The recent publication of a review entitled ‘Chronic maladaptive pain in cats: A review of current and future drug treatment options’ by Adrian et al (2017) raises a number of interesting questions. This is my interpretation of the review which I feel is a useful update to where our understanding is of chronic pain in cats and what we know of treatment options.
The current knowledge we have regarding feline pain is focused on peri-operative pain management and further work is required to evaluate and treat chronic pain effectively. This gap is in part due to slower progress in chronic pain assessment tools versus acute pain. If we cannot effectively measure pain, it is difficult to fully evaluate the effect of analgesics.
The paper starts by reviewing terminology associated with acute and chronic pain, reminding us that this is a continuum and that perhaps the terms adaptive and maladaptive are more useful in describing pain that has a purpose (protective) versus pain which has no benefit.
In considering how best to treat pain, an understanding of the type of pain is essential. In addition to nociceptive and neuropathic pain, IASP recently added a third pain type, nociplastic. This definition was required to classify pain beyond nociceptive or neuropathic.
Nociceptive pain
• Pain/tenderness due to inflammation
• Heat, redness, swelling
• Usually responds to NSAIDs & opioids
Neuropathic pain (NeuP)
• Injury to PNS or CNS
• Burning, stabbing, shooting
• Poorly responsive to conventional analgesics
Nociplastic pain
• Altered nociception without tissue damage or somatosensory abnormalities
• Pain and hypersensitivity
• Examples are fibromyalgia and low back pain
• Exists in the absence of a primary cause
Key to the existence of maladaptive pain is central sensitisation. The authors lead us to the evolution of this term to that of central plasticity. There are several components of these changes, not all of which are sensitising – some being down regulated. The components of central plasticity are;
· The output from the peripheral neuron is increased.
· This excitability outlasts the initiating stimulus.
· The higher level of excitability can be maintained with low-level nociceptor input.
· Receptive fields of the neurons are increased.
· Synaptic transmission is facilitated by changes in dorsal horn ion channel activity.
· Down regulation also occurs.
A variety of mechanisms may be at play in the individual and we have no way of differentiating these. The examples of degenerative joint disease and gingivostomatitis are given whereby active inflammatory and maladaptive neuronal changes with plasticity occur.
Diseases associated with a component of maladaptive pain in cats include;
· Degenerative joint disease
· Interstitial cystitis
· Gingivostomatitis
· Diabetic neuropathy
· Cancer
· Ocular pathology
· Dermatological conditions
Treatment options
Whilst NSAIDs are first line treatments for many of these conditions, where there is maladaptive pain the efficacy of NSAIDs will be limited. Although tests currently applied to dogs are being adapted to cats, right now we accept a trial and error approach to pain management. As an initial therapy it is recommended that NSAIDs are used. Licensed NSAIDs for long-term use in cats include meloxicam and robenacoxib.
Gabapentin
Mode/site of action
Alpha 2 delta subunit of voltage gated calcium channels in the dorsal root ganglion to reduce neuronal excitability.
Analgesic efficacy studies
No clinical studies.
Case reports
Vettorato & Corletto 2011, Lorenz et al 2012
Dose
5-10mg/kg q8-12h although this is not based on studies of analgesic efficacy
Tramadol
Mode/site of action
Weak opioid effects, noradrenaline & serotonin reuptake inhibitor. Alpha 2 adrenergic receptor effects.
Analgesic efficacy studies
Two studies of chronic OA in cats. One comparing tramadol (3mg/kg q12h) versus placebo in meloxicam treated cats was able to document benefits in both groups to certain outcome measures. The second study comparing tramadol (3mg/kg) to placebo was able to document efficacy in OA affected cats.
Dose
2-4mg/kg q8h
Amantadine
Mode/site of action
NMDA antagonist. Protective effect on dopamine neurons.
Analgesic efficacy studies
No clinical studies.
Dose
3-5mg/kg PO SID based on work in dogs (BSAVA dose 1-4mg/kg SID).
Amantadine blog link here
Doses above are taken from the BSAVA formulary and are clarified according to available evidence for the reader.
Amitriptyline
Mode/site of action
Noradrenaline and serotonin reuptake inhibitor.
Analgesic efficacy studies
Objective assessments in chronic pain conditions required.
Flupirtine
Mode/site of action
Selective neuronal potassium channel opener which stabilises the membrane and decreases neuronal activity. NMDA receptor antagonist – maintains the magnesium block within the receptor.
Animal studies
Pharmacokinetics reported in 6 cats.
Some data in dogs, cats and rats.
Tapentadol
Mode/site of action
MORphine receptor agonist-Noradrenaline Reuptake Inhibitor (MOR-NRI).
Animal studies
Pharmacokinetics reported in 6 cats.
Significant effect on thermal thresholds reported in 6 cats compared to baseline but not placebo. Further PK data required.
Maropitant
Mode/site of action
Selective neurokinin-1 receptor antagonist. This is the receptor for Substance P.
Animal studies
Lack of data regarding analgesia.
Grapiprant
Mode/site of action
Selective prostaglandin EP4 receptor antagonist.
Animal studies
Studies in dogs detailed here.
Only safety and toxicokinetic data are available in cats.
Further studies in chronic pain in cats are warranted.
Conclusions
The Feline Musculoskeletal Pain Index is a simple but non-validated option. Vetmetrica is a validated option for cats.
Maladaptive pain may not respond to NSAIDs and this should raise the index of suspicion.
NSAIDs remain a first line treatment option and should be given for a suitable period of time prior to reassessment. Recommended – 28 day course.
Beyond NSAIDs there is limited evidence to suggest most appropriate options.
References
Adrian, D., Papich, M., Baynes, R., Murrell, J., & Lascelles, B. D. X. (2017). Chronic maladaptive pain in cats: A review of current and future drug treatment options. Veterinary Journal (London, England : 1997), 230, 52–61. http://doi.org/10.1016/j.tvjl.2017.08.006