Anesthesia update — Incorporating methadone into companion animal anesthesia and analgesic protocols: A narrative review

Abstract

Opioid analgesics are routinely used during the perioperative period, to provide analgesia and reduce anesthetics doses required to maintain a surgical plane of anesthesia in companion animals. Acting on receptors in the brain, spinal cord, and peripheral nervous system, opioids provide reliable and consistent analgesia; however, they are not without adverse effects. Methadone, a mu agonist opioid analgesic, was recently licensed for veterinary use in Canada. In addition to its action on opioid receptors, methadone contributes to analgesia through other pathways, including inhibition of N-methyl-D-aspartate (NMDA) receptors. It has physiologic effects similar to other mu opioid agents, but fewer adverse gastrointestinal effects. This review discusses methadone’s mechanism of action, pharmacologic characteristics, and clinical effects in dogs and cats. Current recommendations for using methadone in companion animals are also provided.

Introduction

Several classes of analgesic drugs are used to manage pain in companion animals, including opioid analgesics, nonsteroidal anti-inflammatories drugs (NSAIDs), N-methyl-D-aspartate (NMDA) antagonists, local anesthetics, and behavior-modifying drugs. Whereas use of multiple drugs with different mechanisms of action to treat pain is regarded as ideal, opioid analgesics remain the cornerstone of acute and perioperative pain management in companion animals due to their efficacy, ease of administration, and relative safety (1). They exert analgesic effects primarily by activating mu and kappa opioid receptors in the nervous system. Their classification is based on receptor affinity, with mu agonists, partial mu agonists, kappa agonistsmu antagonists, and mu antagonists routinely used in veterinary patients (2). In addition to profound analgesia, administration of mu agonists before general anesthesia has other desirable effects, including a reduction in the dose of general anesthetic required to achieve and maintain a desired plane of anesthesia with a stimulus such as surgery. Because general anesthetics usually cause dose-dependent depression of cardiovascular function, addition of an opioid analgesic improves intraoperative hemodynamic stability in dogs and cats (3,4). A variety of routes of administration, compatibility with other drugs, and reversibility of their effects also contribute to their utility.

Mu agonists have adverse effects, particularly reduced central respiratory drive (2). In addition, in dogs and cats, parenteral administration of the common mu agonists hydromorphone and morphine consistently results in vomiting and signs associated with nausea; e.g., hypersalivation and lip-licking (2,5). Vomiting and associated increased intracranial pressure and risk of aspiration are potential consequences; therefore, these drugs should be used with caution as preanesthetics in animals with increased intracranial pressure or intraocular pressure or upper airway disease or dysfunction (e.g., brachycephalic syndrome or laryngeal paralysis) (6). Similarly, these agents are not recommended as preanesthetics for animals with esophageal disease, including esophageal foreign bodies (7). As perianesthetic emesis is considered undesirable by many veterinarians, effects of opioid analgesics on vomiting are relevant. Maropitant, a neurokinin-1 receptor antagonist, reduces emesis in dogs and cats associated with mu opioid agonists if administered 45 to 120 min before the opioid (8,9). Although effective, the latter strategy has additional costs and requires additional animal handling. Acepromazine, a phenothiazine sedative, reduces, but does not eliminate, vomiting associated with hydromorphone, morphine, or oxymorphone; however, it also requires prior administration (10).

Methadone, a synthetic mu agonist opioid analgesic, was recently licensed in Canada for veterinary use as a preanesthetic medication in cats at 0.5 mg/kg IM, prior to elective neutering. It has been licensed for veterinary use for several years in Australia, New Zealand, and countries within the United Kingdom and European Union, labeled for use as an analgesic and preanesthetic agent in dogs (IV, IM, and SC) and cats (IM). Substantial investigative and clinical experience in veterinary patients supports extra-label use in a broader context in these species. Methadone has some unique characteristics, including effects on pain pathways and a low incidence of vomiting, potentially increasing its desirability as a routine opioid analgesic in dogs and cats.

For this article, PubMed and Google Scholar databases were searched for articles related to methadone’s mechanism of action, pharmacokinetics, and clinical effects. Key findings are reviewed and current recommendations for incorporating methadone into companion animal clinical practice based on the literature and the authors’ experience are provided.

Pain physiology and methadone’s mechanism of action

“Pain” is defined as an unpleasant emotional or physical experience associated with, or resembling that associated with, actual or potential tissue damage (11). Nociception is the neural process involved in the transduction and transmission of a noxious stimulus to the brain, but pain is the result of a complex interplay among signaling systems, signal modulation at several sites along the pain pathway, and perception by the individual (11). Acute pain, resulting from activation of nociceptors, is most notably associated with surgery, trauma, or a medical condition. It occurs during the expected time (< 3 to 6 mo) of inflammation and healing after injury (12). Chronic pain, also referred to as maladaptive or pathological pain, is pain that exists beyond the expected duration of inflammation or healing (12). Numerous cellular and molecular processes are implicated in development of chronic pain; however, ongoing nociceptive input to the central nervous system (CNS) and somatosensory dysfunction — specifically, a reduction in inhibitory signaling in the dorsal horn of the spinal cord — are considered common etiologies (13).

A general strategy to prevent or treat acute pain associated with nociception or inflammation is to inhibit, reduce, or modulate neural processes involved in transduction, transmission, or perception of noxious stimulus (including inflammation) to the brain via pain pathways. Opioid analgesics modulate pain by binding to opioid receptors, primarily located within the brain and dorsal horn of the spinal cord and involved in both ascending and descending inhibition of pain (2). Unlike other opioid analgesics, but like the alpha-2 adrenergic agonist medetomidine, methadone is a synthetic chiral compound with 2 isomers (d- and l-methadone). The l-isomer binds to the mu opioid receptor with 10 to 15 × higher affinity than the d-isomer, providing a rapid onset of profound analgesia similar to other mu agonists; e.g., morphine or hydromorphone (2).

Unlike other opioids, methadone contributes to analgesia by binding to and antagonizing endogenous ligands at NMDA receptors (2). There is experimental animal evidence to suggest that methadone’s ability to antagonize the NMDA receptor inhibits central sensitization (neuropathic pain); prevents hyperalgesia (an exaggerated response to a noxious stimulus) and opioid tolerance; and may prevent remodeling of pain pathways, which contributes to chronic pain (14,15). A third proposed mechanism of analgesia and mood elevation is methadone’s ability to inhibit the reuptake of serotonin and norepinephrine, important modulators and inhibitors of pain, within the CNS (2).

Clinical pharmacology

Pharmacokinetics

Measurements of serum or plasma concentrations over time after drug administration characterize absorption, distribution, and elimination, and inform dosing regimens. However, target tissue concentrations, e.g., in neurons, may not mimic plasma concentrations. Even if it is feasible to measure target tissue concentrations, effects of a drug on its target site may not be immediate or proportional to tissue concentration. As such, there can be variability between expected effects (based on pharmacokinetic data) and clinical manifestation. For analgesic drugs, it is therefore important to also consider experimental nociceptive testing, as well as results of clinical investigations, to make recommendations for clinical use.

Pharmacokinetics of methadone when administered alone have been investigated following IV, IM, and oral transmucosal (OTM) or buccal administration in the cat, and following IV, SC, and oral administration in the dog (16–21). Unlike in humans, oral administration of opioids, including methadone, is not clinically effective in many domestic animals due to a high first-pass metabolism effect and very low bioavailability (2). Bioavailability following buccal or OTM administration of methadone in cats was reported to be highly variable (18.7 to 70.5%) (17), and excessive salivation (ptyalism) was reported in 7 of 8 cats administered methadone via this route (18). Although OTM administration of methadone alone has not been reported in dogs, pharmacokinetics of a dexmedetomidine (10 μg/kg) and methadone (0.4 mg/kg) combination administered via this route were reported (22). Severe ptyalism was reported in most dogs within minutes after treatment and bioavailability of methadone relative to IM administration was very low (15%) (22). In contrast, when administered SC, methadone has relatively high bioavailability (79%) in dogs, with ~1 h to peak plasma concentrations (20). In cats, following IM administration, peak plasma concentrations occurred at ~20 min, with a wide range (5 to 360 min) (16). Pharmacokinetic variables for methadone when administered alone are not available in cats after SC or in dogs after IM administration; however, antinociceptive and analgesic effects were demonstrated in both species after these routes of administration, and bioavailability was likely high (23–26).

Methadone is a highly lipophilic opioid with a large volume of distribution and a rapid onset of effect following IV administration (17,18,20). In cats, a reduced response to thermal or mechanical nociception was reported within 10 min after IV administration, with a similar rapid onset of antinociceptive effect in dogs (18,19). Once absorbed, methadone is approximately 60 to 70% bound to plasma proteins in the dog (27). It is predominantly cleared from plasma and metabolized in the liver into polar compounds that are excreted in the urine (2). The elimination half-life was ~2 to 4 h following IV administration in dogs and cats, 2 to 12 h following SC administration in dogs, and ~10 h following IM administration in cats (16–20). Despite the long elimination half-life following SC and IM administration in dogs and cats, respectively, a dosing interval of ~4 h has been proposed for both species following parenteral administration (16,19,20). Considering variability in pharmacokinetics of analgesic agents, including methadone, careful assessment of their clinical effects over time is highly recommended.

Analgesic effects

Opioid drugs are highly effective at preventing and treating acute pain in both dogs and cats. In general, mu agonists such as morphine and hydromorphone provide better analgesia than partial mu agonists (buprenorphine) and mu antagonist-kappa agonists (butorphanol) for moderate-to-severe pain associated with thoracic, intra-abdominal, or orthopedic surgery in companion animals. Antinociceptive effects of methadone, as assessed by thermal or mechanical stimuli, were studied in healthy cats at doses ranging from 0.2 to 0.6 mg/kg administered IV, IM, SC, or OTM (16,18,24); and in healthy dogs receiving a bolus dose of 0.2 mg/kg IV, followed by a constant rate infusion of 0.1 mg/kg per hour for 72 h (19). Although individual studies reported some variations in onset and duration of antinociceptive effects, methadone consistently resulted in antinociceptive effects overall, with suggested target plasma concentrations of 40 to 124 ng/mL (cats) and 17 ng/mL (dogs) (16,19).

Clinical trials in cats have predominantly assessed methadone’s efficacy in preventing pain associated with elective neutering. Methadone, alone or in combination with acepromazine or an alpha-2 adrenergic agonist, was administered as a premedication agent before elective castration, ovariectomy, and ovariohysterectomy, at doses and routes similar to those of the experimental studies (23,28–31). Based on facial expressions, posture, behaviors, and response to pressure application via palpation or mechanical nociceptive testing, there was adequate analgesia for 4 to 6 h following premedication (23,28–31). In a study assessing analgesia using mechanical nociceptive testing following surgery, cats receiving methadone with acepromazine had no changes in their nociceptive thresholds, whereas cats that received buprenorphine or butorphanol with acepromazine had nociceptive thresholds significantly below their baseline values (29). Therefore, methadone may reduce hyperalgesia to a greater extent than the latter 2 agents (29). Consistent with methadone’s superiority over partial agonists, methadone provided better analgesia compared to buprenorphine and butorphanol in cats undergoing ovariohysterectomy (23,32). When methadone was administered at 0.5 mg/kg IM, onset of analgesia occurred 13 min after cats had undergone an ovariohysterectomy with no analgesia (31). The sole study assessing methadone’s efficacy for nonelective surgery in cats compared l-methadone to carprofen and buprenorphine in cats following fracture repair (33). Although none of the analgesics provided sufficient analgesia, methadone provided analgesic effects similar to buprenorphine (33).

In the dog, methadone’s analgesic efficacy in clinical trials involving orthopedic or soft-tissue surgery had positive outcomes (25,26,34,35). For example, in dogs undergoing femorotibial joint surgery, 0.3 mg/kg methadone (preservative-free) administered IV or into the epidural space resulted in low postoperative pain scores and limited need for rescue analgesia in the immediate postoperative period (34). Furthermore, mean intraoperative end-tidal isoflurane concentrations were 0.83 and 1.0% in dogs in the epidural and IV methadone groups, respectively, during surgery, supporting methadone’s anesthetic-reducing effect. Methadone was effective, and superior to buprenorphine, for orthopedic or soft-tissue surgery in dogs (25,26).

In summary, in experimental and clinical settings, methadone produced analgesic effects in cats and dogs. Although most animals that received methadone alone were evaluated as having adequate analgesia for at least 4 to 5 h postoperatively, some individual animals required additional analgesic therapy (rescue treatment) sooner (25,26,30,31). This was attributed to various factors, including pharmacokinetic differences, the animal’s underlying disease conditions, pain state before surgery, or individual sensitivity to perception of pain. This highlights the need for vigilant assessment of pain state perioperatively and supports multimodal pain management, as discussed below.

Behavioral effects

Opioid drugs produce variable behavioral changes when administered parenterally at currently recommended doses to young, healthy, pain-free dogs and cats prior to noxious stimulation, including surgery. For years, opioid use in cats was not recommended due to potential adverse behavior. However, excitement and dysphoria in cats likely resulted from doses exceeding current recommendations. More often, cats exhibit mild sedation or increased activities such as kneading, rolling, and purring (considered euphoric) after administration of morphine, oxymorphone, hydromorphone, or butorphanol (36).

Several studies detailed the behavioral effects of methadone in cats, either alone or in combination with sedative agents, with variable results (18,28–31). When methadone was administered IM at doses ranging from 0.1 to 0.5 mg/kg without other agents to healthy cats scheduled to undergo elective procedures, behavior, including ease of handling, was relatively unchanged from the pre-methadone state (31). Other studies reported either no change in behavior, or an increase in activities such as purring and rolling after administration of either methadone (0.6 mg/kg) or l-methadone (0.3 mg/kg) IM. However, in 1 study, 25% of cats that received methadone became more difficult to restrain (30), with most cats exhibiting passive acceptance to moderate resistance when an IV catheter was placed 20 min after methadone administration. In the absence of control cats, effects of repeated handling on cat behavior cannot be determined, and it was concluded that neither sedation nor excitement was produced by methadone or l-methadone at the doses evaluated. Most healthy, awake cats receiving methadone 0.3 mg/kg IV and 0.6 mg/kg via the OTM route following brief anesthesia had moderate sedation followed by euphoric behavior, and some had an increased sensitivity to noise (18). Without a control group for comparison, responses were attributed to high serum methadone concentrations in pain-free cats without a sedative.

Cat behavior following methadone, administered IM in combination with either acepromazine or an alpha-2 adrenergic agonist, was reported (28,29). As in cats receiving methadone at 0.5 mg/kg IM, the combination of acepromazine and methadone resulted in some cats purring, rolling, forepaw-kneading, and rubbing, with similar observations for cats receiving acepromazine and buprenorphine or butorphanol (29). Combined with an alpha-2 adrenergic agonist, methadone generally induces sedation similar to other opioids (28). Comparisons between acepromazine or an alpha-2 adrenergic agonist, alone or in combination with methadone, have not been reported in cats.

Assessing behavioral effects of analgesics postoperatively is challenging, as it is difficult to differentiate drug effects on behavior from effects related to a change in pain state. Co-administered sedative drugs may also mask effects of opioid analgesics. In cats undergoing ovariohysterectomy, no adverse behavioral effects were noted postoperatively in cats receiving methadone (0.6 mg/kg IM), or l-methadone (0.3 mg/kg IM) (30). In cats given levomethadone 0.3 mg/kg SC at 8-hour intervals over 5 d as a postoperative analgesic following fracture repair, sedation was greater compared to that with an NSAID only; however, 2 of 15 cats had increased motor agitation after 2 d, perhaps due to relative overdosing of the opioid (33).

When administered alone to healthy dogs, methadone induced mild sedation, with greater sedation occurring at higher doses (37–39). Using multiple 5-minute observation periods, investigators noted that dogs administered 0.4 mg/kg of methadone IV or SC had a decreased incidence of licking and swallowing (20), with increased whining noted after methadone administered SC. Others reported increased vocalization following methadone administered IM at doses ranging from 0.5 to 1.0 mg/kg (39).

In dogs, sedation associated with methadone is enhanced by an alpha-2 adrenergic agent or acepromazine, and sedation with an alpha-2 adrenergic agonist alone is improved when methadone is added (40,41). When combined with acepromazine (0.05 mg/kg IV) in dogs, methadone (0.5 mg/kg IV) produced greater sedation than in dogs that received morphine (0.5 mg/kg IV), butorphanol (0.15 mg/kg IV), or tramadol (2 mg/kg IV) (38). More profound sedation was reported in dogs receiving butorphanol (0.2 mg/kg IV) versus methadone (0.2 mg/kg IV) when combined with dexmedetomidine (2 μg/kg IV) (42). There were no differences in sedation scores among dogs receiving methadone (0.5 mg/kg IM) or morphine (0.5 mg/kg IM) when the latter agents were combined with dexmedetomidine (10 μg/kg IM), likely due to its profound effect (41).

In summary, in healthy cats and dogs, methadone at doses of 0.1 to 0.6 mg/kg most commonly caused limited change in behavior to mild sedation, consistent with other opioids. In dogs, the degree of sedation associated with either acepromazine or dexmedetomidine is enhanced with coadministration of methadone.

Cardiovascular effects

Opioid drugs are generally considered to have relatively minor direct negative cardiovascular effects. At clinical doses, they frequently reduce heart rate (~10 to 20%) and cardiac output (10%), with variable, but minimal, effects on blood pressure in dogs and cats (2). Reduced heart rate is attributed to increased centrally mediated vagal tone and reduced sympathetic tone (43,44). Heart rate was decreased in cats that received methadone via OTM or IV routes; although the reduction was greater in the latter group, mean heart rates were > 165 beats/min in both groups (18).

Methadone administered at 0.5 and 1.0 mg/kg IV was compared to morphine administered at 1.0 mg/kg IV in dogs (44). Relative to baseline values, methadone caused dose-dependent reductions in heart rate and cardiac index, plus increases in systemic arterial pressures, systemic vascular resistance, central venous pressure, and pulmonary artery pressure (44), with changes more profound than those induced with morphine. An increase in centrally mediated vagal tone and baroreceptor-mediated activity secondary to an increase in systemic arterial pressures were likely responsible for the reduced heart rate (44). Proposed etiologies of increased arterial pressures and systemic vascular resistance included vasoconstriction secondary to CNS excitatory effects or increased vasopressin (44). Despite the high doses of opioids administered IV in the latter study, mean physiologic variables remained within acceptable limits, consistent with previous reports (43,44). In dogs given 0.3 to 1.0 mg/kg methadone administered IM, heart rate decreased, and bradycardia (heart rate < 60 beats/min) occurred in some dogs (39). One dog that received 1.0 mg/kg methadone developed a significant ventricular arrythmia (idioventricular rhythm), and the authors concluded that cardiac rhythm should be monitored carefully in dogs when methadone is administered alone at high doses (39). In another study, on effects of IV methadone (0.5 mg/kg) and hydromorphone (0.1 mg/kg) on cardiac conductivity in dogs while conscious or under sevoflurane anesthesia, all treatment groups had reduced heart rates and prolonged PR and QT intervals on an ECG (45). Although all dogs in the study had a decrease in heart rate, the most profound changes were in methadone-treated dogs under sevoflurane general anesthesia (45).

Overall, in dogs, cardiovascular effects of methadone follow a similar pattern of changes to those of other mu agonists, with reduced heart rate and cardiac index at clinically relevant doses. At high doses (> 0.5 mg/kg IV), methadone may increase the incidence of arrhythmias and systemic arterial pressures. As with all opioids, IV administration of methadone to animals under general anesthesia should start at the lower range of the recommended dose, with additional doses administered based on achieving the desired effect while monitoring the animal’s cardiovascular status.

Respiratory effects

When opioids were administered alone at clinically relevant doses to dogs and cats, there was generally minimal alteration in pulmonary gas exchange (2). Coadministration of opioid drugs, such as hydromorphone, morphine, or fentanyl, with other drugs (high doses of alpha-2 adrenergic agonists, injectable or inhalant anesthetics) can result in clinically significant respiratory depression (2). Mild elevations in PaCO₂ (< 50 mmHg) have minor physiologic consequences in healthy animals, but hypoventilation can contribute to hypoxemia, particularly without supplemental oxygen.

In cats, reduced respiratory rate has been reported following IV methadone; however, there are no reports on the effects of methadone on gas exchange (18). In healthy, pain-free dogs, one of the most notable changes after methadone was administered IV or IM was a change in respiration — either a dramatic increase in respiratory rate, or panting (37–39,44,46). Similar findings were reported in dogs administered hydromorphone or oxymorphone (2). Despite panting, there was no change in PaCO₂ values in healthy, conscious dogs receiving 0.5 mg/kg and 1.0 mg/kg of methadone IV (44). Panting in pain-free dogs following opioid administration is attributed to resetting of the hypothalamic thermoregulatory center and a perceived need to cool the body, rather than a response to increased PaCO₂ (2). In these dogs, there was a transient decrease in arterial oxygen without changes in PaCO₂; however, hypoxemia occurred in 1 dog that received 1.0 mg/kg of methadone (44), likely due to increased ventilation perfusion mismatching in the lung rather than to hypoventilation (44). Greater changes in PaO₂ and PaCO₂ have been reported in dogs receiving medetomidine (20 μg/kg) in combination with l-methadone (0.1 mg/kg) (47). In clinically healthy dogs given 3 doses of methadone (0.25 to 0.75 mg/kg) combined with acepromazine (0.05 mg/kg) administered IM, there was increased PaCO₂ and concurrent respiratory acidosis. However, none of the dogs had hypoxemia and hypoventilation resolved without treatment (48). In isoflurane-anesthetized dogs scheduled for femoro-tibial surgery, administration of 0.3 mg/kg of methadone IV over 2 min caused apnea in 50% of dogs, which was managed by positive pressure ventilation (34). Unfortunately, duration of apnea, PaCO₂, and subsequent ventilatory management were not reported. Similarly, in an experimental setting with no surgical stimulation, when 1.0 mg/kg of methadone was administered IV to healthy dogs receiving isoflurane at 1 minimum alveolar concentration (1.43%), all dogs developed apnea that persisted for > 1 min (46).

At clinical doses, the respiratory effects of methadone were similar to those of other mu agonists; e.g., morphine and hydromorphone. When methadone is administered IV, particularly in combination with general anesthetics, close monitoring of ventilation is strongly recommended.

Gastrointestinal effects

The mu opioid agonists hydromorphone and morphine are both associated with a high incidence of vomiting (50 to 75%) in the dog and cat (2). Experimental and clinical trials evaluating methadone administered parenterally, alone or in combination with acepromazine, reported few adverse gastrointestinal signs, such as vomiting or hypersalivation, in cats. Licking the nose and lips, which may be indicative of nausea, was reported after 0.3 mg/kg of methadone administrated IV in healthy, pain-free cats (18), but not after administration via IM or SC routes (16,24).

In dogs, low incidences of vomiting or clinical signs associated with nausea, such as retching or hypersalivation, were reported following methadone administration in numerous experimental studies (20,37,38,40). As the use and reporting of methadone in the clinical setting has expanded and repeated dosing has been evaluated, adverse gastrointestinal effects have been observed. In a study evaluating repeat methadone dosing at 4-hour intervals versus administration based on pain scoring in dogs after tibial plateau leveling, dogs receiving repeat dosing were 23 × more likely to vomit and their food intake was 38% less than in dogs treated based on pain scoring (49). Overall, dogs that received methadone every 4 h received 4 × more methadone; it was concluded that these dogs were overdosed and adverse gastrointestinal signs were more prevalent (49). Similar findings were reported in other studies, particularly when dogs were pain-free or received multiple doses or an infusion of methadone (19,50).

In dogs scheduled for gastroduodenal endoscopy, mu opioid agonists are generally avoided due to reported increase in duodenal sphincter tone. In dogs undergoing endoscopy, premedication with butorphanol (0.4 mg/kg IV) allowed for greater ease of duodenal entry compared with methadone (0.3 mg/kg IV) alone (51). In a comparison of effects of butorphanol (0.3 mg/kg IM) or methadone (0.2 mg/kg IM) in combination with acepromazine on the feasibility of gastroduodenoscopy (52), there were no differences, implying that methadone and butorphanol were equivalent at the doses evaluated when combined with acepromazine (52). Unless acepromazine is co-administered with methadone, butorphanol remains the recommended opioid analgesic in animals scheduled for gastroduodenal endoscopy.

Effects on thermoregulation

In the dog, at clinically relevant doses, opioids, including methadone, typically decrease or cause no measurable change in body temperature (38,44). Following mu agonist opioid administration, dogs often pant, a typical mechanism used to reduce body temperature. However, this is secondary to a decrease in the set point in the hypothalamic thermoregulatory center (2). In contrast, clinically significant hyperthermia has been reported in cats following the administration of opioid analgesics, most notably hydromorphone. Experimental studies of methadone’s nociceptive effects and clinical trials evaluating analgesic efficacy at doses ranging from 0.3 to 0.5 mg/kg have not reported hyperthermia, but effects of repeated dosing or higher doses are unknown (18,28,32).

Ocular effects

Considerable intra- and interspecies differences exist in observed ocular effects of opioid analgesics. Differences in effects within a species have been attributed to variations in dose, route, and rate of administration, plus concurrent drug administration and individual animal characteristics. In healthy dogs, methadone administered IV or IM at a dose of 0.3 mg/kg induced no clinically significant effects on intraocular pressure, pupil size, or tear production (53). However, when methadone was combined with acepromazine for sedation in dogs, tear production was reduced, which may predispose to ocular injuries if appropriate precautions such as topical therapy are not instituted (54). In the cat, as with other opioids, mydriasis has been reported following methadone administration, either alone or in combination with sedatives (29,30). Effects of methadone, alone or in combination, on tear production in the cat have not been reported. Topical therapy to protect the cornea is currently recommended following opioid administration in both dogs and cats.

Clinical recommendations

A summary of the clinical recommendations for the use of methadone is provided in Table 1. Use of methadone in cats for purposes other than preanesthetic medication before ovariohysterectomy or castration, at a dose of 0.5 mg/kg IM, is currently considered extra-label use in Canada. Based on the literature, there is evidence to support methadone extra-label use as a preanesthetic medication or analgesic drug in cats and dogs at a dose range of 0.2 to 0.5 mg/kg administered IV, IM, or SC. It is currently marketed in a multidose bottle containing preservatives; therefore, epidural administration is not recommended. When used as a preanesthetic medication before elective neutering in healthy cats and dogs, a dose of 0.3 mg/kg IM is considered suitable as an initial dose, particularly if combined with sedatives such as dexmedetomidine or acepromazine. As with other opioid analgesics, use of methadone with other analgesics drugs such as NSAIDs and strategies such as local anesthetic blocks should be considered based on the individual animal’s health status and planned surgical intervention. In animals for which multimodal analgesia with highly efficacious locoregional anesthesia is planned (e.g., ultrasound-guided femoral and sciatic block for femorotibial surgery), a lower dose (0.2 mg/kg) of methadone may provide adequate intraoperative analgesia while minimizing adverse effects (50). In dogs for which an analgesic infusion with methadone is desired, a loading dose of 0.2 mg/kg IV is recommended, followed by 0.1 mg/kg/h IV, with dose adjustments based on the animal’s response.

Table 1.

Recommendations for clinical use of methadone in dogs and cats.

Indication	Methadone is suitable for use as an analgesic drug and preanesthetic agent in both dogs and cats.
Dose	0.2 to 0.5 mg/kg. A dose of 0.3 mg/kg administered IM is a suitable initial dose prior to major surgery. Additional drug (0.1 to 0.2 mg/kg) can be administered based on an individual animal’s response.
Dosing interval	Duration of analgesic effect of methadone is ~4 h. Additional drug should be administered based on assessment of an individual animal’s signs of pain.
Advantage relative to other mu opioid agonists	Due to the associated reduced incidence of vomiting, methadone should replace morphine or hydromorphone in animals requiring analgesia with upper airway disease (brachycephalic syndrome, laryngeal paralysis, tracheal collapse), raised intracranial or intraocular pressure, or esophageal disease.
Precautions	In animals with cardiovascular disease, in particular hypertension or bradyarrhythmias, methadone should be administered slowly, IV, to effect, while monitoring the animal’s cardiovascular status.

In addition to its use in healthy patients, methadone is a suitable mu agonist opioid drug for use in those for which vomiting is undesirable. Intravenous administration, particularly in those with underlying cardiovascular disease, should be done slowly, while monitoring heart rate and rhythm. As with other mu agonist opioids, when using methadone as a preanesthetic medication, the dose of anesthetic required to induce and maintain anesthesia will be reduced.

The average duration of action of methadone is ~4 h; however, individual animals may require additional analgesia sooner. To avoid overdosing, administration of a lower dose (0.1 to 0.2 mg/kg IV, IM, or SC) is recommended initially, with subsequent dose adjustments based on an individual animal’s pain status. If parenteral administration of methadone is not possible, the OTM route can be considered in cats; however, due to variability in bioavailability, there should be an alternative pain management strategy. Irrespective of the route of analgesic administration, assessment of an animal’s level of pain is a critical component of any pain management strategy. A structured approach to patient assessment, including patient observation, physical examination with response to palpation, and use of a pain assessment tool, is highly recommended (1). Clinicians unfamiliar with current pain assessment tools should determine which assessment tools are best suited to their clinical practice (1).

Although inadequate pain management is undesirable, adverse effects of excessive opioid analgesic administration are recognized, including adverse gastrointestinal signs and behavioral alterations that impair overall patient well-being and recovery (49). When administered preoperatively at recommended doses, methadone has a low incidence of side effects; however, repeated administration for postoperative analgesia increased the frequency of vomiting (49). The use of multimodal analgesia, including NSAIDs and locoregional anesthetic techniques, may reduce the need for additional postoperative opioid drugs. Recognizing that animals may require additional analgesia 4 h following methadone administration, it is still recommended that thorough evaluation of postoperative pain commence within 2 h after methadone administration, with subsequent dosing based on the individual animal.

In the event of an overdose, naloxone (0.01 to 0.04 mg/kg IV) or butorphanol (0.4 mg/kg IV) can be used to reverse the effects of opioid agonists, including methadone (2). Irrespective of the reversal agent selected, it is recommended that the agent be titrated to effect; and, as methadone has a longer duration of action than either naloxone or butorphanol, patients should be monitored for return of adverse clinical signs consistent with excessive mu agonists.

Behavior-modifying drugs are increasingly being used in veterinary medicine to treat separation anxiety and reduce pre-appointment fear, among other disorders (55,56). Serotonin toxicity (syndrome), which manifests with autonomic hyperactivity (diarrhea, tachycardia, mydriasis), neuromuscular signs (tremors, myoclonus, rigidity), and altered mental status, is a potential adverse effect associated with drugs that increase serotonin in the CNS, such as the serotonin reuptake inhibitors and tricyclic antidepressants (56). It can occur from an overdose associated with 1 or more medications that affect the serotonergic system. Some opioid analgesics (e.g., methadone, fentanyl, and tramadol) also alter the serotonin system and have been associated with serotonin toxicity in humans when used with other agents that affect serotonin metabolism and release (56). The authors are unaware of any published reports of serotonin toxicity associated with acute perioperative methadone use in a clinical setting in animals receiving therapeutic doses of behavior-modifying agents or other opioid analgesics, such as tramadol. Regardless, clinicians should consider relative risks of concurrent behavioral therapy prior to anesthesia, and should be vigilant when using methadone, tramadol, or fentanyl in animals receiving agents that alter serotonin, to permit rapid discontinuation of drug therapy and initiation of supportive care if required (56).

Availability and cost

In Canada, methadone is currently available as a solution of 10 mg/mL in 5-milliliter, multiuse bottles (Comfortan; Dechra Pharmaceuticals, Northwich, United Kingdom) and is labeled for IM use (0.5 mg/kg) in healthy cats as part of a premedication regime for control of postoperative pain associated with ovariohysterectomy and castration. Approximate costs in Ontario associated with methadone, hydromorphone, butorphanol, and buprenorphine at typically used doses in companion animals are provided in Table 2. Durations of effect of individual drugs should be considered when determining the total cost of providing analgesia for an individual animal. CVJ

Table 2.

Approximate costs^a of opioids at typically used doses in dogs and cats.

Body weight (kg)	Methadone (10 mg/mL) $8.37/mL Dose: 0.3 mg/kg	Hydromorphone (2 mg/mL) $1.94/mL Dose: 0.05 mg/kg	Hydromorphone (10 mg/mL) $4.87/mL Dose: 0.05 mg/kg	Butorphanol (10 mg/mL) $7.19/mL Dose: 0.4 mg/kg	Buprenorphine (0.3 mg/mL) $8.99/mL Dose: 20 μg/mL
4	$1.00	$0.20	NA	$1.15	$2.42
10	$2.51	$0.49	NA	$2.87	$6.02
20	$5.02	$0.98	$0.48	$5.76	$11.96
30	$7.53	$1.47	$0.73	$8.64	$17.98
40	$10.04	$1.96	$0.96	$11.52	$24.00

NA — Not applicable.

^aPrices were obtained in February 2023 from a veterinary supply company in Ontario.