Managing Neuropathic Pain in Dogs

Managing Neuropathic Pain in Dogs – 2016 Feb – free full-text PMC article

Though this text refers to dogs, the biological aspects neuropathic pain are the same in most mammals. This article gives an excellent explanation of the basics of such pain.

Disorders of the somatosensory system such as neuropathic pain are common in people with chronic neurologic and musculoskeletal diseases, yet these conditions remain an underappreciated morbidity in veterinary patients.

This is likely because assessment of neuropathic pain in people relies heavily on self-reporting, something our veterinary patients are not able to do.  

The development of neuropathic pain is a complex phenomenon, and concepts related to it are frequently not addressed in the standard veterinary medical curriculum such that veterinarians may not recognize this as a potential problem in patients.

The goals of this review are to

  • discuss basic concepts in the pathophysiology of neuropathic pain,
  • provide definitions for common clinical terms used in association with the condition, and
  • discuss pharmacological treatment options for dogs with neuropathic pain.

The development of neuropathic pain involves key mechanisms such as

  • ectopic afferent nerve activity,
  • peripheral sensitization,
  • central sensitization,
  • impaired inhibitory modulation, and
  • pathologic activation of microglia.

Treatments aimed at reducing neuropathic pain are targeted at one or more of these mechanisms.

Several drugs are commonly used in the veterinary clinical setting to treat neuropathic pain. These include

  • gabapentin,
  • pregabalin,
  • amantadine, and
  • amitriptyline.

Proposed mechanisms of action for each drug, and known pharmacokinetic profiles in dogs are discussed.

Strong evidence exists in the human literature for the utility of most of these treatments, but clinical veterinary-specific literature is currently limited.

Future studies should focus on objective methods to document neuropathic pain and monitor response to therapy in veterinary patients.

Introduction

Disorders of the somatosensory system such as neuropathic pain affect up to 8% of the general population and up to 90% of people living with chronic spinal cord injury (SCI), yet these conditions remain an underappreciated morbidity in veterinary patients

The goal of this review is

  1. to summarize basic concepts in the literature related to somatosensory disturbance and neuropathic pain and
  2. to review recent publications related to the diagnosis and management of neuropathic pain in dogs.

The Somatosensory System: An Overview

The somatosensory system serves three major functions.

  1. It allows perception and reaction to sensory stimuli originating inside the body (interoceptive),
  2. responds to stimuli originating outside the body (exteroceptive), and
  3. mediates proprioceptive function

The first order neurons in pathways of the somatosensory system reside in the dorsal root ganglia (DRG), cranial sensory ganglia, or the brainstem.

The anatomy of DRG neurons has been described as pseudounipolar, meaning that they possess a single-branched axon, which extends both into the periphery to associate with sensory receptors and into the spinal cord to form synapses with second-order neurons in either the dorsal gray matter or brainstem nuclei

The general somatic afferent system (GSA) is commonly referred to as the “pain, temperature, touch” system, which is partially a misnomer because pain is not actually a sensory modality but rather a feeling provoked in response to a sensory stimulus.

This is the system that transmits information related to thermal, mechanical, and chemical stimuli from peripheral receptors to the somatosensory cortex

The general proprioceptive (GP) system is responsible for detecting the movement and position of muscles and joints, encompassing both conscious and unconscious proprioceptive components

Pain and the General Somatic Afferent System

The generation of pain in response to tissue injury involves four basic processes:

  1. transduction,
  2. transmission,
  3. modulation, and
  4. perception.
  1. Transduction involves the conversion of a noxious stimulus to a nociceptive signal at the level of the nociceptor.
  2. Transmission is the process by which nociceptive signals are propagated along nerve fibers from the site of original injury to the CNS.
  3. Modulation is the mechanism by which nociceptive signals are altered within the CNS through either facilitation or inhibition.
  4. Perception is the last and most important part of the “experience” of pain, involving integration of cognitive and emotional responses to the noxious stimulus

In general, pain can be categorized as either nociceptive or neuropathic.

Nociceptive pain is caused by noxious stimuli which are processed by an otherwise normally functioning somatosensory system

Nociceptive pain is evolutionarily advantageous by allowing an animal to detect and respond to a potentially damaging stimulus. It can be further classified as somatic (originating from skin, muscles, and joints) or visceral (originating from visceral organs)

Neuropathic pain is defined as pain caused by a disease or lesion, which leads to damage or dysfunction of the somatosensory system

The term mixed pain refers to the condition of coexisting nociceptive and neuropathic pain.

Neuropathic pain is a maladaptive phenomenon caused by pathologic neuroplasticity, and can become a disease of the neurologic system in its own right by persisting beyond resolution of an inciting caus

It is caused by a broad range of conditions affecting any organ or tissue that possesses nerve endings. Specifically, conditions such as peripheral neuropathy, spinal cord disease, chronic musculoskeletal conditions, and brain lesions are commonly reported

Manifestations of neuropathic pain include both evoked pain (stimulus dependent hypersensitivity) and spontaneous pain.

These signs may be either continuous or intermittent in nature

Stimulus-evoked hypersensitivity is often categorized further in the literature in to the two most common types of neuropathic pain recognized and discussed in the clinical setting: allodynia or hyperesthesia

  1. Allodynia refers to a condition where a stimulus not typically considered painful and not encoded by nociceptors is perceived to be painful by an individual with somatosensory dysfunction.
  2. Hyperesthesia refers to a condition of increased sensitivity to a stimulus. …denotes an exaggerated level of pain in response to a stimulus

Allodynia and hyperesthesia can both be present in conjunction with hyperpathia, and the terms are frequently confused and used incorrectly in both the veterinary and human medical literature.

Managing Neuropathic Pain

The first, and perhaps most important step, in the management of neuropathic pain is identification and treatment (whenever possible) of the underlying disease affecting the somatosensory system.

Examples include

  • Chiari-like malformation/syringomyelia (CM/SM),
  • radiculopathy caused by chronic cervical or lumbosacral disc disease,
  • diabetic or other polyneuropathy,
  • SCI caused by intervertebral disc extrusion,
  • chronic osteoarthritis, and
  • stroke

Many of the conditions associated with neuropathic pain may also have a clinical component of nociceptive pain

Management of neuropathic pain in the veterinary setting presents challenges, as apparent in CM/SM, where the clinical manifestations of neuropathic pain may be refractory to treatment and often progress over time

Treatments can be targeted at any or all of the five mechanisms underlying neuropathic pain, which were described above.

A recent meta-analysis of the human neuropathic pain literature makes strong recommendations for the use of drugs such as gabapentin, pregabalin, and tricyclic antidepressants (TCA), while weaker recommendations are made for tramadol and strong opioids such as morphine (related to both efficacy and side effects) and topical lidocaine or capsaicin (45).

The most common drugs used specifically for neuropathic pain the veterinary setting are gabapentin and pregabalin, with TCA occasionally referenced (46, 47). A summary of dosing recommendations for medications used to manage neuropathic pain in dogs can be found in Table 2.

Table 2

Common medications used for the management of neuropathic pain in dogs.

Drug Dosage (mg/kg) Frequency (h) Reference
Gabapentin 10–20 Q8 (48, 49)
Pregabalin 4 Q12 (50)
Amitriptyline 3–4 Q12 (51)
Amantadine 3–5 Q12–24 (42, 52)

Gabapentin

Gabapentin was originally marketed as an anticonvulsant medication but was subsequently found to have beneficially effects in the management of neuropathic pain

Gabapentin is a structural analog of GABA. It appears to decrease central sensitization by inhibiting presynaptic calcium channels in the dorsal horn (55). Gabapentin may also have efficacy related to sodium channel blockade and elimination of ectopic nerve activity

However, below are two studies that found no benefit from these drugs:

Wagner et al. (56) found no difference between gabapentin and placebo to reduce the need for postoperative opioids when dosed at 10 mg/kg Q12 h in patients undergoing forelimb amputation.

Aghighi et al. (57) found no difference in gabapentin compared to placebo in management of postoperative pain after intervertebral disc extrusion.

This study reported no improvement in pain scores assigned via visual analog scale; however, improvement in quality of life scores for dogs receiving gabapentin was observed.

While it is likely that gabapentin has efficacy against neuropathic pain based on the human literature and on anecdotal evidence, controlled studies will be required to understand the role of gabapentin to manage neuropathic pain in veterinary patients.

Pregabalin

Pregabalin is structurally similar to gabapentin but has higher oral bioavailability and a longer half-life

There are no controlled studies evaluating the efficacy of pregabalin to treat neuropathic pain in veterinary patients

Tricyclic Antidepressants

The effects of neuromodulatory drugs such as TCA in managing neuropathic pain are distinct from their antidepressant effects

TCAs exert analgesic effects in several ways, including

  1. inhibiting reuptake of serotonin and norepinephrine,
  2. antagonism of voltage-gaited sodium channels, and
  3. antagonism of NMDA receptors.

There are no clinical trials, or experimental studies evaluating the use of TCAs for neuropathic pain in dogs, but a case for their utility can be made based on the human literature

Amantadine

Amantadine is an NDMA antagonist that has shown mixed results in the treatment of neuropathic pain in humans

Amantadine

  • may decrease central sensitization,
  • decreases opioid tolerance in some patients, and
  • is suggested to enhance the effects of NSAIDS, gabapentin, and opioids

However, a randomized, placebo-controlled trial evaluated the use of amantadine in conjunction with meloxicam in dogs with osteoarthritis and showed significant improvement in pain scores for dogs receiving amantadine compared to placebo

Opioids

The role of opioids in the management of people with neuropathic pain is both controversial and complex.

A recent meta-analysis found moderate evidence for their use to decrease the intensity of neuropathic pain with intermediate-term treatment, but also cited significant bias in currently available studies, and the need for prospective studies focusing on adverse effects

The only studies being done of opioids are focused on their adverse effects, rather than their efficacy.

This alone seems like an extraordinary bias.

Cannabinoids

Many pharmacologically active cannabinoids have been identified but the two with the strongest evidence for analgesic effects are

  1. tetrahydrocannabinol (THC), which also has psychoactive effects, and
  2. cannabidiol (CBD).

Cannabinoids exert their effects within the body via two well-studied receptors: CB1 and CB2.

CB1:

CB1 receptors are present in high numbers in the brain and spinal cord, as well as visceral organs and adipose tissue.

Activation of CB1 receptors leads to inhibited release of acetylcholine, dopamine, and glutamate. CB1 also modulates opioid, NMDA, and GABA receptors (74, 75)

Most known adverse effects associated with cannabinoids are associated with central CB1 receptor effects.

CB2:

CB2 receptors are found in the highest concentrations on hematopoietic and immune cells, including microglial cells

In normal health, CB2 receptors are expressed only at low levels in the CNS but are rapidly upregulated in both neurons and microglia after injury or inflammation  

Summary

Neuropathic pain is likely an under-recognized condition in veterinary patients with an assortment of neuromusculoskeletal diseases.

Specific literature related to diagnosis and treatment of neuropathic pain in dogs is limited, although information related to mechanisms and treatment options can be extrapolated from the human literature.

Drugs specifically targeted at reducing neuropathic pain, such as gabapentin and pregabalin, will require controlled prospective studies evaluating their efficacy to reduce clinical signs compatible with neuropathic pain such as hyperesthesia and allodynia.

Veterinary clinicians should be aware of neuropathic pain as a potential entity in patients and should consider it when developing a multimodal approach to pain management.

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