Amitriptyline for neuropathic pain

Amitriptyline is one drug option that always appears in pain reviews. Should amitriptyline be part of your therapeutic options for neuropathic pain? Much of what we know is based on this case series reported here.

Three cases of NeuP were reported by Cashmore et al (2009) which may be useful in assisting the reader to recognize similar clinical presentations. Symptoms in people which are characteristic of NeuP include burning, shooting pain.

The first case detailed by Cashmore et al describes a dog with mechanical allodynia over the antebrachium and palmar forepaw. ‘Stroking with a pen consistently caused marked agitation in the dog, displayed by it pulling its leg away while concurrently vocalising and attempting to bite the examiner. The limb was held in a flexed position at the shoulder and elbow joints, which was thought to be a consequence of the abnormal sensation experienced by the dog’.

Electromyography suggested a lesion of the median and ulnar nerve roots and MRI failed to demonstrate a nerve root lesion.

The dog was treated with amitriptyline 1.4mg/kg PO BID for a month. Within two weeks the owners reported no significant change in the dogs presenting signs and several adverse effects including altered mentation. Amitriptyline was discontinued and gabapentin 14mg/kg BID prescribed. One month later the lameness had improved and the mechanical allodynia had resolved. Following 3 months treatment with gabapentin the lameness has resolved and the dog was using the limb normally.

This case is a useful addition to the literature as it describes clinical signs in a dog which appear similar to those described by people with NeuP. It also reinforces the human perspective regarding treatment whereby the first line choice may be ineffective or rather the beneficial effects limited due to side effects.

The second case report is of a 3.5 year old Cairn Terrier with a progressive history of intermittent spontaneous and inducible scratching of the right side of its face. Each episode lasted 20s during which the episodes could not be stopped by the owner nor the clinician. No response was seen to NSAIDs or corticosteroids. Neurological and dermatological exams revealed no further abnormalities, except mechanoallodynia over the right side of the face located to the dermatome supplied by the infraorbital nerve. MRI was unremarkable. A diagnosis of NeuP was presumed.

A one month trial of gabapentin did not improve clinical signs. One month of amitriptyline produced an immediate and dramatic response until the owner stopped treatment having considered the dog to be cured. Signs recurred within 3 days and were controlled again by amitriptyline.

The third case in the series was a 12 year-old Fox Terrier presented for back pain. The owners were unable to touch the dog’s lower back without eliciting severe discomfort, agitation and sometimes aggression. Radiographs taken by the referring vet were unable to account for clinical signs and trial treatment with meloxicam failed to show improvement. Upon presentation at the referral centre diffuse mechanical allodynia was noted over the lumbar region. Otherwise neurological, orthopaedic, radiographic and MRI & EMG exams were considered normal. A presumptive diagnosis of NeuP with no inciting factor was made. The dog showed a marked improvement in response to amitriptyline, with marked deterioration upon cessation of treatment.

The dose used by Cashmore et al is consistent with the dose in the BSAVA formulary of 1-2mg/kg PO SID-BID which is similar to other sources. Work by Norkus et al (2015) questions the dose based on the use of 4mg/kg PO. They conclude amitriptyline at 4 mg/kg administered orally produced low amitriptyline and nortriptyline plasma concentrations. They state ‘this brings into question whether the currently recommended oral dose of amitriptyline (1-4 mg kg) is appropriate in dogs'. Clinically I’m sure we are using the lower end of this dose range and it is therefore worth questioning our dose if we see no response.

A study by Monteiro et al (2018) investigated outcome measures used in dogs with osteosarcoma pain. We recognise that the pain of osteosarcoma is difficult to treat and using these measures the authors concluded that the pain was refractory to a multimodal combination of cimicoxib 2mg/kg SID, amitriptyline 1-1.5mg/kg SID and gabapentin 10mg/kg TID. From the previous work by Norkus et al we could conclude that the dose of amitriptyline used here was not high enough,.

Amitriptyline has several mechanisms of action (Su et al 2015) which have been reported as complex and unclear! It is a tricyclic antidepressant, but the antidepressant actions are distinct from the analgesic effect.

· Inhibition of presynaptic reuptake and noradrenaline and serotonin increases concentrations of both neurotransmitters which enhance descending modulatory control. This is a supraspinal effect.

· Blockade of sodium channels. Neuropathic pain can be thought of as a result of abnormal electrical activity which can occur when nerves (and ion channels) are damaged.

· Opioid receptor interactions – amitriptyline may increase the release of endogenous opioid peptides.

· NMDA antagonist effect

It is also worth touching on cats. Amitriptyline was reported as an option for treatment of recurrent idiopathic cystitis by Chew and colleagues in 1998. They concluded that amitriptyline treatment successfully decreased clinical signs of severe recurrent IC in 9 of 15 cats treated. Interstitial cystitis clearly has a pain component with some considering this an example of nociplastic pain.

In conclusion it appears that amitriptyline may offer a therapeutic option for neuropathic pain in dogs and perhaps worth more consideration in cats.

References

Cashmore R.G., Harcourt-Brown T.R., Freeman P.M., Jeffery N.D., Granger N. (2009) Clinical Diagnosis and treatment of suspected neuropathic pain in three dogs. Australian Veterinary Journal 87 (1) 45-50

Chew DJ, Buffington CA, Kendall MS, DiBartola SP, Woodworth BE. Amitriptyline treatment for severe recurrent idiopathic cystitis in cats. J Am Vet Med Assoc. 1998 Nov 1;213(9):1282-6. PMID: 9810383.

Monteiro BP, de Lorimier LP, Moreau M, Beauchamp G, Blair J, Lussier B, Pelletier JP, Troncy E. Pain characterization and response to palliative care in dogs with naturally-occurring appendicular osteosarcoma: An open label clinical trial. PLoS One. 2018 Dec 6;13(12):e0207200. doi: 10.1371/journal.pone.0207200. PMID: 30521538; PMCID: PMC6283659.

Norkus C, Rankin D, KuKanich B. Pharmacokinetics of intravenous and oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Vet Anaesth Analg. 2015 Nov;42(6):580-9. doi: 10.1111/vaa.12248. Epub 2015 Feb 14. PMID: 25683584.

Su et al (2015) Amitriptyline Therapy in Chronic Pain International Archives of Clinical Pharmacology https://clinmedjournals.org/articles/iacp/iacp-1-001.pdf

This post was written by Matt Gurney.

Matt sees referrals in the pain clinic at Anderson Moores Veterinary Specialists. You can also receive telemedicine advice from us here if you have a pain case where you need a helping hand.

Matt & Carl established Zero Pain Philosophy to provide educational resources & telemedicine to veterinary professionals enabling optimal management of pain.

Matt Gurney is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and works at Anderson Moores Veterinary Specialists. Matt is President of the European College of Veterinary Anaesthesia & Analgesia.

Carl Bradbrook is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and is President of the Association of Veterinary Anaesthetists. Carl works at Anderson Moores Veterinary Specialists.

The intended audience for this pain update is veterinary professionals. This pain update is based on clinical experience and independent opinion.