Opioids

The opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic activity. Despite some well-known side effects and disadvantages, opioids are the most effective analgesics available for the systemic treatment of acute pain in many species, particularly dogs and cats. Opioids combine reversibly with specific receptors in the brain, spinal cord, and periphery, altering the transmission and perception of pain. In addition to analgesia, opioids can induce other CNS effects that include sedation, euphoria, dysphoria, and excitement. The clinical effects of opioids vary between the mu opioid receptor agonists (eg, morphine, hydromorphone), partial mu agonists (ie, buprenorphine), and agonist-antagonists (eg, butorphanol). Species and individual differences in the response to opioids are marked, necessitating the careful selection of opioid and adjustment of dose for different species. For example, a 30-kg dog may receive a preoperative dose of morphine (15–30 mg) that is similar to that for a 500-kg horse. Likewise, although butorphanol is widely used as an effective analgesic in horses, its use as an analgesic in small animals is falling out of favor because of its expense, relatively poor somatic analgesic effect, and short duration of action. The clinical effect of an opioid depends on additional patient factors, including the presence or absence of pain, health status of the animal, concurrent drugs administered (eg, tranquilizers), and individual sensitivity to opioids.

Recent information regarding the peripheral endogenous opioid system (PEOS) has presented a unique opportunity to utilize the powerful analgesic effect of opiates while minimizing untoward systemic effects. The PEOS includes peripheral opioid receptors (POR) and peripheral leukocyte-derived opioids (PLDO): endomorphins, endorphins, enkephalins, and dynorphins. To activate the PEOS, tissue must have sufficient numbers of leukocytes able to secrete PLDO as well as functional POR in sufficient numbers. Inflammation due to tissue damage results in accumulation of PLDO-secreting leukocytes at the site of injury. Inflammation also increases the number and efficiency of POR. These receptors, inactive under normal conditions and expressed on primary sensory neurons, are synthesized in the dorsal root ganglion and transported distally to peripheral sensory nerve endings due to tissue injury and inflammation. Experimental trials and clinical studies show peripheral opiates are effective, particularly in the presence of inflammation. For example, preservative-free morphine has been instilled into canine and equine joints after arthroscopy or arthrotomy.

Nonsteroidal Anti-inflammatory Drugs and Corticosteroids

NSAID are useful adjuncts in the treatment of postsurgical pain in a variety of species. Decreasing inflammation after surgery or trauma can greatly improve analgesia. Inflammation is a key component in both peripheral and central sensitization leading to wind-up. Early and aggressive control of wind-up is critical in the prevention of chronic pain syndromes. Significant advantages of NSAID include availability, a relatively long duration of action, low cost, and relative ease of administration. NSAID have long been used to decrease inflammation and provide analgesia and should be considered as part of the analgesic plan provided the animal does not have pre-existing renal, hepatic, coagulation, or GI problems. NSAID should be administered only to well-hydrated animals.

Although a number of NSAID have been approved for use in dogs and horses, only meloxicam is approved for use in cats in the USA. As with all analgesic agents, special attention to drug withdrawal times is necessary when using NSAID in agricultural species.

Corticosteroids also reduce inflammation and provide analgesia. Depending on the product, they are administered PO, IV, IM, SC, and intra-articularly. Corticosteroids are used less frequently in the post-operative period due to the potential for decreasing immune function and due to other well-known adverse effects (eg, polyphagia, polydipsia, polyuria) after repeated dosing. However, they are used occasionally in chronic pain syndromes including PO for degenerative disk disease in dogs and intra-articularly for unresponsive osteoarthritis. Corticosteroids and NSAID should not be administered concurrently.

For pharmacology of NSAID and corticosteroids, see Anti-Inflammatory Agents.

α₂-Agonists

Xylazine, medetomidine, dexmedetomidine, detomidine, and romifidine are potent analgesics. α₂-Agonists are used in large animals for standing restraint and provide both analgesia and sedation, although there is evidence to suggest that sedation lasts longer than analgesia. Combination therapy with α₂-agonists and opioids induces profound analgesia and sedation that is additive or synergistic as compared with the effects of either drug alone in both large and small animals. α₂-Agonists are used as part of multimodal analgesia in the perioperative period in many species. α₂-Receptors play an important role in the modulation of pain by the CNS. α₂-Agonists may be used to induce analgesia when administered as anesthetic premedications (preemptive analgesia), may be used as a constant rate infusion intra-operatively, and may be used to supplement postoperative analgesia. In general, postoperative doses of α₂-agonists are considerably lower than would be required preoperatively.

Caution is advised to prevent excessive sedation and concomitant ataxia, particularly in large animals. Furthermore, even at relatively low doses, these agents cause profound reductions in cardiac output and may cause significant arrhythmia in all species. Ruminants in particular require lower doses, and pulmonary edema has been reported in sheep. Careful patient selection is warranted.

Xylazine, medetomidine, and dexmedetomidine (the pure s-enantiomer of the racemic medetomidine) may be reversed in small animals after surgery to hasten recovery and minimize cardiopulmonary depression. Once reversed, however, these drugs provide no analgesia.

Ketamine

Ketamine has long been known to provide excellent somatic analgesia but rather poor visceral analgesia. Interest in ketamine has increased because of its role in preventing sensitization of central nociceptive pathways. Ketamine is an antagonist at the NMDA receptors in the spinal cord and brain. Inhibition of the NMDA receptors prevents or decreases central sensitization in laboratory animals and people. Ketamine may be incorporated into the anesthetic protocol either as a bolus or a constant rate infusion to prevent development of exaggerated or chronic pain states. Amantadine, an oral antiviral agent, has recently been shown to decrease wind-up in chronic pain through its action at NMDA receptors.

Other Analgesic Agents

Tramadol, an increasingly popular veterinary drug, is a centrally acting agent with multimodal analgesic effects. It has moderate affinity for the mu opioid receptor. Tramadol also inhibits neuronal uptake of norepinephrine and serotonin, monoamine neurotransmitters involved in descending inhibitory pathways in the CNS. Compared with pure mu agonists, tramadol results in less sedation, less respiratory depression, and improved oral bioavailability; it is not a controlled substance. Adverse effects include decreased seizure thresholds, nausea/vomiting, and in some animals, altered behavior.

There are few clinical studies examining the use of tramadol in veterinary species. However, it has been shown to reduce minimum alveolar concentration of sevoflurane in cats and is reported to have similar analgesic effects after ovariohysterectomy when compared with morphine in dogs. Caution is warranted in patients receiving monoamine oxidase inhibitors or selective serotonin (5-hydroxytryptamine) reuptake inhibitors because of the increased risk of serotonin syndrome. Despite these advantages, tramadol should not be used as a sole agent for the treatment of severe pain. Tramadol may be used alone to treat mild pain and adjunctively in a multimodal plan for treating moderate to severe pain.

Gabapentin was originally developed and licensed as an antiepileptic agent. In recent years, it has been prescribed extensively for neuropathic pain in people. There is increasing evidence for its use in the perioperative setting as well. Its mechanism of action remains an area of intense research, and interaction with several receptors and ion channels has been proposed. Recent data suggest effects are mediated through altered trafficking of voltage-gated calcium channels to the neuronal cell membrane, ultimately resulting in decreased neurotransmitter release.

Use in veterinary species should be approached with caution because safety, efficacy, and dosing have not been established. Adverse effects include somnolence, fatigue, and weight gain; however, in general, gabapentin appears to be well tolerated at a wide range of doses. Extrapolation from human data and anecdotal veterinary evidence suggest a starting dosage range in small animals of 5–10 mg/kg, PO, bid-tid; this can be increased, with somnolence being the primary adverse effect.

Acetaminophen is not approved for use in veterinary species but has been used effectively for the treatment of breakthrough pain in dogs at a dosage of 10–15 mg/kg, bid for up to 5 consecutive days. The exact mechanism of action is unclear, although recent evidence suggests indirect activation of the cannabinoid CB(1) receptor. The so-called COX-3, splice variant of COX-1, has been suggested as an additional mechanism for acetaminophen in dogs. Acetaminophen is not considered a classic NSAID in part because of its low anti-inflammatory action; as such, the risk of thrombocytopenia, bleeding, and GI adverse effects is minimal. Hepatopathy is of concern, and routine serum chemistry evaluation is warranted. Acetaminophen should not be used in cats because of inadequate cytochrome P₄₅₀-dependent hydroxylation (glucuronidation) and subsequent fatal methemoglobinemia.

Last full review/revision July 2011 by Peter W. Hellyer, DVM, MS, DACVA; Patrice M. Mich, DVM, MS, DABVP (Canine/Feline), DACVA