Neuropathic pain in Mechanisms and multimodal management

Authors: Clare Rusbridge

Abstract

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

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

The review draws on current literature, where available, along with the author's extensive experience and research.

Nociception and pain perception

Pain is defined by the International Association for the Study of Pain (ISAP) as an 'unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue

damage'.^ 1 ^ Pain and nociception are not the same. Noci-ception is the process by which the sensory nervous system encodes and transmits a painful stimulus to protect the body from injury. By contrast, pain perception is subjective, and influenced by biological, psychological and social factors.^ 1 ^ Significantly, in a recent change to the ISAP definition of pain, the phrase 'or described in terms of such damage', which previously appeared at the end of the definition, was deleted because some humans as well as animals are unable to verbally articulate their pain. It also acknowledges that pain is expressed by many behaviours, and not just by a verbal description.^ 1 ^ Chronic pain is considered both a clinical sign and a disease and, as such, is often referred to as maladaptive pain.

The anatomy of nociception and pain perception is illustrated in Figure 1. Table 1 details the pathophysiology of pain, with a specific focus on neuropathic pain, and describes possible drug targets. For ease of reference, some key terms are summarised in highlight boxes.

Chronic (maladaptive) pain

Chronic pain is pain that persists or recurs and is associated with significant emotional distress or functional disability. In humans, chronic pain is defined as pain that persists for longer than 3 months, but it has been suggested that this definition should be adapted to incorporate a shorter duration for companion animals to reflect their shorter lifespan.^ 17 ^ Chronic pain may be associated with a chronic health condition such as degenerative joint disease or cancer.^ 18 ^ See box 'Chronic pain syndromes (with examples) in the cat' for a description of chronic pain categories.

Regardless of the aetiology, chronic pain will result in neuroplastic changes in the nervous system, leading to amplified pain signals, altered pain perception and changes in emotional processing. Therefore, management of chronic pain has some similarity with, and relevance for, management of neuropathic pain.

Neuropathic pain

Neuropathic pain is a subcategory of chronic pain that is a consequence of damage to or dysfunction of the nervous system.^ 21 ^ It is characterised by spontaneous pain, heightened sensitivity to touch and what humans describe as abnormal sensations, such as tingling, burning or electric shocks (Table 2).

There are three fundamental phenomena intrinsic to the development of neuropathic pain - central sensitisation, central disinhibi-tion and phenotypic change.^ 22 ^

Central sensitisation

Central sensitisation is the amplification of pain signal processing as it travels to the brain, leading to increased pain sensitivity (disproportionate pain in relation to the injury or stimulus), allodynia and hyperalgesia

(Table 2).

The spinal cord and the medullary dorsal horn neurons play a crucial role in pain perception through a mechanism known as 'wind-up' (Table 1). This involves substance P (neurokinin-1 receptors) as well as glutamate (NMDA receptors).^ 23 ^ These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions.

Although neural lesions are necessary, they are not sufficient in themselves to generate neuropathic pain; genetic polymorphisms, sex and age all influence the risk of developing persistent pain.^ 21 ^

Central disinhibition

Central disinhibition refers to an imbalance between the excitatory and inhibitory side of the nervous system, such that there is reduced inhibition to the spinal cord dorsal horn.

Phenotypic change

In response to ongoing pain signals, injury or inflammation, neurons and glial cells may undergo phenotypic changes. These changes can include increased expression of pain-related receptors, altered neurotransmitter release and enhanced synaptic plasticity. Mechanoreceptive A-p fibres in the deeper laminas of the dorsal horn (Table 1) become activated and produce substance P so that input from them is perceived as pain (tactile allodynia).^8,24^

Interplay between chronic pain and emotional health

The corticolimbic system (Figure 2) integrates emotion with cognition and produces a behavioural output that must be flexible, dependent on the environmental and social circumstances.^25,26^

The corticolimbic circuitry of the prefrontal cortex, amygdala and hippocampus is connected to the hypothalamic-pituitary-adrenal axis. Environmental and social factors leading to stress and fear-anxiety affect decision-making, emotion regulation and memory.^ 26 ^ The corticolimbic system is also the modulator for acute pain, a mediator for chronic pain and critical for the chronification of pain.^ 27 ^ Owing to the anatomical overlap in the corticolimbic circuitry for pain, emotion regulation, decision-making and memory, there is influence of these brain functions on each other. Consequently, there is a high comorbidity of negative affective disorders

with chronic pain, hypothesised because of similar changes in neuroplasticity and overlapping neurobiological mechanisms.^ 28 ^

Pain is not just an unpleasant sensory and emotional experience, but something that requires a behavioural response to the danger to the body tissue. Due to the implications for survival, pain demands the brain's attention, affecting other cortical processing as well as other body systems, including the immune system, hypothalamus-pituitary-adrenal axis, sympathetic nervous system and reproductive system.^ 29 ^ Consequently, pain affects cognition, and vice versa. In rodent models, chronic pain impairs learning and memory, interrupts attention and affects decision-making.^ 30 ^ Animals in pain may be more predisposed to stress-related behavioural disorders, and the converse is also true - that is, chronic stress may trigger or worsen behavioural signs of pain.^ 13 ^ For example, in feline orofacial pain syndrome (FOPS), the expression of signs of pain is influenced by environmental stress.^ 31 ^

Most drug treatments are directed towards peripheral, spinal and brainstem targets, and neglect a pivotal area in pain perception. In human medicine, it is increasingly recognised that successful management of chronic pain employs a more holistic approach that includes cognitive behavioural therapy, physical therapy and neuromodulation tech-niques.^ 32 ^ In cats, pain management should also focus on addressing emotional compromise and increasing available emotional capacity (see box 'Prioritising emotional health') to mitigate the clinical impact of neuropathic pain.^33-35^

Confirmation of neuropathic pain

Tentative diagnosis

As discussed, neuropathic pain is characterised by abnormal hypersensitivity to stimuli (hyperalgesia) and pain due to a stimulus that does not normally provoke pain (allody-nia),^ 36 ^ and can be caused by a lesion or disease affecting central or peripheral somatosensory processing. These conditions are difficult to objectively define in animals and are subjectively assumed to be present based on behavioural responses to touch (including from collars and grooming) and occasionally other stimuli; caregivers may, for example, report a reaction to wind or draughts.

Neuropathic pain may be suggested by marked and persistent hyperaesthesia associated with nerve trauma. The first of three case vignettes included in this review (case 1) describes a cat with sciatic nerve injury following orthopaedic surgery. Note that self-injurious behaviour does not in itself imply neuropathic pain, but does suggest the animal may experience abnormal sensations that provoke self-mutilation (as illustrated by all three cases). Animals showing self-mutilation often have sensory loss (hypoaesthesia or analgesia), which permits scratching or licking to continue to the point of self-injury extending into tissue below the dermis (case 2).

Definitive diagnosis

Confirming a diagnosis of neuropathic pain (Figure 3) - that is, pain originating from the nervous system - is challenging and

✜ Demonstrating that distribution of the pain corresponds to an area of abnormal sensation (eg, decreased or increased sensitivity to touch);

✜ Ideally, demonstrating that the distribution of the pain corresponds to an underlying lesion or disease of the somatosensory system.^ 20 ^ In some cases, there may be a known historical injury (eg, previous surgery). In others, further diagnostic testing is required, such as MRI to demonstrate a lesion or neuroelectrophysiol-ogy to confirm a peripheral neuropathy.

A positive response to trial treatment with drugs effective for neuropathic pain can additionally be used to support a tentative diagnosis. However, caution is advised because many drugs that are useful for treating neuropathic pain can also affect emotional state - for example, gabapentinoid drugs.^37,38^ Thus, without the above requirements having been met, a positive response to these drugs does not 'prove' a diagnosis of neuropathic pain. Given, however, that a negative emotional state can influence pain, it can be argued that the cat's quality of life is improved regardless.

Pharmacological management of neuropathic pain

Treatment of neuropathic pain depends on the aetiology, with humans recognised to respond best to multimodal therapy. This multimodal approach is required because single agents have poor success. For example, if effective treatment is defined as a 50% reduction in pain, the average number of human patients with neuropathic pain who need to be treated for just one person to benefit has been shown in a controlled clinical trial to be 7.7 for pregabalin and 7.2 for gabapentin.^ 39 ^ Also, it is

important to address the underlying cause of neuropathic pain and, furthermore, to consider the impact of emotional health on chronic pain (as discussed earlier).

There are no licensed preparations for the management of feline neuropathic pain and many of the agents referred to in this article are adjuvants - that is, medications that are not primarily designed to relieve pain but are used alongside primary pain-relieving drugs (eg, opioids or non-steroidal anti-inflammatory drugs [NSAIDs]) to enhance their effectiveness or address specific aspects of pain or its management.

The implications of using a non-licensed drug should be discussed with the client. It should also be remembered that licensed NSAIDs can still have a role in the management of a cat with neuropathic pain, especially as they do not have a sedative adverse

effect and/or may allow a reduction in the dose of a drug with sedative effects. Cyclooxygenase (COX-2) mediated prostaglandins, such as prostaglandin E2 (PGE2), contribute to the development of neuropathic pain.^ 40 ^ In the central nervous system, PGE2

modulates pain sensitivity and, in the peripheral nervous system, PGE2 sensitises nociceptive afferent neurons through E-prostanoid receptors.^ 41 ^ Further information is provided in the '2024 ISFM and AAFP consensus guidelines on the long-term use of NSAIDs in

cats'.^ 42 ^

Table 3 details possible treatment options (pharmacological and non-pharmacological) for neuropathic pain in cats and describes where they are effective in the anatomical pathway. Dose rates, monitoring recommendations and adverse effects of commonly used adjuvant analgesic drugs are provided in Table 4.

Treatment algorithm

See 'Treatment algorithm for the management of neuropathic pain in cats' for a summary of the author's recommended therapeutic approach.

Conclusions

Unravelling the intricacies of feline neuropathic pain demands understanding of noci-ception, pain perception and emotional health, coupled with the application of personalised multimodal interventions. The dynamic field of veterinary pain management is evolving, emphasising the pressing need for sustained research and collaborative efforts. By advancing our knowledge and refining treatment strategies, we pave the way to elevate the quality of life for cats with this potentially life-limiting condition.