Analgesics in practice: non-traditional analgesics (Proceedings)
The veterinary practitioner may be involved in some cases where pain management with NSAIDs or opioids is not possible due to the unacceptable risk of adverse effects. In other cases, the analgesia achieved with these drugs may not be adequate. Therefore many of the recent advances in veterinary pain management have focused on non-traditional analgesics that can be used place of NSAIDs and opioids or as a multimodal approach in conjunction with traditional analgesics. Some of these drugs are reviewed below.
NMDA (n-methyl d-aspartic acid) Antagonists
The NMDA antagonist group of analgesics include the drugs ketamine, amantadine and dextromethorphan. These drugs have been shown to interrupt wind-up. Wind-up, or central sensitization, occurs due to changes in dorsal horn neuron excitability when a summation of potentials causes seconds of nociceptive activation to produce minutes of post-synaptic depolarization ("wind-up"). This phenomenon is mediated by NMDA receptors which bind glutamate and tachykinin receptors that bind substance P (SubP) and neurokinin A. Activation of the NMDA receptor increases sensitivity to glutamate and lowers the pain threshhold, resulting in an increased responsiveness as well as increased sensitivity in neighboring areas. NMDA antagonist can be used to inhibit or break this cycle, and they are also known to potentiate the effects of opioids.Ketamine is a commonly used dissociative injectable anesthetic. Interrupting wind-up can be accomplished at sub-anesthetic doses with minimal risks for behavior changes, but needs to be given intravenously, typically as a CRI. Anti-inflammatory effects at these lower doses have also been seen. CRI doses recommended for peri-operative analgesia in dogs and cats are 0.5 mg/kg loading dose followed by 10 mg/kg/min intra-operatively then 0.002 mg/kg/min post-operatively.
Amantadine is a cyclic amine that has antiviral activity against influenza viruses in addition to its analgesic properties. The advantage of this drug is that it comes in oral formulations that can be administered once daily. Doses studied in dogs and cats for analgesia are 3-5mg/kg PO SID. There is a very low incidence of adverse effects, which is limited mainly to agitation and diarrhea. Amantadine can be given with other drugs. The beneficial effects may take days to weeks to reach full effects.
Dextromethorphan is the D-isomer of the opiate levorphan, but itself does not bind to either the µ or κ receptors. It is most commonly used as an antitussive, but it is also used in people as an analgesic for neuropathic pain, as its active metabolite is an NMDA antagonist. Studies in drugs have shown that they do make the active metabolite required for NMDA antagonism, therefore this drug is unlikely to be effective as an analgesic.
The local anesthetics, such as lidocaine, block sodium channels, thereby interrupting neural transmission of pain and producing analgesia. Limitation of use of local anesthetics include a short half-life and duration of action (2-6 hr). Additionally, these drugs are most effective with parenteral administration, perineurally or via CRI. Constant rate infusion doses used in dogs include a bolus dose of 1 mg/kg followed by 30 mg/kg/min. Lidocaine CRIs are best avoided in cats as they have the potential to cause cardiotoxicity. In treating chronic pain, the placement of "soaker-catheters" may be used where appropriate. Lidoderm® patches provide a topical option and are convenient in that they can be cut to appropriate sizes. Catheters and patches should not be combined with CRI lidocaine, and perineural injections with lidocaine or other local anesthetics should not be used until more information is availble about toxicity.
Gabapentin and pregabalin (Lyrica®) are structural analogues of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), although its mechanism of action as an analgesic or anticonvulsant are not related to any interactions with GABA receptors, through an effect on GABA uptake or degeneration, or through any other interactions with neurotransmitter receptors. Instead, the analgesic/anticonvulsant effects may be due to inhibition of the α2δ subunit of the N-type voltage-dependent calcium ion channels (VDCC). Many of these channels in the dorsal root ganglia and spinal cord are upregulated after peripheral nerve injury. These drugs have been used in humans to treat neuropathic pain states including diabetic neuropathy, malignant pain, central pain, complex regional pain syndrome, and trigeminal neuralgia.
Gabapentin has been successfully used in both dogs and cats. Doses recommended in dogs vary widely and include 2.5-10 mg/kg PO SID-TID. In cats, doses of 50mg (5-10 mg/kg) PO BID – TID are used clinically. Discontinuation of gabapentin should be achieved by weaning off of the drug over 2-3 weeks to prevent seizures (reported in humans) and a rebound pain phenomenon.
Pregabalin is newer and more potent than gabapentin, and clinical evidence for use is minimal. One study suggests a dose of 4 mg/kg/day in dogs.