Neuropathic pain in cats: Mechanisms and multimodal management.

PRACTICAL RELEVANCE: Chronic pain is a significant welfare concern in cats, and neuropathic pain, which arises from aberrant processing of sensory signals within the nervous system, is a subcategory of this type of pain. To comprehend this condition and how multimodal pharmacotherapy plays a central role in alleviating discomfort, it is crucial to delve into the anatomy of nociception and pain perception. In addition, there is an intricate interplay between emotional health and chronic pain in cats, and understanding and addressing the emotional factors that contribute to pain perception, and vice versa, is essential for comprehensive care.Clinical approach:Neuropathic pain is suspected if there is abnormal sensation in the area of the distribution of pain, together with a positive response to trial treatment with drugs effective for neuropathic pain. Ideally, this clinical suspicion would be supported by confirmation of a lesion at this neurolocalisation using diagnostic modalities such as MRI and neuroelectrophysiology. Alternatively, there may be a history of known trauma at that site. A variety of therapies, including analgesic, anti-inflammatory and adjuvant drugs, and neuromodulation (eg, TENS or acupuncture), can be employed to address different facets of pain pathways.Aim:This review article, aimed at primary care/ general practitioners, focuses on the identification and management of neuropathic pain in cats. Three case vignettes are included and a structured treatment algorithm is presented to guide veterinarians in tailoring interventions.Evidence base:The review draws on current literature, where available, along with the author's extensive experience and research.

Interleukin-31 in serum and cerebrospinal fluid of dogs with syringomyelia.

BACKGROUND: Syringomyelia is a spinal cord cavity containing cerebrospinal fluid (CSF)-like fluid. If syringomyelia asymmetrically involves the dorsal horn grey matter of the spinal cord, affected dogs show increased signs of dysesthesia and neuropathic pain, like increased itching behaviour. In the dorsal horn, amongst others, receptors for Interleukin-31 (IL-31) can be found. IL-31 is one of the main cytokines involved in the pathogenesis of pruritus in atopic dermatitis in different species. This study investigates suspected elevated levels of IL-31 in serum and CSF of dogs showing signs of pain or increased itching behaviour related to syringomyelia. The IL-31 were measured in archived samples (52 serum and 35 CSF samples) of dogs with syringomyelia (n = 48), atopic dermatitis (n = 3) and of healthy control dogs (n = 11) using a competitive canine IL-31 ELISA. RESULTS: Mean serum IL-31 level in dogs with syringomyelia was 150.1 pg/ml (n = 39), in dogs with atopic dermatitis 228.3 pg/ml (n = 3) and in healthy dogs 80.7 pg/ml (n = 10). Mean CSF IL-31 value was 146.3 pg/ml (n = 27) in dogs with syringomyelia and 186.2 pg/ml (n = 8) in healthy dogs. Individual patients with syringomyelia (especially dogs with otitis media or otitis media and interna or intervertebral disc herniation) showed high IL-31 levels in serum and CSF samples, but the difference was not statistically significant. IL-31 serum and CSF levels did not differ significantly in dogs with syringomyelia with or without itching behaviour and with or without signs of pain. CONCLUSION: Based on this study, increased IL-31 levels seem not to be correlated with itching behaviour or signs of pain in dogs with syringomyelia, but might be caused by other underlying diseases.

The pain-relieving effects of lactoferrin on oxaliplatin-induced neuropathic pain.

Oxaliplatin (OXL) therapy often causes side effects including chronic peripheral neuropathy. We investigated the pain-relieving effects of recombinant human lactoferrin (rhLf) as well as a long-acting IgG-Fc fused rhLf (rhLf-Fc) on OXL-induced neuropathic pain. We used the hLf in this study, because the homology between mouse Lf and hLf is higher than that of bovine Lf. In addition, rhLf-Fc is expected to enhance the analgesic effect due to the life extension effect in the body. We administered OXL (2 mg/kg, i.v.) to mice twice weekly for 4 weeks. Phosphate buffered saline (PBS), rhLf (100 mg/kg, i.p.) or rhLf-Fc (100 mg/kg, i.p.) was administered once a week from day 15 to 32. We also assessed the continuous infusion of same drugs (10 mg/kg/day) into the external jugular vein by using an osmotic pump. Both of rhLf and rhLf-Fc significantly reduced the hypersensitivity to mechanical stimulation when they were administered intraperitoneally. The continuous infusion of rhLf resulted in a more pronounced effect. Histopathological analysis of sciatic nerve showed that both rhLf and rhLf-Fc tended to reduce nerve fiber damage, but no significant difference was observed in nerve fiber cross-sectional area. Therefore, it was suggested that rhLf or rhLf-Fc injection could be an option for controlling neuropathic pain, which are side effects of OXL.

Long-term postoperative pain evaluation in dogs with thoracolumbar intervertebral disk herniation after hemilaminectomy.

BACKGROUND: Chronic neuropathic pain is a common complication in people with spinal cord injury (SCI) but has not been investigated in dogs. OBJECTIVE: To determine the reliability of measuring spinal mechanical sensory thresholds (MSTs) in dogs and to compare MSTs of healthy dogs and dogs with SCI caused by acute thoracolumbar intervertebral disk extrusion after hemilaminectomy over a 1-year period. STUDY DESIGN: Prospective study. ANIMALS: Thirty-two healthy and 40 SCI dogs. METHODS: Dogs were divided into group 1 (healthy Dachshunds), group 2 (healthy dogs including several breeds), and SCI group. The MSTs were measured using algometry at an incision (thoracolumbar) and control site. Dogs in group 1 were tested once; those in group 2 were tested for 5 consecutive days; and SCI dogs were tested on days 7, 14, 28, 42, 180, and 365 postoperatively. The MSTs were compared among days in healthy and SCI dogs and between SCI and healthy dogs using mixed effect models. P < .05 was considered significant. RESULTS: At the incision site of SCI dogs, MST was significantly lower than in healthy dogs for 42 days postoperatively, but not subsequently. However, 4/27 dogs had control site MST below the reference range 1 year after surgery. CONCLUSIONS AND CLINICAL IMPORTANCE: Mechanical sensory thresholds normalize by 6 months after surgery in most dogs with SCI. Approximately 15% of SCI dogs may develop chronic neuropathic pain. Improving long-term pain assessment of SCI dogs is important for offering treatment options and advising owners.

Feline Neuropathic Pain.

Neuropathic pain represents the extreme in maladaptive pain processing. In itself, it is a disease in which pain has become exaggerated in some combination of scope, severity, character, field, duration, and spontaneity. It is almost certainly an underappreciated, underdiagnosed cause of possible significant patient morbidity in cats. This article explores the basic mechanisms, recognition, known and suspect syndromes, and prospective treatment of feline maladaptive and neuropathic pain.

Mechanical quantitative sensory testing in cavalier King Charles spaniels with and without syringomyelia.

BACKGROUND: Syringomyelia (SM) is a debilitating condition in the cavalier King Charles spaniel (CKCS) that results in neuropathic pain and diminished quality of life. Von Frey aesthesiometry (VFA) is a method of mechanical quantitative sensory testing that provides an objective sensory threshold (ST) value and can be used to quantify neuropathic pain (NP) and monitor response to therapy. The utility of VFA has been previously established in client-owned dogs with acute spinal cord injury but the technique has not been evaluated in dogs with SM. The goal of this study was to evaluate ST, as determined by VFA, in dogs with and without SM, to assess the utility of VFA in quantifying NP in SM-affected dogs. We hypothesized the SM-affected CKCS would have lower ST values, consistent with hyperesthesia, when compared to control CKCS. Additionally, we hypothesized that ST values in SM-affected dogs would be inversely correlated with syrinx size on MRI and with owner-derived clinical sign scores. RESULTS: ST values for the thoracic and pelvic limbs differed significantly between the SM-affected and control CKCS (p = 0.027; p = 0.0396 respectively). Median ST value (range) for the thoracic limbs was 184.1 g (120.9-552) for control dogs, and 139.9 g (52.6-250.9) for SM-affected dogs. The median ST value (range) for the pelvic limbs was 164.9 g (100.8-260.3) in control dogs and 129.8 g (57.95-168.4) in SM-affected dogs. The ST values in SM-affected dogs did not correlate with syrinx height on MRI (r = 0.314; p = 0.137). Owner-reported clinical sign scores showed an inverse correlation with pelvic limb ST values, where dogs with lower ST values (hyperesthesia) were reported by their owners to display more frequent and severe clinical signs (r = - 0.657; p = 0.022). CONCLUSION: ST values were lower in SM-affected CKCS compared to control dogs, suggesting the presence of neuropathic pain. Dogs with lower ST pelvic limb values were perceived by their owners to have more severe clinical signs classically associated with SM. Our results suggest that VFA might offer quantitative assessment of neuropathic pain in SM-affected dogs and could be useful for monitoring response to therapy in future clinical studies.

Pregabalin alleviates clinical signs of syringomyelia-related central neuropathic pain in Cavalier King Charles Spaniel dogs: a randomized controlled trial.

OBJECTIVE: We aimed to assess the efficacy and benefit-risk profile of pregabalin (PGN) to reduce the clinical signs of central neuropathic pain (CNeP) as reflected by scratching episodes in dogs with symptomatic syringomyelia (SM). STUDY DESIGN: Randomized, double-blind, placebo-controlled crossover study. ANIMALS: A total of 12 client-owned Cavalier King Charles Spaniels (age, 1.1-7.4 years, bodyweight, 8.2-10.8 kg) with magnetic resonance imaging-confirmed SM and clinical signs of CNeP. METHODS: Dogs were randomized to either PGN 150 mg or placebo for 25 days, followed by 48 hour washout period before crossover to the alternate phase of 25 days. The primary outcome was defined as number of scratching events during 10 minutes of video-recorded physical activity. Treatment effect was estimated using a generalized estimation equation model. Benefit-risk and quality of life assessments were obtained through owner interviews focusing on potential adverse events. RESULTS: The treatment effect estimate was an 84% (95% confidence interval = 75-89%) reduction in mean number of scratching events relative to baseline compared with placebo (p < 0.0001). Owner-assessed satisfactory quality of life was status quo and rated as 'good' or 'could not be better' in six/11 dogs and improved in four/11 dogs. The most prevalent adverse events were increased appetite in nine/12 dogs and transient ataxia in nine/12 dogs. There was one dog withdrawn by the owner 7 days after crossover to PGN owing to persistent ataxia. No dogs needed rescue analgesia during the trial. CONCLUSIONS AND CLINICAL RELEVANCE: PGN is superior to placebo in the reduction of clinical signs of SM-related CNeP in dogs. At a dose range of 13-19 mg kg-1 orally twice daily, the encountered adverse events were acceptable to all but one owner.

Pregabalin for the treatment of syringomyelia-associated neuropathic pain in dogs: A randomised, placebo-controlled, double-masked clinical trial.

Pregabalin is the first-line treatment for neuropathic pain (NeP) in humans. Dogs with Chiari-like malformation and syringomyelia (CM/SM) associated with NeP could benefit from pregabalin. The aim of this study was to evaluate the efficacy of pregabalin for NeP in dogs with CM/SM. Eight dogs with symptomatic CM/SM were included in a double-masked, randomised, crossover placebo-controlled clinical trial. All dogs received anti-inflammatory drugs as base-line treatment during placebo or pregabalin phase of 14±4 days each. Analgesic efficacy was assessed with a daily numerical rating scale (NRS) recorded by dog owners (0-10, 10=worst pain) and quantitative sensory testing at baseline, placebo and pregabalin phases. Blood samples were collected to report pregabalin exposure and to assess renal function. Daily NRS scores recorded by dog owners in the pregabalin group were lower than in the placebo group (P=0.006). Mechanical thresholds were higher with pregabalin compared to baseline or placebo (P=0.037, P<0.001). Cold latency at 15°C was prolonged on the neck and humeri with pregabalin compared to baseline (P<0.001 for both) or placebo (P=0.02, P=0.0001). Cold latency at 0°C was longer on pregabalin compared to baseline and placebo (P=0.001, P=0.004). There was no pregabalin accumulation between first and last dose. This study demonstrates the efficacy of pregabalin for the treatment of NeP due to CM/SM on daily pain scores recorded by dog owners. Pregabalin significantly reduced mechanical hyperalgesia, cold hyperalgesia (0°C) and allodynia (15°C) compared to placebo. Pregabalin was non-cumulative and well tolerated with occasional mild sedation.

Understanding and Treating Chiari-like Malformation and Syringomyelia in Dogs.

Chiari-like malformation (CM) and syringomyelia (SM) are common and debilitating conditions in toy and small breed dogs. CM, considered ubiquitous in the cavalier King Charles spaniel (CKCS) population, results in abnormal cerebrospinal fluid dynamics which can lead to the development of SM. The clinical signs associated with CM/SM are frequently confused with other otologic and dermatologic conditions, which may delay appropriate treatment. A definitive diagnosis of CM/SM requires advanced imaging; however, due to expense associated with this, many cases are managed presumptively and symptomatically for the condition. The primary goal of treatment is to manage neuropathic pain and neurologic deficits through pharmaceutical or surgical approaches. Current literature suggests that most CM/SM-affected dogs have progression of their clinical signs in spite of medical or surgical management; however, most maintain a good quality of life based on owner assessments. Lack of correlation between structural markers of disease and clinician and owner-derived measures of neuropathic pain highlight the need for more robust, quantitative measures of pain in this common veterinary disease.

Comparison of neural histomorphology in tail tips from pigs docked using clippers or cautery iron.

Tail docking of pigs is commonly performed to reduce the incidence of unwanted tail-biting behaviour. Two docking methods are commonly used: blunt trauma cutting (i.e. using side clippers), or cutting and concurrent cauterisation using a hot cautery iron. A potential consequence of tail amputation is the development of neuromas at the docking site. Neuromas have been linked to neuropathic pain, which can influence the longer-term welfare of affected individuals. To determine whether method of tail docking influences the extent of neuroma formation, 75 pigs were allocated to one of three treatments at birth: tail docked using clippers; tail docked using cautery iron; tail left intact. Tail docking was performed at 2 days of age and pigs were kept under conventional conditions until slaughter at 21 weeks of age. Tails were removed following slaughter and subjected to histological examination. Nerve histomorphology was scored according to the following scale: 1=discrete well-organised nerve bundles; 2=moderate neural proliferation and disorganisation affecting more than half of the circumference of the tail; 3=marked neural proliferation to form almost continuous disorganised bundles or non-continuous enlarged bundles compressing the surrounding connective tissue. Scores of 2 or 3 indicated neuroma formation. Scores were higher in docked pigs than undocked pigs (P<0.001), but did not differ between pigs docked using clippers and those docked using cautery (P=0.23). The results indicate that tail docking using either clippers or cautery results in neuroma formation, thus having the potential to affect long-term pig welfare.

Comparison of gabapentin versus topiramate on clinically affected dogs with Chiari-like malformation and syringomyelia.

To date there is no evidence-based data for efficacious treatment of neuropathic pain in dogs with Chiari-like malformation (CM) and syringomyelia (SM). The objective of this prospective cross-over study was to compare the effect of gabapentin versus topiramate, as an add-on treatment to carprofen, on quality of life (QoL) of dogs experiencing signs of neuropathic pain due to CM/SM. A visual analogue scale (VAS) was used to assess the QoL: (1) on day 0; (2) after 1 week of carprofen only; (3) after 2 weeks on carprofen and gabapentin; and (4) after 2 weeks on carprofen and topiramate. No significant difference was observed between VAS after gabapentin or topiramate (P=0.91). However, an improvement in QoL was observed when gabapentin was compared with baseline (P=0.009), but not for topiramate. In conclusion, the addition of gabapentin was more effective in improving QoL than carprofen alone, but the study failed to identify that gabapentin was more efficacious than topiramate. Perhaps the more favourable side effect profile of the former makes it more suitable for the treatment of neuropathic pain associated with CM/SM but further placebo-controlled trials are required to assess the efficacy of these drugs.

Identifying neuropathic pain using (18)F-FDG micro-PET: a multivariate pattern analysis.

Pain is a multidimensional experience emerging from the flow of information between multiple brain regions. A growing body of evidence suggests that pathological pain causes plastic changes of various brain regions. Here, we hypothesized that the induction of neuropathic pain alters distributed patterns of the resting-state brain activity in animal models, and capturing the altered pattern would enable identification of neuropathic pain at the individual level. We acquired micro-positron emission tomography with [(18)F]fluorodeoxyglucose (FDG micro-PET) images in awake rats with spinal nerve ligation (SNL) and without (sham) (SNL group, n=13; sham group, n=10). Multivariate pattern analysis (MVPA) with linear support vector machine (SVM) successfully identified the brain with SNL (92.31% sensitivity, 90.00% specificity, and 91.30% total accuracy). Predictive brain regions with increased metabolism were mainly located in prefrontal-limbic-brainstem areas including the anterior olfactory nucleus (AON), insular cortex (IC), piriform cortex (PC), septal area (SA), basal forebrain/preoptic area (BF/POA), amygdala (AMY), hypothalamus (HT), rostral ventromedial medulla (RVM) and the ventral midbrain (VMB). In contrast, predictive regions with decreased metabolism were observed in widespread cortical areas including secondary somatosensory cortex (S2), occipital cortex (OC), temporal cortex (TC), retrosplenial cortex (RSC), and the cerebellum (CBL). We also applied the univariate approach and obtained reduced prediction performance compared to MVPA. Our results suggest that developing neuroimaging-based diagnostic tools for pathological pain can be achieved by considering patterns of the resting-state brain activity.

A potential role for substance P and interleukin-6 in the cerebrospinal fluid of Cavalier King Charles Spaniels with neuropathic pain.

BACKGROUND: Neuropathic pain can be a clinical sign in Cavalier King Charles Spaniels (CKCS) with syringomyelia. The pathophysiology of this pain is not fully understood. HYPOTHESIS: Neuropathic pain in CKCS is a result of a neuroinflammatory process. ANIMALS: Twenty-six client-owned dogs: 15 dogs with clinical signs of cervical hyperesthesia (group 1), and 11 dogs without of clinical signs (group 2). METHODS: Dogs were examined by magnetic resonance imaging (MRI). Interleukin-6, tumor necrosis factor alpha, and substance P were measured in CSF and compared with morphological findings on MRI and clinical pain scores. RESULTS: All dogs without clinical signs had symmetrical syringomyelia, whereas in the group with pain, 6 dogs had symmetrical and 9 dogs had asymmetrical syringomyelia. Pain and syringomyelia asymmetry were correlated, and a strong association between pain and dorsal horn involvement of syringomyelia was observed. There was no significant difference between the mean width of the syringomyelia in dogs with or without pain. The concentrations of interleukin-6 and substance P were significantly higher in dogs with neuropathic pain. Tumor necrosis factor alpha was not detected in either group. Concentrations of substance P were significantly higher in dogs with asymmetrical syringomyelia or dorsal horn involvement, whereas interleukin-6 concentrations were not significantly different between groups. CONCLUSION: Release of interleukin-6 and substance P may initiate proinflammatory effects leading to development of persistent pain in CKCSs with syringomyelia.

Developmental changes in voltage-gated calcium channel α(2)δ-subunit expression in the canine dorsal root ganglion.

The voltage-gated calcium channel subunit α(2)δ plays a fundamental role in propagation of excitatory signals associated with release of glutamate and neuropeptides substance P (SP) and calcitonin gene-related protein (CGRP). It can be selectively inhibited by gabapentinoids. Hence, investigation of the α(2)δ subunit may predict the efficacy of gabapentinoid therapy in neuropathic pain. Since sensory processing underlies significant age-related changes, this study was conducted in order to elucidate the role of the α(2)δ subunit in the sensory transmission during canine development. Dorsal root ganglia (DRG) were harvested from four spinal segments of 16 puppies and 10 adult dogs without a history of neurological signs, pain, spinal disease or orthopedic disorders. α(2)δ-Subunit expression and coexpression with SP and CGRP was evaluated immunohistochemically regarding the number of immunopositive ganglion cells, staining intensity and subcellular distribution. All tested ganglia were immunopositive for α(2)δ. Cell counts and expression levels were significantly lower in pups than in adult dogs (p < 0.05). In the cervical segments of both groups, the number and percentage of immunopositive neurons was significantly higher than in lumbar DRG (p < 0.05). Multilabeling studies in all tested animals confirmed the coexpression of α(2)δ and pain peptides SP and CGRP. This anatomical study for the first time documents the involvement of α(2)δ subunits in sensory signal processing in dogs. The proportion of positive neurons and the intracellular expression levels show a net increase from early postnatal life to adulthood. A significant portion of α(2)δ-positive cells in the dogs exhibited C- and Aδ-phenotypes compatible with nociceptive neurons. The coexpression of α(2)δ, SP and CGRP imply that these neurons are involved with peptidergic nociception. The cervicolumbar gradient of α(2)δ expression in adults reflects functional differences in between forelimbs and hind limbs. These data will facilitate translational studies on neuropathic pain states in this species such as common canine nerve entrapment syndromes.

Long-term outcome of Cavalier King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia.

The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (±14.3) months from diagnosis. At the end of the study, 36 dogs were still alive; five dogs died of an unrelated or unknown cause, and seven were euthanased due to severe clinical signs suggestive of NeP. During the follow-up period, the clinical signs of scratching, facial rubbing behaviour, vocalisation and exercise ability were evaluated. Nine out of 48 dogs stopped scratching (P<0.001), but there was no statistically significant change in the number of dogs exhibiting exercise intolerance, vocalisation or facial rubbing behaviour. The overall severity of clinical signs based on a visual analogue scale (VAS) (0 mm: no clinical signs 100 mm: severe clinical signs) increased (from median 75 mm (interquartile ranges (IQR) 68-84) to 84 mm (IQR 71.5-91), P<0.001). A quarter of the dogs were static or improved. In general, the majority of the owners felt that the quality of life of their dogs was acceptable. Medical treatments received were gabapentin or pregabalin and/or intermittently, carprofen. The owner's perception of their animal's progress, and progress based on VAS, had strong positive correlation (Spearman's rank correlation (s(r)) 0.74, P<0.001). Overall, this study suggests that clinical signs suggestive of NeP progress in three-quarters of CKCSs with CM and/or SM.

Questionnaire-based behaviour analysis of Cavalier King Charles spaniels with neuropathic pain due to Chiari-like malformation and syringomyelia.

Chiari-like malformation (CM)/syringomyelia (SM) is a disease complex recognised in Cavalier King Charles spaniels (CKCSs) that can lead to neuropathic pain (NeP). In humans, NeP is associated with anxiety, depression and reduced quality of life (QoL). In this study, databases of three specialist veterinary centres were searched and CKCS breed societies and health forums were contacted to identify CKCS with an imaging diagnosis of CM/SM. Owners completed questionnaires on behaviour, signalment, general health status, NeP and QoL. Data were analysed from 122 dogs out of 564 questionnaires completed, after incomplete questionnaires and data from dogs that had other potentially debilitating disease processes were excluded. NeP severity score was significantly and positively correlated with 'stranger-directed' fear (r(S)=0.28), non-social fear (r(S)=0.34), 'separation-related' behaviour (r(S)=0.38), attachment behaviour (r(S)=0.24), excitability (r(S)=0.21) and proxy for pain sensation (r(S)=0.29). Increased NeP was also significantly associated with decreased QoL (r(S)=0.47), ability to settle (r(S)=0.26) and willingness to exercise (r(S)=0.50). Severity of NeP was positively associated with certain fear-associated behaviour and with decreased owner-perceived QoL. Thus, neurobehavioural changes should be considered in the management of NeP in CKCS with CM/SM.