Pain management in horses: What are our alternatives? (Proceedings)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesic agents in equine medicine. They are quite effective in controlling pain and inflammation in a wide variety of conditions. However, there are occasions where NSAIDs alone are insufficient or when their potential adverse effects are unacceptable for a patient. The risk of adverse effects can be minimized or eliminated in some patients if alternative drugs, combinations of drugs or alternative routes of administration are considered. An understanding of available analgesic drugs, their mechanisms of action, potential adverse effects, possible routes of administration, and the type of pain being treated enables the practitioner to develop a patient-specific analgesic protocol.

Opioids

Opioids are often used in the control of perioperative pain in other species but have been less widely used in horses because of concerns regarding possible adverse effects. The combination of an opioid drug with a NSAID provides synergistic analgesia and represents a relatively straightforward approach to multimodal analgesia. Butorphanol has been the most widely used of the opioid drugs in equine medicine. It is predominantly a kappa agonist and therefore has fewer and less severe adverse effects as compared to morphine and other mu agonists. Butorphanol is not sedative in adult horses when used on its own. It is approved for use IV but is often administered IM for analgesic effects. Absorption of butorphanol after IM administration is very rapid (half life of absorption of 6 min) but systemic availability after IM injection is surprisingly low (37%) in adult horses. Terminal half-life after IM administration is 0.57 hrs. To maintain targeted plasma butorphanol concentrations above 10 ng/mL, administration of 0.08 mg/kg IM every 3 hours may be necessary. High intravenous dosages of butorphanol (0.1 - 0.5 mg/kg) are associated with excitatory behavior, increased locomotion and inhibition of gastrointestinal activity. These effects are less frequently observed with lower doses or when the drug is administered IM or by continuous rate infusion (CRI). When used as a CRI, butorphanol may decrease gastrointestinal motility and fecal production should be monitored appropriately. If a decrease in fecal production is observed, administration of mineral oil via nasogastric tube and/or decreasing infusion rates is recommended. Butorphanol CRI should rarely be continued for more than 12-24 hours. Epidural butorphanol may potentiate lidocaine-induced analgesia but is unlikely to provide significant analgesia when used as the sole agent. Unlike adult horses, neonatal foals receiving butorphanol by IV or IM injection appear profoundly sedated. This may represent differences in opioid receptor distribution or differences in P glycoprotein distribution within the central nervous system of neonates as compared to adults.

Other opioids that have been used as analgesic medications in horses include fentanyl, morphine and methadone. Transdermal fentanyl patches have been used in horses of all ages without significant reported adverse effects. However, recent experimental data demonstrates that absorption of drug is erratic at best, peak drug concentrations are often below the predicted therapeutic range, and even when administered intravenously, fentanyl may not be an effective analgesic agent for horses (Sellon et al, 2007, unpublished data). Therefore, use of fentanyl patches in adult horses cannot be recommended at this time. Morphine may be used intravenously as an analgesic agent in combination with alpha 2 agonists. When used intravenously as a sole analgesic agent, it may result in profound excitation. Anecdotally, IM morphine use is not associated with CNS excitation and this may represent an underappreciated analgesic option. Morphine may be administered epidurally on its own or in combination with detomidine to provide effective analgesia of the caudal half of the body. Epidural morphine administered at 0.05 to 0.1 mg/kg produces segmental analgesia; dorsal nerve branches of the lumbosacral plexus appear to be preferentially affected. Morphine is typically used at dosages of 0.1 to 0.2 mg/kg diluted to 10-20 ml with 0.9% saline (total volume of 0.04 ml/kg body weight). Analgesic effects are seen within 20-30 minutes and may last 8-24 hours without adverse effects on motor function. Some surgeons have anecdotally reported efficacy of intra-articular morphine for control of pain associated with arthroscopy or arthrotomy. Oral opioids are rarely used in horses; however, there are anecdotal reports that oral methadone may be efficacious.

Ketamine

Ketamine is a dissociative anesthetic with several mechanisms of action including noncompetitive antagonism of N-methyl-D-aspartate (NMDA) receptors. It also has effects on opioid, monoaminergic, and muscarinic receptors a well as voltage-sensitive Ca channels. Recent experimental evidence suggests that ketamine also has potent anti-inflammatory actions that include reduction in chemotactic activation of neutrophils and suppression of cytokine production (e.g. tumor necrosis factor alpha, interleukin 6 and interleukin 8). In an equine macrophage cell line ketamine reduced lipopolysaccharide induced TNF-alpha and IL-6 activities. Ketamine is metabolized in the liver by the cytochrome P450 enzyme system to norketamine and has a disappearance half-life in horses of 42 to 65 minutes. It appears to have minimal effect on gastrointestinal motility and respiratory function. In horses ketamine has been used for more than 20 years as an anesthetic agent in combination with alpha-2 agonists, diazepam and/or butorphanol. The recommended anesthetic dose is 2.2 mg/kg; anesthesia is maintained with plasma concentrations of approximately 1 ug/ml. More recently, ketamine has been recommended for caudal epidural analgesia in horses, local anesthesia with peripheral nerve blocks, or as a CRI at subanesthetic doses for its analgesic effects in the standing horse. When administered to horses as a CRI at doses of 0.4 to 1.2 mg/kg/hour the dissociative and excitatory effects of ketamine are not observed and there is no obvious sedative effect. Fielding et al reported that horses receiving CRI ketamine had significant decreases in heart rate and mean arterial blood pressure after infusion, but there was no control group receiving placebo treatment in that study. The maximum plasma concentration of ketamine obtained during an infusion rate of 0.8 mg/kg/h was 0.137 ug/ml (range 0.056 to 0.176 ug/ml). In a separate study, Lankveld et al showed that the average plasma ketamine concentration during an infusion of 1.5 mg/kg/hr was 0.235 ug/ml. Higher infusion rates (3.0 – 4.8 mg/kg/hr) were associated with behavioral changes including increased alertness, shifting of weight and muscle twitching as well as significant increases in respiratory rate, heart rate and arterial blood pressure. Concentrations rapidly decrease to undetectable levels when infusion is discontinued. Because of its antagonism of NMDA receptors, ketamine may be most appropriate as an analgesic agent to decrease secondary hyperalgesia in horses with a longer duration of pain (e.g. chronic laminitis or some orthopedic conditions). Pharmacodynamic data in support of the use of ketamine CRI for analgesia in horses is limited; however anecdotal clinical evidence strongly supports its efficacy. Ketamine CRIs have been used for days to weeks in some horses with chronic pain secondary to musculoskeletal problems.

Alpha 2 Agonists

In the United States, the most commonly used alpha 2 agonist drugs for equine analgesia are xylazine and detomidine. They are quite potent analgesic agents that are useful for short-term control of pain when administered IV or IM. They produce their effect by activation of alpha 2 receptors in the brain and spinal cord, decreasing the release of excitatory neurotransmitters and interfering with sensory processing and transmission. In addition to their analgesic effects, these drugs have potent sedative and muscle relaxant effects that can result in profound stupor, ataxia and reluctance to move. Their effect is potentiated when combined with an opioid such as butorphanol or morphine or with acepromazine. Alpha 2 agonists have profound inhibitory effects on the cardiovascular (hypotension, bradycardia, arrhythmia) and gastrointestinal (decreased motility) systems. CNS depression results in a decrease in respiratory rate and tidal volume. Relaxation of muscles of the upper airway can cause inspiratory dyspnea in some horses, especially those with pre-existing upper airway obstruction. Increased urine production is common due to increased glomerular filtration rate, inhibition of anti-diuretic hormone release, inhibition of anti-diuretic hormone response by renal tubules, and increased release of atrial natriuretic factor. Alpha 2 agonists can produce pronounced increases in respiratory rate and effort when administered to some horses with preexisting fever. The mechanism of this adverse reaction is unclear. Alpha-2 agonists are most widely used in equine practice to provide relatively short term (minutes to hours) sedation and analgesia. Detomidine CRI may be useful in some horses to provide a steady plane of sedation and analgesia without the fluctuations between severe ataxia and insufficient sedation often experienced with intermittent bolus injections. Detomidine and xylazine are also useful for caudal epidural anesthesia in horses. The combination of xylazine and lidocaine for caudal epidural anesthesia is often preferred because of synergistic effects result in a more rapid onset of action and a longer duration of analgesia. Detomidine is frequently used in horses for lumbosacral epidural analgesia to provide pain relief to the caudal half of the body. The analgesic effects of morphine administered via this route are potentiated by concurrent epidural administration of detomidine at 0.03 mg/kg. Ataxia is not usually observed at these doses. However, detomidine is a lipophilic drug and is rapidly absorbed systemically so that higher doses (up to 0.06 mg/kg) recommended for use without concurrent morphine are likely to produce significant ataxia, sedation, recumbency and cardiovascular effects. Particular care should be taken with detomidine use in debilitated horses or horses that are otherwise prone to recumbency. Lumbosacral epidural catheters may be safely maintained in horses for 1-2 weeks if appropriate sterile technique is observed. This provides a convenient method for analgesia for severe hind limb pain while minimizing adverse effects seen with systemic administration of the same drugs.

Local Anesthetics

Local anesthetic agents such as lidocaine, bupivicaine and mepivacaine are frequently used for local nerve blocks or intra-articular injection to desensitize a specific area of the body. Their use during surgery can decrease the response to painful surgical stimuli and decrease the amount of general anesthesia needed. Perineural injections, intra-articular infusions and local line or tissue blocks have been used to facilitate analgesia during or after surgery. These drugs do not appear to delay wound healing. Local anesthetic agents act by blocking fast sodium ion channels, preventing the initiation and conduction of action potentials in sensory nerve fibers. Large dosages can also block motor function and induce temporary paralysis. Lidocaine is a short-acting local anesthetic with a rapid onset of action (<10 minutes). In addition to its use as a local anesthetic, lidocaine has been used via epidural and intravenous routes for its systemic analgesic effects. Continuous rate infusion of lidocaine is often used for treatment or prevention of postoperative ileus. However, it also has significant analgesic activity and some anti-inflammatory activity. It appears to be synergistic with opioids and alpha-2 agonists. Lidocaine may decrease cardiac output, arterial blood pressure and heart rate when administered intravenously because of its inhibitory effect on sympathetic output and myocardial contractile force and decreases in venous return. Rapid intravenous infusion may result in a decrease in heart rate and blood pressure. Rapid injection of lidocaine may produce CNS stimulation with excitement, agitation, seizures, coma and respiratory arrest.

Gabapentin

Gabapentin, is an anti–epileptic drug which was introduced in 1993 and was originally approved for the treatment of seizures in humans. Recently, however, reports have documented its efficacy in the treatment of neuropathic pain in people. Gabapentin is reportedly completely ineffective in altering threshold responses to acute nociceptive stimuli at doses up to 300 mg/kg. Presently the mechanism of action as either an anticonvulsant or an analgesic is unknown. Gabapentin has a relatively benign side effect profile and is well tolerated if dosing proceeds in a gradually escalating manner. It has few if any drug interactions and is primarily renally excreted. To date, there is no information in the veterinary literature regarding its safety or efficacy for treatment of pain in horses.