Management of outpatient pain: difficult cases (Proceedings)

Nonsteroidal antiinflamatory drugs (NSAIDs) are commonly used in veterinary medicine for a variety of reasons including the management of acute postoperative pain and chronic pain associated with degenerative joint disease among other conditions. However adverse effects preclude their use in many patients and severe adverse effects such as nephrotoxicity, hepatotoxicity, and gastrointestinal ulceration and perforation, and death occur infrequently. A variety of other medications have demonstrated efficacy in humans, but information on their use and efficacy in veterinary medicine are lacking. Fentanyl patches have been used successfully to manage pain in dogs and cats, but liability and abuse potential are concerns in veterinary medicine.

A variety of oral opioids have been evaluated in dogs. Pharmacokinetic studies examining morphine, methadone, butorphanol, and oxycodone indicate they have poor systemic absorption after oral dosing and are unlikely effective. The oral absorption of codeine is also limited as well as the formation of the active metabolite morphine in dogs. However recent studies indicate another metabolite, codeine-6-glucuronide (C6G) may produce analgesic effects in humans. Dogs may produce C6G in large amounts after codeine administration, but data are extremely limited.

Hydrocodone

Studies evaluating the oral bioavailability of hydrocodone in dogs have shown variable results (~40-80%) but indicate it is absorbed systemically following oral administration to dogs. Hydrocodone is mu opioid agonist most commonly used in veterinary medicine as an antitussive; however it is routinely used in humans as an analgesic. Hydrocodone is metabolized to hydromorphone, an active metabolite which is also a mu agonist. Recent studies in dogs suggest that hydrocodone is metabolized to hydromorphone in dogs with hydromorphone concentrations persisting to at least 8 hours after 0.5 mg/kg hydrocodone bitartrate PO. The analgesic effects of hydrocodone have not been determined in dogs. Hydrocodone tablets containing 10 mg hydrocodone bitartrate and 300 mg acetaminophen can be quartered with relatively good precision, therefore a dose of ¼ tablet per 11# of body weight to dogs q 8-12 hours PO can be administered. Hydrocodone is inexpensive, but is subject to abuse. Therefore it may be best not to stock hydrocodone in the clinic, but script it out to a local pharmacy to decrease liability potential. Do not administer the combination product to cats as the acetaminophen is toxic to cats.

Tramadol

Tramadol is a central acting analgesic with multiple mechanisms of action. Tramadol and its active metabolite (o-desmethyltramdol or M1) are serotonin and norepinephrine reuptake inhibitors which may contribute to its analgesic effects by stimulating descending pain inhibitory pathways. Tramadol's active metabolite also appears to act through the mu opiate receptors to elicit analgesic effects. Although no efficacy studies are available in dogs, studies in humans demonstrate the metabolite is necessary for tramadol to be effective as an analgesic. Studies in dogs and cats have identified the active metabolite, although the formation appears variable. Selective serotonin reuptake inhibitors (SSRI's), such as fluoxetine and paroxetine, inhibit the metabolism of tramadol to the active metabolite decreasing its efficacy and increasing the risk of toxicity (serotonin syndrome). Other drug-drug interactions due to serotonin toxicity with tramadol include tricyclic antidepressants (clomipramine, amitriptyline) and serotonin norepinephrine reuptake inhibitors (venlafaxine, duloxetine). Ondansetron (Zofran) and other serotonin antagonists (5HT3) may decrease the efficacy of tramadol, but the results have been variable. Tramadol is inexpensive and currently not a scheduled drug in the USA. Tramadol may lower the seizure threshold, therefore should be used cautiously in animals prone to seizures such as epileptics. Current dosing recommendations for dogs are 5 mg/kg q 6-8 hours and for cats 1-2 mg/kg q 12 hours. The efficacy of these dosages has not been evaluated. It is important to remember that maximum analgesic effects may not occur immediately and may be delayed up to 10-14 days for chronic pain conditions such as cancer and degenerative joint disease. Tramadol can be administered with NSAIDs, gabapentin, and amantadine.

Gabapentin

Gabapentin in a γ-amino-butyric acid (GABA) analogue which may increase brain GABA concentrations in humans, but the precise mechanism of action has not been determined. Gabapentin does not appear to act directly on GABA receptors, but may increase GABA concentration by decreasing GABA metabolism, increase non-synaptic GABA release, or decrease reuptake. Gabapentin may also decrease the release of glutamate, a stimulatory neurotransmitter, in the spinal cord which may contribute to its analgesic effects. Gabapentin inhibits the voltage gated calcium channels in the spinal cord which may also contribute to its analgesic effects. Gabapentin is labeled for use in humans as an anticonvulsant and for the management of neuropathic pain. Studies in humans have demonstrated variable efficacy of gabapentin for chronic and cancer pain. Gabapentin exhibits additive to synergistic effects when combined with tramadol. Recent findings in a small clinical trial in humans indicated gabapentin was effective in decreasing acute postoperative pain and analgesic consumption although other studies found no benefit compared to a placebo. In dogs approximately 40% of gabapentin is metabolized (hepatic) with the remainder eliminated by renal mechanisms. No studies have evaluated the efficacy of gabapentin in dogs or cats for treating acute or chronic pain, however anecdotal dosage regimens for pain in dogs (10 mg/kg PO q 12 –24 h) have been made. Adverse effects in humans include sedation, ataxia, fatigue, tremors, and rebound seizures upon discontinuation of therapy. Gabapentin can be combined with NSAIDs, tramadol, and amantadine for the management of pain.

Amantadine

Amantadine was originally introduced as an antiviral drug. However, it may be effective in treating chronic pain and as an adjunct in acute pain due to its activity as an n-methyl-d-aspartate (NMDA) receptor antagonist. Another effect of amantadine is as a dopamine agonist. As an NMDA antagonist, amantadine's primary action is to decrease central sensitization (windup pain) and does not typically provide analgesia as a stand-alone treatment. Therefore amantadine is often used in combination with analgesics such as tramadol, NSAIDs, or opioids. Some clinical trials in humans have demonstrated efficacy in chronic pain conditions, however little information is available on appropriate dosages, efficacy, and adverse effects in animals. A recent study in dogs that were poorly responsive to NSAIDs alone coadministration of amantadine (3-5 mg/kg PO q 24h) resulted in significantly improved activity by day 42. Common adverse effects in humans (up to 33% of patients) include nausea, anorexia, insomnia, and difficulty concentrating. In humans, adverse effects may increase when amantadine is administered concurrently with antihistamines, anticholinergics, and psychotropic drugs. Tolerance may develop with long-term use of amantadine. The current dose recommendations are 3-5 mg/kg PO q 24h and are based anecdotally.

Tricyclic antidepressants (clomipramine, amitriptyline)

Tricyclic antidepressants (TCAs) have been used in the management of chronic pain in humans due to their activity as serotonin and norepinephrine reuptake inhibitors. Serotonin and norepinephrine act to modulate pain by enhancing the descending inhibitory pathways. In humans, adverse effects are typically dose limiting, primarily due to their anticholinergic effects. TCAs should not be combined with tramadol as serotonin syndrome (toxicity) may occur with effects such as tremors, rigidity, coma, incoordination, agitation, arrhythmias, hyper- and hypotension, and dyspnea among others. The efficacy of TCAs for the control of pain in dogs and cats have not been extensively evaluated.

Multimodal analgesia

Combining drugs with different mechanisms of action (i.e. opioid, NSAID, GABA-ergic) may increase the overall effectiveness of pain management. In humans, tramadol combined with NSAIDS or gabapentin produces better pain control than any of the drugs by themselves. Gabapentin combined with NSAIDs provides better analgesic than either drug alone. Although little data is available on drug combinations in animals, many believe it is an effective management strategy.