Opioids continue to be the cornerstone of effective pain treatment in veterinary medicine. The opioids are a diverse group of naturally occurring and synthetic drugs used primarily for their analgesic activity. Despite some well-known adverse effects and disadvantages, opioids are the most effective analgesics available for the systemic treatment of acute pain in many species, particularly dogs and cats. Opioid receptors are part of a large superfamily of membrane-bound receptors that are coupled to G proteins. Each opioid receptor has a unique distribution in the brain, spinal card, and periphery. Opioids combine reversibly with these receptors and alter 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 use 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 that 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
NSAIDs are useful adjuncts in the treatment of postsurgical pain in a variety of species, because they block prostaglandin synthesis mediated by inhibition of cyclooxygenase (COX). 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. NSAIDs appear to confer synergism when used in combination with opioids and may demonstrate an opioid-sparing effect. Significant advantages of NSAIDs include availability, a relatively long duration of action, low cost, and relative ease of administration. Lack of CNS alteration (sedation or dysphoria) make NSAIDs ideal for treating acute and chronic pain in animals. Careful patient selection is critical.
Although a number of NSAIDs have been approved for use in dogs and horses, only meloxicam and robenacoxib are FDA approved for use in cats in the USA. Meloxicam is approved for a single dose and robenacoxib for up to 3 days. As with all analgesic agents, special attention to drug withdrawal times is necessary when using NSAIDs in production animals.
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 postoperative period because of the potential to decrease immune function and because of 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 disc disease in dogs and intra-articularly for unresponsive osteoarthritis. Corticosteroids and NSAIDs should not be administered concurrently.
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. The mechanism of action is through G protein–coupled receptors. Alpha 2A and alpha 2C receptors mediate analgesia. 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), as a constant-rate infusion intraoperatively, and 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 arterial hypoxemia and pulmonary edema have been described 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 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 (wind-up) 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.
Other Analgesic Agents
Tramadol, a synthetic codeine analogue, is a weak mu opioid receptor agonist. In addition to opioid activity, it inhibits neuronal reuptake of norepinephrine and 5-hydroxytryptamine (serotonin) and may facilitate serotonin release. It is recommended for acute and chronic pain of moderate to severe intensity. Because of its inhibitory effects on serotonin uptake, tramadol should not be used in animals that may have received monoamine oxidase inhibitors such as selegiline, in animals on selective serotonin reuptake inhibitors, or in animals with a recent history of seizure activity. In people, the principal active metabolite (O-desmethyl tramadol, M1) is more active at mu receptors than the parent drug. Cats produce significant amounts of M1, whereas dogs produce minimal amounts. Oral bioavailability is 93% in cats but only 65% in dogs. Dogs eliminate and clear tramadol more rapidly than cats. The dosing interval must be adjusted in cats. 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 animals. However, it has been shown to reduce minimum alveolar concentration of sevoflurane in cats and is reported to have an analgesic effect after ovariohysterectomy similar to that of morphine in dogs. Tramadol may be used alone to treat mild pain and adjunctively in a multimodal plan to treat moderate to severe pain.
Gabapentin was originally developed and licensed as a human anticonvulsant agent and has been approved by the FDA since 1993. Reports of its antihyperalgesic effects in rodent experimental pain models and case reports involving human patients suffering from neuropathic pain suggest increasing evidence for its use in neuropathic pain. The mechanism of action appears to be voltage-dependent Ca2+ channel blocker, and it may increase central inhibition or reduce the synthesis of glutamate, even though it does not appear to interact directly with NMDA receptors. Adverse effects are usually mild and self-limiting (drowsiness, fatigue, and weight gain with chronic administration).
Amantadine, an antiviral agent developed to inhibit the replication of influenza A in human patients, has efficacy in the treatment of drug-induced extrapyramidal effects and in treatment of Parkinson disease. It exerts its analgesic effects through antagonism of NMDA receptors. Amantadine seems most efficacious in the management of chronic neuropathic pain with signs of hyperalgesia and allodynia. Animals suffering from opioid tolerance may also benefit. A 2008 study demonstrated improved activity in dogs with NSAID-refractory osteoarthritis when amantadine was added to meloxicam.
Acetaminophen is not approved for use in animals but has been used effectively for the treatment of breakthrough pain in dogs at a dosage of 10–15 mg/kg, bid, for as long as 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 partly 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.
Maropitant is a potent selective neurokinin (NK1) receptor antagonist that acts in the CNS by inhibiting substance P, the key neurotransmitter involved in vomiting. It provides visceral analgesia for conditions such as pancreatitis, cholangitis, and painful GI disorders.