Analgesics in practice part 3: 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 in 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 threshold, resulting in an increased responsiveness as well as increased sensitivity in neighboring areas. NMDA antagonists 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 ketamine 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 are 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.

Local Anesthetics

The local anesthetics, such as lidocaine, block sodium channels, thereby interrupting neural transmission of pain and producing analgesia.  Limitations 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 0.03 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 available about toxicity.

Anticonvulsants

Gabapentin and pregabalin (Lyrica®) are structural analogues of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), although their 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 α2δsubunit 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, but clinical evidence for use is minimal at that time.  One study suggests a dose of 4 mg/kg/day in dogs.

Bisphosphonates

The bisphosphonates are a group of drugs that decrease osteoclastic activity, thereby decreasing bone destruction. As such, they can be used to reduce the risk of fracture and reduce discomfort in cases of skeletal neoplasia.  In vitro studies suggest that bisphosphonates also have a direct toxic effect on bone cancer cells and they may inhibit the growth of new blood vessels within the cancer, thereby inhibiting cancer growth. They have a very long duration of action and bind to areas of bone with the highest turnover, only releasing as the bone matrix is remodeled. These drugs are considered to have a wide safety margin, however side effects can include hypocalcemia, gastrointestinal irritation and renal toxicity. Oral administration is associated with severe esophageal ulceration in humans.

Pamidronate is an IV bisphosphonate that has been shown to provide pain relief in ~50% of dogs with skeletal neoplasia. The recommended dose is 1-2 mg/kg IV over 2 hours q 21 to 28 days.

Alendronate is an oral amino-bisphosphonate that has been used for skeletal neoplasia in dogs at doses of 10 mg PO q24h.

Alpha-2 agonists

The α-2 agonists (i.e. xylazine, medetomidine and dexmedetomidine) are profound sedatives and analgesics.  In human medicine, alpha-2 agonists are used for rescue analgesia when opioids have failed.  While they produce reliable analgesia after parenteral or epidural administration, they also produce significant sedative and cardiovascular effects, which may limit their use, particularly for chronic pain.

Medetomidine has been used as a CRI in dogs and cats with a loading dose of 0.001-0.002 mg/kg followed by 0.001-0.002 mg/kg/hr.  Do not use in cases of severe heart disease.  Use in mild to moderate heart disease can be achieved as long as careful monitoring is performed.  Although medetomidine causes a significant increase in systemic vascular resistance, this effect appears to decrease over time with the CRI administration.

Dexmedetomidine contains the active enantiomer of medetomidine only.  It is more potent than medetomidine, but the dose volume is the same, due to a difference in concentration in the formulation.  CRI doses in dogs and cats are 0.5-3 μg/kg/hr  (typical doses 1-2 μg/kg/hr).  Do not use in cases of severe heart or respiratory disease.

Resiniferatoxin (RTX)

RTX is an ultra-potent capsaicin analog that binds at the vanilloid (VR1) receptor, a ligand gated sodium/calcium cation channel expressed by small sensory neurons (unmyelinated C-fibers).  C-fibers transmit noxious, inflammatory, and thermal information.  Binding to VR1 receptor causes prolonged increases in free intracellular calcium concentration, resulting in calcium toxicity of the neuron and subsequent neuronal desensitization. Blocking C-fiber information can stop inflammatory/ hyperalgesic/ cancer/ osteoarthritis pain while maintaining normal proprioception and mechano-sensation. This neurotoxic effect can last weeks to months.  Be aware, however, that the drug activates the pain pathway before it desensitizes it.  Intrathecal administration of 1.2 µg/kg was shown to be an effective analgesic in a canine model of bone cancer. Interestingly, it has also been studied in dogs as an anti-emetic for cancer chemotherapy at 10 µg/kg SC. RTX is still experimental although capsaicin cream is available in alternative medicine stores.

Phenothiazine Tranquilizers

Acepromazine (ACP) is a phenothiazine, major tranquilizer that causes sedation by antagonizing dopamine (D2) receptors.  The major side effect of acepromazine is a peripheral alpha-1 blockade that causes vasodilation and is therefore contraindicated in conditions such as cardiac insufficiency, hypovolemia, or hypotension.  When administered alone, acepromazine provides sedation only and no analgesia.  However, when administered with an opioid agonist, acepromazine potentiates the analgesic effects of the opioid.

Tricyclic Antidepressants

Various serotoninergic and noradrenergic pathways are involved in the pain response. Stimulation  of these pathways reduces pain transmission in the spinal cord.  The tricyclic antidepressants (TCAs) inhibit the reuptake of various monoamines, including serotonin (clomipramine, fluoxetine, paroxetine) and norepinephrine (amitriptylline, imipramine). In human medicine, the analgesic effects are seen at doses much lower than those used to treat depression.

Amitriptylline is the drug in this class most studied as an analgesic medication, and it may have a significant effect not only on norepineprhine, but also on serotonin, histidine and cholinergic receptors. In cats, a dose of 0.5-2 mg/kg PO q24h has been used to treat pain associated with interstitial cystitis for up to 12 months. Adverse effects associated with administration include somnolence, weight gain, decreased grooming and transient cystic calculi. This drug is often administered in combination with NSAIDs for chronic pain states.