Intraoperative Methadone

Adequate relief of perioperative pain has been deemed a fundamental right of patients and an obligation of practitioners.1 Inadequately relieved postoperative pain has numerous physiologic complications, attendant risk of increased morbidity, and causes needless suffering. More than 40% of postoperative patients report inadequate pain relief, or pain of moderate or greater intensity, despite treatment.1–3 Unrelieved acute postoperative pain is a risk factor for the development of chronic postsurgical pain.4,5 It seems axiomatic that the duration of analgesia should match the duration of pain. But how best to do so? The trend in anesthesia care over the past decades has been the use of opioids with successively faster elimination and successively shorter duration of effect (fentanyl, sufentanil, alfentanil, and remifentanil). Use of short-duration intraoperative opioids, awakening patients in discomfort, and then attempting to play “catch-up” in the recovery room, often with the standard postoperative opioid morphine, the opioid with the longest (and long—1 hour to peak effect) time to onset, appears to some to be suboptimal. The transition from intraoperative anesthesia based on ultrashort-duration opioids to postoperative analgesia can be challenging, particularly for painful operations.6 With a focus on perioperative opioids, IV patient-controlled analgesia (PCA) has become the mainstay for providing postoperative pain relief over the past 2 to 3 decades. It is generally accepted that PCA provides better analgesia and patient satisfaction than does conventional or nurse-administered opioids.3,5,7 However, there is also awareness of the limitations of PCA. PCA is better suited to maintaining analgesia after administration of appropriate opioid loading doses than to achieving analgesia de novo. Although PCA may be considered advantageous because it consumes less nursing time,3 the cost of pumps, disposables, and adverse events clearly also factors into assessing the overall cost-effectiveness of PCA. Adverse events may relate in part to pump programming errors, equipment malfunctions, PCA by proxy, and respiratory depression. The incidence of significant respiratory depression with PCA ranges from 0.1% to 1%, depending in part on the definition.8–11 Although this incidence has been variably referred to by some as low and by others as high, events can be catastrophic. It would seem axiomatic that decreasing postoperative opioid use, and the number of doses, would diminish the risk of untoward effects. This issue of Anesthesia & Analgesia reports an investigation that reminds us of a long-available, effective, and infrequently utilized (and perhaps underutilized) alternative to the more conventional opioid paradigms described above.12 That alternative is intraoperative methadone. For patients undergoing complex thoracolumbar spine surgery, Gottschalk et al. provided total IV anesthesia with propofol (50 to 150 μg/kg/min titrated to a target bispectral index) and either (by randomization) a sufentanil infusion (0.25 μg/kg/h after a loading dose of 0.75 μg/kg) or a single bolus dose of methadone (0.2 mg/kg), both supplemented with 0.1 μg/kg sufentanil for inadequate anesthesia. Postoperative analgesia was provided by PCA (fentanyl, morphine, or hydromorphone). Patients receiving methadone had significantly lower postoperative opioid requirements (median 98 vs. 219 mg morphine equivalents 0 to 72 hours postoperatively). Moreover, despite PCA, they also reported less postoperative pain. There was no difference in the incidence of side effects with methadone versus sufentanil. The authors concluded that a single intraoperative bolus of methadone improves postoperative pain control for patients undergoing complex spine surgery. Their results are unquestionably related to the slow rate of methadone elimination, and also attributed by the authors potentially to N-methyl-D-aspartate receptor antagonism by methadone. Methadone is the opioid with the longest elimination half-life (Table 1). It is an effective and cost-effective analgesic for acute, chronic, neuropathic, and cancer pain in adults, children, and even neonates, and can be administered via oral, IV, and other parenteral routes.13–15 For cancer and neuropathic pain, it is an often-used alternative to morphine, and growing rapidly in first-line use.16,17 Nevertheless, it remains relatively invisible in the operating room and postoperatively.Table 1: Onset of Effect and Elimination of OpioidsThe seminal investigations that introduced the use of methadone in the perioperative period were reported by Gourlay et al.18–20 They studied orthopedic (typically anterior spinal fusion) and general surgery (typically open cholecystectomy) patients administered 20 mg methadone as an IV bolus following induction of anesthesia. Postoperatively, approximately one-third were entirely pain free and did not request any analgesics during the 72 hours postoperative observation period, approximately one-third used only oral nonopioid analgesics (aspirin or paracetamol), with a median duration of methadone analgesia (time to first oral analgesic request) of 26 hours, and only one third of patients requested postoperative opioid analgesics, with a median duration of methadone analgesia (time to first opioid analgesic request) of 20 hours. Importantly, no patient had postoperative respiratory depression (rate 10-minute intervals) is administered in the postanesthesia care unit as needed, if a patient complains of pain and has an unstimulated respiratory rate greater than 10.20 There are also unanswered questions about perioperative methadone use. There is little information available about the pharmacokinetics and pharmacodynamics of methadone in pediatrics.22,23,39 More information is needed about the effectiveness and safety in outpatients,40 those who are opioid tolerant, and, perhaps, the cost-effectiveness and safety of methadone in comparison with conventional PCA. Nevertheless, as reminded by Gottschalk et al.,12 perhaps it is opportune to rediscover, reappraise, and reinvigorate the use of methadone in the perioperative period.