Amantadine in the management of chronic pain in dogs and cats

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Why do this module?

A non-steroidal anti-inflammatory drug (NSAID) is the first-line drug therapy for cats and dogs with chronic pain. If NSAIDs are not tolerated, are contraindicated or become ineffective, there are few alternative drug treatments available to try. Amantadine, a dopamine agonist and anti-viral drug licensed in humans, is also an antagonist of N-methyl-D-aspartate (NMDA) receptors in the central nervous system, which have been implicated in the pathology of chronic pain. Here we review the evidence on, and practical aspects of using, amantadine in the management of chronic pain in dogs and cats.

By doing this module you will:

  • Understand the pharmacology of amantadine and the rationale for using it in chronic pain.
  • Be aware of the published evidence on the use of amantadine in dogs and cats.
  • Find out what is known about the adverse effects of amantadine. 
  • Know the potential role of amantadine in the management of chronic pain and how to monitor its effects.

Pain is categorised as peripheral (nociceptive), neuropathic or central. In reality, dogs and cats present with a combination of types and causes of pain. Chronic pain (i.e. lasting more than about 3 months) can be due to under-managed acute pain from causes such as trauma or surgery, osteoarthritis, spondylosis or cancer. Behavioural indicators of pain are important for pain assessment in dogs and cats (Epstein et al. 2015).

In humans, osteoarthritis pain is associated with a complex process known as central sensitisation that results in ‘pathological pain’. This is defined as pain initiated peripherally resulting in central nervous system hyperexcitability that with time becomes self-sustaining and persists despite elimination of the peripheral stimulus (Kosek and Ordeberg 2000). Heightened sensitivity to painful stimuli has been shown in dogs with osteoarthritis (Knazovicky et al 2016).

Central sensitisation is thought to involve stimulation of NMDA receptors, which triggers a cascade of events that contribute to neuro-plastic changes in the central nervous system. 

Pathological pain no longer serves a protective or preventive purpose and it may not resolve through treatment of the peripheral source (e.g. with NSAIDs or local anaesthetics). However it may respond to drug treatment directed at central targets of pain modulation, such as the use of NMDA-receptor antagonists. Several drugs have NMDA-receptor antagonist properties, including amantadine, dextromethorphan, ketamine and memantine (Fisher et al. 2000). 

Management of chronic pain includes pain assessment, owner questionnaires, and consideration of practical aspects such as ease of administration, palatability and cost (Murrell 2014). Effective management requires an understanding of the confounding factors and mechanisms of pain. Interventions may include: 

  • weight management and avoidance of obesity; 
  • dietary management and appropriate supplementation;
  • physical rehabilitation and physiotherapy; 
  • exercise and environmental adaptations; 
  • environmental enrichment and positive experiences;
  • acupuncture; 
  • tailored analgesia and other symptom-modifying drugs;
  • intra-articular therapy;
  • surgery. 

There is growing evidence that using several approaches together (known as multi-modal therapy) is beneficial in the management of chronic pain and osteoarthritis (Fox 2016).

Vets have a duty of care to their patients, and ensuring adequate quality of life in a patient is a daily challenge. Undermanaged chronic pain leads to premature euthanasia (Epstein et al. 2015). However, if analgesia is not adequately achieved and the prognosis is poor, euthanasia should be considered (Mathews et al. 2014).

The first choice drug treatment for dogs and cats with chronic pain with an inflammatory cause is usually an NSAID. Some animals may not tolerate NSAIDs, though the true incidence of adverse effects of NSAID therapy is unknown (Hunt et al. 2015). Therapy with an NSAID alone may become ineffective in more advanced disease. 

There are few other licensed drugs for long-term treatment of chronic pain in small animals. Injectable pentosan polysulphate (Cartrophen) is licensed in the UK for use in dogs and may provide analgesia through effects on articular metabolism and inflammation (Cartrophen SPC). Paracetamol plus codeine phosphate (Pardale-V) has a marketing authorisation for 5 days’ use; the codeine content of this is unlikely to provide analgesia because evidence suggests dogs gain very little benefit from oral opioids due to poor bioavailability (KuKanich et al 2010); it is therefore not recommended for routine use (Murrell 2014). Anecdotally, longer-term paracetamol (an unlicensed use) may provide valuable analgesia for some dogs (Murrell 2014). Paracetamol must not be used in cats. 

There are some drugs licensed for use in other conditions, or for acute pain, in dogs and cats that may help in the management of chronic pain, usually administered in hospital for a chronic pain flare-up. These include lidocaine, ketamine, opiates (buprenoprhine, methadone, fentanyl) or alpha-2-antagonists (dexmedetomidine, medetomidine). Drugs licensed for humans that may contribute to a combination therapy approach to chronic pain management include amantadine, amitriptyline, corticosteroids, gabapentin, bisphosphonates (for bone cancers), paracetamol and tramadol. Unfortunately, there are very few veterinary clinical trials assessing any of these options in chronic pain. 

As well as being an NMDA-receptor antagonist, amantadine is a weak dopamine agonist with some anticholinergic effect; it is also an antiviral that inhibits replication of influenza type A virus (Martindale 2017). In humans it is a prescription-only medicine licensed for the treatment of Parkinson’s disease, post-herpetic neuralgia, and for the treatment and prophylaxis of influenza A (although it is not recommended in the NHS for either use against influenza) (British National Formulary 2017).

In dogs, amantadine is completely absorbed after oral administration, and completely eliminated within 24 hours; it is metabolised to some extent to N-methylamantadine. The half-life is around 5– hours (Bleidner et al. 1965; Norkus et al. 2015). More studies are needed to determine if the handling of amantadine differs with the breed of dog. 

In cats, amantadine is well absorbed after oral administration and has a high volume of distribution indicating extensive tissue binding, but routes of metabolism have not been studied; half-life is 5.4 hours (Siao et al. 2011).

In humans, the half-life of amantadine is reported to be about 15 hours. It is excreted mostly unchanged in the urine and clearance is significantly reduced by renal insufficiency (Martindale 2017).

The analgesic effects of amantadine have been compared with placebo in a blinded randomised controlled trial involving 31 client-owned dogs with osteoarthritis refractory to treatment with NSAIDs (Lascelles et al. 2008). After a week of no analgesia, dogs in both groups received oral meloxicam (0.1mg/kg once daily) for 2 weeks; they then also received either oral amantadine (3–5mg/kg once daily) or placebo for a further 3 weeks. The primary outcome measures were blinded owner assessments of activity impairment (e.g. difficulty getting up from lying down, getting into a car) and behaviour (e.g. restlessness, sociability). By the end of the trial, owner-assessed activity impairment was significantly reduced in dogs on amantadine + meloxicam (a score of 3.9 vs. 6.7 for placebo + meloxicam, p=0.03). Vet-assessed lameness, a secondary outcome measure, also improved (p=0.03). However, there was no significant improvement in owner-assessed behaviour or vet-assessed weight-bearing or reaction to joint manipulation. No adverse effects were noted by the owners.

A case report described the successful management of suspected neuropathic pain with amantadine (Madden et al. 2014). The young crossbred dog had a chronic vertebral fracture after being hit by a car 15 months earlier. Oral amantadine (100mg [14mg/kg] once daily) plus meloxicam (0.1mg/kg once daily) appeared to cause marked improvement in signs within 14 days; signs returned on cessation of amantadine therapy but after re-introduction the dog continued to be free of clinical signs 11 months later. The dog had previously shown a poor response to tramadol (2mg/kg twice daily), and gabapentin (10mg/kg twice daily), in combination with meloxicam. 

There are no published dose-finding studies in dogs and cats with chronic pain, and no reports on the clinical efficacy of amantadine in cats.

Amantadine is reported to be useful for chronic low back pain, surgical pain and neuropathic pain in people. In a double-blind randomised placebo-controlled trial lasting 1 week in 26 patients with chronic low back pain, oral amantadine sulphate (100mg daily) reduced clinical pain and experimental sensitisation to heat pain (Kleinbohl et al. 2006). In a double-blind randomised placebo-controlled trial involving 60 people undergoing elective spine surgery, oral amantadine (50mg or 100mg) administered 1 hr before and 8, 20, 32 hours after surgery significantly reduced intra-operative fentanyl use and post-operative morphine intake (Bujak-Giżycka et al. 2012). In a double-blind randomised placebo-controlled trial, intravenous amantadine 200mg over 3 hours reduced neuropathic pain associated with surgery (e.g. mastectomy) in 15 patients with cancer (Pud et al. 1998).

The adverse effects of amantadine in dogs and cats are not well studied. It is reported that some dogs may develop agitation, vomiting, flatulence, or diarrhoea (which may be watery), particularly in the early days of amantadine therapy (Plumb’s 2017; personal communication with specialists). Specialists advise stopping amantadine if adverse signs occur, reintroducing it once they have resolved; giving the drug with food may prevent vomiting. Any adverse effects should be reported to the VMD.

In humans, common or very common adverse effects (occurring in 1–10% of patients or more) include: dry mouth; anorexia; anxiety; dizziness; gastro-intestinal disturbances; hallucinations; headache; impaired concentration; insomnia; lethargy; skin rash; mood changes; myalgia; palpitations; peripheral oedema; postural hypotension; slurred speech; and sweating. Uncommon effects (in 0.1 to 1% of patients) include confusion; movement disorders; neuroleptic malignant syndrome; psychosis; rash; seizure; tremor; urinary incontinence; urinary retention; and visual disturbances. Heart failure; leucopenia; and photosensitisation have also been reported (British National Formulary 2017).

The safety of amantadine in pregnant or lactating dogs and cats is not known; teratogenic effects have been reported after high doses in rats. Amantadine is distributed into human milk (Martindale 2017).

In humans, amantadine is contraindicated in people with epilepsy and a history of gastric ulceration, but the relevance of this in animals is unknown.

In theory there is a potential for interaction with the following (Stockley 2018): 

  • anticholinergic drugs;
  • other NMDA antagonists (e.g. ketamine);
  • drugs that alter renal tubular secretion (e.g. quinidine, quinine, thiazide diuretics, triamterene), which may affect the excretion of amantadine. 

Amantadine may be considered as an adjunct when response to NSAIDs is inadequate or when NSAIDs are not tolerated or contraindicated (Murrell 2014). It has also been suggested as adjunctive analgesia for chronic pain in patients unresponsive to opioids (BSAVA 2017) although there is no clinical evidence to support this. Amantadine is not licensed for use in animals and so must be used according to the prescribing ‘cascade’. The RCVS Code of Professional Conduct considers it good practice for vets to obtain the owner’s consent, in writing, for the animal to be treated under the cascade. 

For dogs, the suggested dose of amantadine is 3–5mg/kg by mouth every 24 hours (BSAVA Formulary 2017). Specialist clinical experience suggests that many dogs gain appropriate analgesia from once daily dosing, but twice daily dosing is well tolerated and often beneficial when once daily dosing is ineffective.

For cats, the suggested dose is 1–4mg/kg by mouth every 24 hours, starting at the lowest dose and increasing slowly (BSAVA Formulary 2017), or 3 mg/kg every 12–24 hours (Vetformulary 2017).  

The dose should be reduced in the presence of renal impairment and the drug used with caution in hepatic impairment. A therapeutic trial of 3–4 weeks is appropriate to confirm whether the treatment has any benefit. 

Amantadine hydrochloride is available as tablets, capsules and syrup: 

  • amantadine hydrochloride 100mg capsules: licensed in humans, available from AAH Pharmaceuticals; Alliance Healthcare (Distribution); Teva UK;
  • amantadine hydrochloride 50mg/5mL oral solution: licensed in humans, available from AAH Pharmaceuticals; Alliance Healthcare (Distribution);Teva UK;
  • amantadine hydrochloride 10mg, 25mg, 50mg, 75mg tablets: veterinary specials available from Summit Veterinary Pharmaceuticals.

The weak evidence on amantadine and other drug options creates a dilemma for prescribers looking for an alternative to NSAIDs. If the decision is made to try amantadine, it is important to have clear goals for monitoring its effects. In the absence of evidence on the best measures for assessing efficacy of treatments for osteoarthritis (Belshaw et al 2016), it makes sense to use ones that are meaningful and easy for the owner to record (e.g. the dog’s demeanour, or how easily it walks up steps). The owner should also look out for any adverse effects. The treatment should be reviewed after a few weeks and if there is no improvement, or adverse effects outweigh any benefit, the drug should be stopped. 

Clients should be warned about potential adverse effects including drowsiness, vomiting, constipation or diarrhoea and advised to stop treatment and seek veterinary advice if agitation or seizures occur. 

Amantadine is a drug with central pain-relieving properties. There is some evidence that it may help relieve neuropathic pain in humans, but there is little clinical evidence in dogs with chronic pain and none in cats. In a single randomised controlled trial in dogs, amantadine in combination with meloxicam improved some subjective measures of pain and was well tolerated. Amantadine may be considered when response to NSAIDs is inadequate or when NSAIDs are not tolerated or contraindicated, although there is no published clinical evidence of its efficacy as monotherapy. It may also be useful for chronic pain in patients unresponsive to opioids, although there is no clinical evidence to support this. If used, it is important to monitor amantadine’s effects, report any adverse effects, and stop the drug if there are no benefits, or benefits are outweighed by adverse effects.

PODCAST

If you prefer, you can listen to the whole audio presentation of this module using the following podcast. Don't forget that you can also download the podcast to your iPod, music player, tablet or smartphone using the Download link on the right of the audio player.

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Click the play button below to answer the multiple choice questions on this module. Start by entering your first and second names and your email address so we can send you a CPD certificate for your records. 

Goal of activity: Update knowledge; help clinical decision-making.

Specific learning objectives: to improve knowledge and understanding of amantadine in clinical practice.

How we produced this module

Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was Gwen Covey-Crump. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, other topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration. 

References

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