, the size of the areas to be treated, and (although more often in cats) the grooming behavior 2,18,21. In cases of chronic and generalized pruritus, systemic treatments are preferred. The most commonly used systemic antipruritic treatments are glucocorticoids, oclacitinib, cyclosporine and lokivetmab (Table 2). 

Table 2. Systemic antipruritic treatments to manage canine pruritus, particularly for cutaneous hypersensitivity.

Glucocorticoids

The most commonly prescribed oral glucocorticoids remain prednisone and methylprednisolone. This class of drug is an affordable and effective way of addressing acute episodes of pruritus and controlling chronic dermatosis, as long as the dose and the frequency of administration are low 2,17,19. Long-acting injectables should be avoided due to their side effects.

Oclacitinib

Oclacitinib is a treatment of choice for both acute and chronic pruritus in dogs over 12 months old due to its fast onset (peak plasma is reached in just one hour). Its inhibitory action on the JAK-STAT pathway interferes with the activity of important pruritogenic cytokines, including IL-4, IL-13 and particularly IL-31 21.

Cyclosporine

Cyclosporine inhibits calcineurin in CD4+ T lymphocytes, which alters the release of potentially inflammatory or pruritogenic cytokines. Oral cyclosporine is indicated for controlling allergic dermatitis as it affects different aspects of the immune response (reducing the synthesis of IL-2 and IL-4, altering the number of mast cells and their histamine content, altering the survival and function of eosinophils, and reducing serum IL-31) 22,23. However, it needs to be administered for a minimum of 4 weeks in order to notice any decrease in pruritus in dogs, and, therefore, is more useful in treating chronic conditions 2,17. 

Lokivetmab

A biological therapy intended for dogs only, lokivetmab is a “caninized” monoclonal antibody that targets circulating IL-31. Highly effective in controlling pruritus, particularly in relation to atopic dermatitis, this treatment stems from a major discovery: the critical role that IL-31 plays as a mediator of pruritus in canine atopic dermatitis 21,24. It is very safe and there are no known interactions with other drugs or associated diseases. This treatment is indicated for acute or chronic pruritus (as it starts to act in less than 3 days) 21.

Antihistamines

For the reasons mentioned above, the beneficial effects of antihistamines are modest. At best, they can be used to treat cases of mild pruritus, as an occasional or regular treatment once an episode of acute pruritus is under control 2,17. Furthermore, it is often necessary to try various antihistamines in order to find the right one for an individual animal.

Others

Amitriptyline is a tricyclic antidepressant with antihistamine properties; tests show it to at least partially control pruritus in about 32% of dogs 25. Other treatments have also been studied (such as misoprostol, arofylline, pentoxifylline and azathioprine), but the results do not suggest that they are particularly effective in managing pruritus 2. 

Conclusion

The key to success is a systematic approach that allows the different causes of pruritus to be eliminated one by one. Maintaining good communication with the owner and using clinical tools such as diagrams, algorithms or information sheets will help ensure that the owner is engaged in the process and understands the steps to follow. Regular pruritus intensity examinations and assessments should be used in order to ensure the most appropriate diagnosis and treatment. Chronic pruritic dermatoses can seriously affect the psychological and physical health of both animals and their owners, and a better understanding of the pathogenesis of the animal’s condition and the mediators of pruritus will help ensure more effective use of the various treatments available. This way the owner can be reassured that their pet will eventually enjoy greater comfort and well-being.