Neuropathic pain, Part 2: Conditions that cause pain signals to go awry

When the normal protective mechanisms of nociception and pain signaling go awry, neuropathic pain results. In Part 1 of this series, I discussed what neuropathic pain is, its effects on the body—manifesting as either hyperalgesia or allodynia—and how to identify it in veterinary patients. Now let's look at specific syndromes and components associated with this form of pain in patients.

Mark-Epstein DVM, Dipl. ABVP, CVPP

Neuropathic pain syndromes

Human medicine has identified a number of quintessentially neuropathic pain syndromes. In animals, it's axiomatic that any trauma or surgery can result in the creation of neuropathic pain, with the possibility increasing proportionate to the degree of tissue and, especially, nerve damage. Examination of the literature supports neuropathic pain in the following conditions in animals:

• Post-amputation: While very common in people, only one case report exists in a cat.1 Yet most clinicians with experience in onychectomy can probably report the occasional patient (especially in years past when, regrettably, little thought was given to perioperative pain management) that continues to be lame many months after surgery. These cats can be suspected to be suffering from post-amputation neuropathic pain. Post-amputation neuropathic pain is an area ripe for investigation in veterinary medicine.

• Spinal cord lesions: Syringomyelia, an inherited defect of the central nervous system (CNS) common to Cavalier King Charles Spaniels, is described with classic neuropathic pain.2 It's well-established in people that the far more common CNS lesions, such as intervertebral disk disease, lumbosacral stenosis, fibrocartilaginous emboli, tumors and so on, elicit neuropathic pain, but the literature is currently lacking in animals. This makes it another area ripe for investigation.

• Feline orofacial pain syndrome: This syndrome is a trigeminal neuralgia-like condition that's been described in Burmese cats.3

• Complex regional pain syndrome: This syndrome has been described in a cow,4 two horses5 and a dog.6

• Feline interstitial cystitis: The neuronal changes of this condition7,8 closely mirror those found in women with interstitial cystitis, which is considered to be a chronic pelvic (neuropathic) pain syndrome and comorbid with other chronic pain conditions.9

• Equine laminitis: Microscopic neuropathic changes have been observed in addition to the gross anatomic pathologic disease.10

• Musculoskeletal disease: Three dogs were described in one case series.11 With regard to osteoarthritis—arguably the most common cause of chronic pain in the veterinary patient population—only recently has attention been given as to whether it can elicit neuropathic changes in people. And indeed, a recent study suggests that up to 25 percent of people with stifle osteoarthritis have a neuropathic component to their pain.12 Furthermore, duloxetine (Cymbalta—Lilly) recently expanded its labeled indications from well-recognized neuropathic diseases such as fibromyalgia, postherpetic neuralgia (shingles) and diabetic neuropathy to also include musculoskeletal pain such as that caused by osteoarthritis.

• Diabetic neuropathy: A motor neuropathy is well-described in cats with diabetes mellitus. However, human diabetics commonly suffer from a sensory neuropathy usually described as walking on barbed wire or broken glass that is considered classically neuropathic in nature. The literature supports peripheral microneuronal changes in cats that parallel those found in humans.13,14 Anecdotally, some cats with diabetes mellitus-associated motor neuropathy can also be observed to have sensitive feet upon handling and palpation.

Neuropathic components

Other conditions encountered in veterinary medicine that are likely to have neuropathic components, based either on established analogous conditions in humans known to be associated with neuropathic pain15 or on empirical observation and suspicion, include feline hyperesthesia syndrome, along with its probable cousin, feline self-mutilation syndrome; aortic thromboembolism; lymphocytic-plasmacytic gingivostomatitis in cats; possibly, chronic periodontal disease of any species; and acral lick granulomas.

In addition to pancreatitis, inguinal hernia repair, delayed union fractures, chronic otitis, keratitis and dermatitis, other conditions that could have neuropathic components include:

• Inflammatory bowel disease: In people, this disease is associated not only with classic gastrointestinal signs but usually also with pain of neuropathic origin, whereby mechanoreceptors modify into nociceptors.16

• Chemotherapy-evoked pain: Well-described in people,17 pain evoked by chemotherapy has also been observed in animal models.18

• Bone cancer: Pain associated with bone cancer can occur, especially with primary osteosarcoma, the disease and exquisite pain of which involves a unique set of attributes suited to produce neuropathic pain. Osteomyelitis and diskospondylitis may do the same, with the latter having the additional complication of possibly contributing to myelopathy.

• Intracranial and meningeal disease: Examples here include brain tumors and the various meningoencephalitides such as granulomatous meningoencephalitis, Pug meningoencephalitis and feline infectious peritonitis.

Summary

The question of whether animals experience neuropathic pain from these conditions or suffer from common human neuropathic pain phenomena such as postherpetic neuralgia (e.g., cats with chronic feline herpesvirus, horses with EHV-1 myelopathy), headache syndromes, fibromyalgia and so on remains unanswered at this time. But based on the emerging literature and the commonality of biologic systems where the literature does not yet exist, we should be attentive to the possibility of neuropathic pain in a much wider population of veterinary patients than previously considered.

This should not be taken as bad news, however. Once a condition or patient is suspected to have a neuropathic pain component, a world of therapeutic targets opens up to the clinician, and the prospect of creating vast improvement in patient comfort is very real.

Dr. Epstein is president of the International Veterinary Academy of Pain Management and medical director at the Total Bond Ainmal Hospital in Gastonia, N.C.

References

1. O'Hagan BJ. Neuropathic pain in a cat post-amputation. Aust Vet J 2006:84(3):83-86.

2. Rusbridge C, Jeffery ND. Pathophysiology and treatment of neuropathic pain associated with syringomyelia. Vet J 2008;175(2):164-172.

3. Rusbridge C, Heath S, Gunn-Moore DA, et al. Feline orofacial pain syndrome (FOPS): a retrospective study of 113 cases. J Feline Med Surg 2010;12(6):498-508.

4. Bergadano A, Moens Y, Schatzmann U. Continuous extradural analgesia in a cow with complex regional pain syndrome. Vet Anaesth Analg 2006;33(3):189-192.

5. Collins NM, Keen JA, Barakzai SC, et al. Suspected complex regional pain syndrome in 2 horses. J Vet Intern Med 2006;20(4):1014-1017.

6. LaBarre A, Coyne BE. Reflex sympathetic dystrophy in a dog. J Am Anim Hosp Assoc 1999;35(3):229-231.

7. Ikeda Y, Birder L, Buffington C, et al. Mucosal muscarinic receptors enhance bladder activity in cats with feline interstitial cystitis. J Urol 2009;181(3):1415-1422.

8. Buffington CA, Teng B, Somogyi GT. Norepinephrine content and adrenoceptor function in the bladder of cats with feline interstitial cystitis. J Urol 2002;167(4):1876-1880.

9. Nickel JC, Tripp DA, Pontari M, et al. Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J Urol 2010;184(4):1358-1363.

10. Jones E, Viñuela-Fernandez I, Eager RA, et al. Neuropathic changes in equine laminitis pain. Pain 2007;132(3):321-331.

11. Cashmore RG, Harcourt-Brown TR, Freeman PM, et al. Clinical diagnosis and treatment of suspected neuropathic pain in three dogs. Aust Vet J 2009;87(1):45-50.

12. Hochman JR, Gagliese L, Davis AM, et al. Neuropathic pain symptoms in a community knee OA cohort. Osteoarthritis Cartilage 2011;19(6):647-654.

13. Mizisin AP, Nelson RW, Sturges BK, et al. Comparable myelinated nerve pathology in feline and human diabetes mellitus. Acta Neuropathol 2007;113(4):431-442.

14. Estrella JS, Nelson RN, Sturges BK, et al. Endoneurial microvascular pathology in feline diabetic neuropathy. Microvasc Res 2008;75(3):403-410.

15. Mathews KA. Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Vet Clin North Am Small Anim Pract 2008;38(6):1365-1414.

16. Bielefeldt K, Davis B, Binion DG. Pain and inflammatory bowel disease. Inflamm Bowel Dis 2009;15(5):778-788.

17. Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Expert Opin Drug Saf 2004;3(6):535-546.

18. Authier N, Balayssac D, Marchand F, et al. Animal models of chemotherapy-evoked painful peripheral neuropathies. Neurotherapeutics 2009;6(4):620-629.