Several drugs that can be incorporated into a pain management protocol are not part of the traditional classes of analgesics such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs). These drugs may be called adjuvant analgesics. Indeed, they had been developed for another reason other than analgesia. In addition, these compounds are rarely used alone and very frequently are part of a multimodal analgesic approach. Gabapentin and amantadine and both examples of adjuvant analgesics.¹

Gabapentin

Gabapentin is a lipophilic structural analogue of the inhibitory neurotransmitter GABA. This drug was initially developed as an anticonvulsant and is now indicated for the treatment of seizures and neuropathic pain. The mechanism of action of gabapentin remains to be elucidated. What is known is that it acts on voltage-gated calcium channels.² Clinically in humans, systematic reviews and meta-analyses reveal that the perioperative administration of gabapentin in combination with opioids reduce postoperative pain scores and opioid requirements, as well as the incidence of opioid-induced adverse-effects such as nausea, vomiting and pruritus.³ Additionally, the perioperative administration of gabapentin decreases the prevalence of chronic postsurgical pain and improves postoperative patient function. Few studies in animals have been designed to study the efficacy of gabapentin in the perioperative setting. In dogs undergoing mastectomy, the perioperative co-administration of gabapentin (10 mg/kg PO) and morphine (IM) decreased postoperative opioid requirements when compared with placebo treatment.⁴ In different studies with dogs undergoing hemilaminectomy or limb amputation, treatment with gabapentin + other analgesics did not differ from those treated with placebo + other analgesics.

One should take into account that other analgesics were used in both these studies which makes it difficult to interpret the results. In an unpublished study of cats undergoing ovariohysterectomy, gabapentin administered pre-operatively in combination with an opioid (buprenorphine) provided similar analgesia when compared with opioid + NSAID (buprenorphine + meloxicam) (Steagall 2016; personal communication). Despite little scientific data available, clinical experience suggests their potential effects for the treatment of acute pain. In fact, a panel of experts (World Small Animal Veterinary Association Global Pain Council) recommends the perioperative use of gabapentin as an adjunctive treatment to prevent postsurgical pain, or in circumstances with limited availability of drugs.⁵ In cats, gabapentin has excellent bioavailability (approximately 89%) after oral administration.⁶ An antinociceptive study and a study on the minimum alveolar concentration of isoflurane did not detect efficacy of gabapentin.

In this species, the analgesic efficacy of gabapentin has only been reported in case-series following major orthopedic procedures, wound debridement,⁷ and musculoskeletal pain and head trauma. Gabapentin is generally recommended for the treatment of chronic neuropathic pain and other maladaptive painful conditions. In humans, their efficacy for the treatment of chronic pain is well recognized and this compound is commonly recommended as an adjuvant for the treatment of neuropathic pain. Along with published data in animals, there seems to exist a strong rationale for using gabapentin in dogs and cats for the treatment of chronic pain. The drug is well tolerated in dogs and cats. Possible adverse-effects include sedation, nausea, and vomiting. Sedation is the most common adverse-effect which seems to resolve with patient acclimation over several days.

Amantadine

Amantadine was initially developed as an antiviral drug. Its analgesics effects result from the antagonism of N-methyl-D-aspartate (NMDA) receptors and by increasing dopamine concentrations in the central nervous system. Amantadine is indicated for the treatment of conditions characterized by central sensitization (e.g., osteoarthritis-related pain, cancer-related pain). Precisely, conditions characterized by central hyperactivity, or that are refractory to opioid or NSAID treatment. It is important to emphasize that amantadine is not recommended to be used a monotherapy.¹ Rather, the drug should enhance the analgesic effects of other analgesic drugs. Scientific data on the use of amantadine in animals is lacking.

One study in dogs with osteoarthritis-related pain refractory to an NSAID showed that physical activity was improved by the addition of amantadine.⁸ Those authors concluded that amantadine might be a useful adjunct therapy for the clinical management of canine osteoarthritic pain. In dogs, pharmacokinetics of amantadine revealed that the drug seems to be well absorbed, with a short half-life (5 hours after 30 mg/kg PO).⁹ In cats, pharmacokinetics of amantadine (5 mg/kg PO and IV) revealed high oral bioavailability and also a short half-life (5.5 hours after 5 mg/kg PO).¹⁰ For this reason, some authors suggest that dosing every 12 hours should be used in dogs and cats.¹ It has been reported that although safety studies are not available for dogs or cats, the administration of amantadine at 50 mg/kg every 24 hours for 30 days did not cause any death.¹ Treatment with amantadine should be attempted for a minimum of 3–4 weeks of treatment for evaluation of efficacy.

References

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2.  Kukkar A, Bali A, Singh N, Jaggi AS. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res. 2013;36:237–251.

3.  Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med. 2006;31:237–47.

4.  Crociolli GC, Cassu RN, Barbero RC, Rocha TL, Gomes DR, Nicacio GM. Gabapentin as an adjuvant for postoperative pain management in dogs undergoing mastectomy. J Vet Med Sci. 2015;77:1011–1015.

5.  Mathews K, Kronen PW, Lascelles D, et al. Guidelines for recognition, assessment and treatment of pain. J Small Animal Pract. 2014:55:E10–68.

6.  Siao KT, Pypendop BH, Ilkiw JE. Pharmacokinetics of gabapentin in cats. Am J Vet Res. 2010;71(7):817–821.

7.  Steagall PV, Monteiro-Steagall BP. Multimodal analgesia for perioperative pain in three cats. J Feline Med Surg. 2013;15:737–43.

8.  Lascelles BD, Gaynor JS, Smith ES, et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med. 2008;22:53–59.

9.  Bleidner WE, Harmon JB, Hewes WE, et al. Absorption, distribution and excretion of amantadine hydrochloride. J Pharmacol Exp Ther. 1965;150:484–490.

10. Siao KT, Pypendop BH, Stanley SD, et al. Pharmacokinetics of amantadine in cats. J Vet Pharmacol Ther. 2011;34:599–604.