Intraoperative Methadone

Postoperative pain is not adequately managed in greater than 40% of surgical patients and is a high priority for perioperative research. In this meta-analysis, we examined studies comparing postoperative opioid consumption and pain scores in surgical patients who received methadone by any route vs those who received another opioid by any route. Studies were identified from PubMed, Cochrane, Web of Science, EMBASE, and Scopus from January 1966 to November 2018. Pooled odds ratios were calculated for a primary outcome of postoperative opioid consumption and secondary outcomes of time-to-extubation, time-to-first postoperative analgesia request, satisfaction, hospital length-of-stay, and complications. Postoperative pain scores were assessed qualitatively. Ten studies (617 patients) were included. Postoperative opioid consumption at 24 hours was lower in the methadone group vs control (mean difference = -15.22 mg oral morphine equivalents, 95% confidence interval -27.05 to -3.38; P = 0.01). Patients in the methadone group generally reported lower postoperative pain scores in 7 of 10 studies. Meta-analysis revealed greater satisfaction scores with analgesia in the methadone group vs control (0-100 visual analog scale; mean difference = 7.16, 95% confidence interval 2.30-12.01; P = 0.004). There was no difference in time-to-extubation, time-to-first analgesia request, hospital length-of-stay, or complications (nausea, sedation, respiratory depression, and hypoxemia). The results demonstrate that surgical patients who received intraoperative methadone had lower postoperative opioid consumption, generally reported lower pain scores and experienced better satisfaction with analgesia. However, these advantages need to be weighed carefully against dangerous risks with perioperative methadone, specifically respiratory depression and arrhythmia. Future studies should explore logistics, safety, and cost effectiveness.

Methadone is a potent opioid exerting an analgesic effect through N-methyl-D-aspartate receptor antagonism and the inhibition of serotonin and noradrenaline reuptake. It has also been used in several procedures to reduce postoperative pain and opioid use. This meta-analysis aimed to determine whether the intraoperative use of methadone lowers postoperative pain scores and opioid consumption in comparison to other opioids. Double-blinded, controlled trials without language restrictions were included from MEDLINE, Embase, LILACS, The Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL via EBSCOhost. The included studies tracked total opioid consumption, postoperative pain scores, opioid-related side effects, and patient satisfaction until 72 hours postoperatively. Mean difference (MD) was used for effect size. In total, 476 articles were identified and 13 were considered eligible for inclusion in the meta-analysis. In 486 patients (7 trials), pain at rest (MD, 1.09; 95% confidence interval (CI), 1.47-0.72; P < .00001) and at movement (MD, 2.48; 95% CI, 3.04-1.92; P = .00001) favored methadone 24 hours after surgery. In 374 patients (6 trials), pain at rest (MD, 1.47; 95% CI, 3.04-1.02; P < .00001) and at movement (MD, 2.03; 95% CI, 3.04-1.02; P < .00001) favored methadone 48 hours after surgery. In 320 patients (4 trials), pain at rest (MD, 1.02; 95% CI, 1.65-0.39; P = .001) and at movement (MD, 1.34; 95% CI, 1.82-0.87; P < .00001) favored methadone 72 hours after surgery. A Trial Sequential Analysis was performed and the Z-cumulative curve for methadone crossed the monitoring boundary at all evaluations, additionally crossing Required Information Size at 24 and 48 hours at rest. Methadone group also showed lower postoperative opioid consumption in morphine equivalent dosage (mg) at 24 hours (MD, 8.42; 95% CI, 12.99-3.84 lower; P < .00001), 24-48 hours (MD, 14.33; 95% CI, 26.96-1.91 lower; P < .00001), 48-72 hours (MD, 3.59; 95% CI, 6.18-1.0 lower; P = .007) postoperatively. Intraoperative use of methadone reduced postoperative pain scores compared to other opioids, and Trial Sequential Analysis suggested that no more trials are required to confirm pain reduction at rest until 48 hours after surgery. Methadone also reduced postoperative opioid consumption and led to better patient satisfaction scores through 72 hours postoperatively compared to other opioids.

Patients undergoing complex spine surgery frequently experience severe pain in the postoperative period. The combined opiate receptor agonist/N-methyl-d-aspartate receptor antagonist methadone may be an optimal drug for these patients given the probable involvement of N-methyl-d-aspartate systems in the mechanism of opioid tolerance and hyperalgesia. Twenty-nine patients undergoing multilevel thoracolumbar spine surgery with instrumentation and fusion were enrolled in this prospective study and randomized to receive either methadone (0.2 mg/kg) before surgical incision or a continuous sufentanil infusion of 0.25 &#x3bc;g/kg/h after a load of 0.75 &#x3bc;g/kg. Postoperative analgesia was provided using IV opioids by patient-controlled analgesia. Patients were assessed with respect to pain scores (visual analog scale from 0 to 10), cumulative opioid requirement, and side effects at 24, 48, and 72 hours after surgery. Demographic data, duration, and type of surgery were comparable between the groups. Methadone reduced postoperative opioid requirement by approximately 50% at 48 hours (sufentanil versus methadone group, median [25%/75% interquartile range]: 63 mg [27.3/86.1] vs 25 mg [16.5/31.5] morphine equivalents, P = 0.023; and 72 hours: 34 mg [19.9/91.5] vs 15 mg [8.8/27.8] morphine equivalents, P = 0.024) after surgery. In addition, pain scores were lower by approximately 50% in the methadone group at 48 hours after surgery (sufentanil versus methadone group [mean &#xb1; SD] 4.8 &#xb1; 2.4 vs 2.8 &#xb1; 2.0, P = 0.026). The incidence of side effects was comparable in both groups. Perioperative treatment with a single bolus of methadone improves postoperative pain control for patients undergoing complex spine surgery.

Methadone is increasingly used for perioperative care. High-dose methadone, for opioid use disorder or chronic pain, can prolong the cardiac QTc interval, which increases the risk of dangerous cardiac arrhythmias. This investigation evaluated single-dose perioperative methadone effects on QTc. This prospective observational cohort study evaluated adults undergoing elective surgery under general anaesthesia. Patients received methadone i.v. or no methadone (typically fentanyl) at induction of anaesthesia (provider discretion). QTc was determined before and for 1 h after opioid administration and rate-corrected using Fridericia's formula (QTcF). The primary outcome was new-onset QTcF >500 ms. Secondary outcomes were any QTcF>500 ms; QTcF increase (&#x394;QTcF)>60 ms; QTcF>500 ms for >15 min; QTcF>450 ms (males) or >470 ms (females); maximum QTcF and &#x394;QTcF; and methadone dose vs QTcF or &#x394;QTcF. Patients were 59 (median; range 18-86) yr of age, and received methadone (n=282, median 20 mg, IQR [15-20], range 10-60 mg) or no methadone (n=265, typically fentanyl, 250 &#x3bc;g [100, 350], 0-750 &#x3bc;g). New QTcF>500 ms occurred in 2.5% of patients receiving methadone and 8.3% receiving no methadone (relative risk [RR] 0.34, 95% confidence interval [0.16-0.75] P=0.009). Secondary outcomes with methadone vs no methadone found that any QTcF>500 ms occurred less (3.5% vs 8.3%, RR 0.43); &#x394;QTcF>60 ms occurred less (4.6% vs 12.1%, RR 0.39); maximum &#x394;QTcF was less (28 ms vs 37 ms); and sex-specific thresholds were exceeded less (22.3% vs 33.6%) (all P<0.03). There was no correlation between methadone dose and QTcF or &#x394;QTcF. A single-dose at induction of methadone i.v. did not prolong QTcF. Methadone had no clinically meaningful QTcF effects, specifically or in comparison with no use of methadone.

Intravenous methadone may be useful in acute and chronic pain management compared with other opioids because of its pharmacokinetic and pharmacodynamic characteristics, including the long duration of effect and ability to modulate both pain stimuli propagation and analgesic descending pathways. However, methadone is underused in pain medicine because of several misperceptions. A review of studies was performed to assess data regarding the use of methadone in perioperative pain and chronic cancer pain. The majority of studies have shown that intravenous methadone produces an effective postoperative analgesia and lowers opioid consumption in the postoperative period, without more adverse effects in comparison with other opioid analgesics, and has an interesting potential to prevent persistent postoperative pain. A minority of studies investigated the use of intravenous methadone for cancer pain management. These studies were mostly case series that showed promising activities of intravenous methadone for difficult pain conditions. There is sufficient evidence suggesting that intravenous methadone is effective in perioperative pain, while more studies are needed in patients with cancer pain.

Methadone is a long-acting opioid with multifaceted analgesic properties that is under increasing investigation as an intraoperative analgesic in cardiac surgery. A systematic search of United States National Library of Medicine Database (MEDLINE) and Excerpta Medica Database (EMBASE) databases identified publications investigating the use of intraoperative methadone in adult cardiac surgical patients. The risk of bias and quality of evidence of these studies were assessed, and data from these reports were extracted and presented in a narrative format. Sixteen eligible publications were included. Although the quality of the studies was moderate to high, the certainty of the evidence is low due to the limited available data regarding optimal dosing strategies, timing of administration in relation to cardiopulmonary bypass, and long-term safety outcomes. The composite data suggest that a single dose of intraoperative methadone results in less postoperative pain and opioid consumption postoperatively without any increased risk for QTc prolongation or respiratory depression. Doses of 0.1 to 0.3 mg/kg are reported in the cardiac surgery literature; however, there is evidence of a dose-response relationship with methadone's analgesic benefits and increased deliriogenic side effects. Studies using 0.1 mg/kg reveal equivocal analgesia, whereas the studies administering &#x2265;0.2 mg/kg consistently report lower postoperative pain scores and opioid consumption compared to short-acting intravenous (IV) opioids. Crucially, the use of cardiopulmonary bypass significantly impacts methadone's plasma concentrations and must be considered when determining the optimal dose and timing of administration. Further, recent observational studies offer valuable insight into methadone's role in multimodal enhanced recovery after cardiac surgery protocols. Additional trials are needed to refine methadone usage in this population.