Amantadine for chronic pain

Amantadine is an oral NMDA antagonist used for the management of chronic pain in dogs and cats.

Amantadine has pharmacological actions as both an anti-Parkinsonian and an antiviral drug in humans. It is a weak dopamine agonist and glutamate antagonist. Glutamate contributes to a range of normal physiological functions but has also been implicated in chronic pain. Targeting abnormal glutamate activity without interfering with normal function is a challenge for drug design.

Where does glutamate feature?

The NMDA, AMPA and kainate glutamate receptors are ionotropic receptors (R).

In the resting state the NMDA R is blocked by a magnesium ion and is unresponsive to glutamate. Under circumstances of significant depolarisation of the AMPA or kainite receptors by glutamate, or substance P at the neurokinin-1 receptor, the magnesium block is displaced and the NMDA R becomes responsive to glutamate.

Peripheral activity leads to central changes

Prolonged peripheral C fibre activity causes this central release of glutamate – the NMDA, AMPA and kainite receptors are located in the dorsal horn of the spinal cord. Activation of these receptors triggers an influx of calcium into the cell, which ultimately affects the neuron’s response to subsequent stimuli, which contribute to the mechanical hyperalgesia seen following peripheral injury.

Receptor sites are targets

There are several sites on the NMDA R complex that can be targeted beyond the NMDA site. Glycine is a co-agonist and serves as a target for drug therapy. Local anaesthetics, magnesium and drugs binding to the phencyclidine site (such as ketamine and memantine) have inhibitory actions on receptor activity. Available NMDA R antagonists include ketamine, amantadine, memantine, magnesium sulphate and opioids such as methadone. In addition to these interleukin antagonists produce anti-allodynic effects in rat neuropathic pain – it is known that astrocytes produce interleukins that act at the NMDA R to promote inflammatory pain.

Amantadine works by increasing the rate of channel closure following activation of the NMDA complex (Blanpied, 2005).

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Amantadine in dogs with chronic pain

Amantadine is of relatively low potency in its NMDA actions and is therefore best suited to use as part of a multimodal regime. The following study evaluated the use of amantadine alongside meloxicam, in comparison to meloxicam alone.

Population

Client owned dogs (31) with osteoarthritis refractive to NSAID therapy alone.

Groups

Meloxicam or meloxicam plus amantadine

Study timelines

Days 0-7 – no analgesia in either group

Days 7-14 meloxicam given to both groups and continued for 5 weeks

Days 21-42 the amantadine group received 3-5mg/kg PO SID plus meloxicam, the meloxicam group received meloxicam plus a placebo capsule.

Outcome measures

Activity assessment using client specific outcome measures days 0, 7, 21 and 42

Results

The amantadine/meloxicam group were more active at day 42 based on owner assessment and less lame based on vet assessment.

It is based on this work that I use amantadine as my second line in dogs with OA that require a multimodal approach. (When should we use a multimodal approach in OA – read more here). My experience of using amantadine in conjunction with NSAIDs is positive. I would encourage you to look beyond lameness and closely assess comfort levels. To do this you will need to incorporate some chronic pain scoring such as the Canine Brief Pain Inventory.

One case report describes the use of amantadine to treat neuropathic pain in a dog. Amantadine was chosen in this case based on the pathophysiology of the condition and the rationale that an NMDA antagonist was required. The dog responded positively to the addition of the amantadine to NSAID therapy. When the amantadine was stopped the signs of pain reverted – but control was gained a second time once amantadine was reintroduced. (Madden, Gurney, & Bright, 2014).

For a review of neuropathic pain click here.

Pharmacokinetics of amantadine

Described in cats (Siao et al., 2011). Half-life of approx. 5hrs following 4mg/kg PO (does suggest that BID dosing may be more suitable in cats).

In greyhounds 2.8mg/kg PO produced a Cmax at 2.6 hours with a terminal half life of 4.96hrs (4.11-6.59hrs) suggesting dosing should be more frequent than SID. (Norkus et al., 2014)

Contraindications

Caution in liver and renal disease because of lack of information.

Drug combinations

Amantadine + NSAID

Amantadine + Paracetamol

Amantadine + Gabapentin

Dose

3-5mg/kg PO SID dogs (Lascelles et al., 2008), 3-5mg/kg cats SID.

If comfort is not improved with SID administration increase to BID.

<37kg = 100mg

>37kg = 200mg

Available in capsule or liquid formulation. Liquid formulation is tolerated well by cats.

Side effects

Diarrhoea. If this happens stop the amantadine, treat supportively and reintroduce the amantadine once the diarrhoea has resolved.

Notes

It is often more cost effective to obtain through the local pharmacy rather than veterinary wholesalers.

Case study

Read here about how the addition of amantadine gave one little dog a huge improvement in comfort.

References

Blanpied, T. A. (2005). Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block. Journal of Neuroscience, 25(13), 3312–3322. http://doi.org/10.1523/JNEUROSCI.4262-04.2005

Lascelles, B. D. X., Gaynor, J. S., Smith, E. S., Roe, S. C., Marcellin-Little, D. J., Davidson, G., et al. (2008). Amantadine in a Multimodal Analgesic Regimen for Alleviation of Refractory Osteoarthritis Pain in Dogs. Journal of Veterinary Internal Medicine, 22(1), 53–59. http://doi.org/10.1111/j.1939-1676.2007.0014.x

Madden, M., Gurney, M., & Bright, S. (2014). Amantadine, an N-Methyl-D-Aspartate antagonist, for treatment of chronic neuropathic pain in a dog - Madden - 2014 - Veterinary Anaesthesia and Analgesia - Wiley Online Library. Veterinary Anaesthesia and Analgesia

Moore, S. A. (2016). Managing Neuropathic Pain in Dogs. Frontiers in Veterinary Science, 3(S1), CD009177. http://doi.org/10.1053/j.tcam.2014.04.001

Norkus, C., Rankin, D., Warner, M., & Kukanich, B. (2014). Pharmacokinetics of oral amantadine in greyhound dogs. Journal of Veterinary Pharmacology and Therapeutics, 38(3), 305–308. http://doi.org/10.1016/0303-8467(92)90006-O

Siao, K. T., Pypendop, B. H., Stanley, S. D., & Ilkiw, J. E. (2011). Pharmacokinetics of amantadine in cats. Journal of Veterinary Pharmacology and Therapeutics, 34(6), 599–604. http://doi.org/10.1111/j.1365-2885.2011.01278.x