Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. December 2019 • Volume 129 • Number 6 www.anesthesia-analgesia.org 1723 DOI: 10.1213/ANE.0000000000004404 GLOSSARY CENTRAL = The Cochrane Central Register of Controlled Trials; CI = confdence interval; ERAS = Enhanced Recovery After Surgery; GRADE = Grading of Recommendations, Assessment, Development and Evaluation; I 2 = heterogeneity index; MD = mean difference; MED = morphine equivalent dose; MOR = μ-opioid receptor; NMDA = N-methyl-D-aspartate; NRS = Numerical Rating Scale; PACU = postanesthesia care unit; PCA = patient-controlled analgesia; PONV = postoperative nausea and vomiting; PRISMA = Preferred Reporting Items for Systematic review and Meta- analysis Protocol; PROSPERO = International Prospective Register of Systematic Reviews; RCT = randomized controlled trial; RevMan = Review Manager software; RIS = required information size; RR = relative risk; SD = standard deviation; VAS = Visual Analog Scale; VRS = Verbal Rating Scale BACKGROUND: 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 postop- erative pain scores and opioid consumption in comparison to other opioids. METHODS: 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. RESULTS: In total, 476 articles were identifed and 13 were considered eligible for inclusion in the meta-analysis. In 486 patients (7 trials), pain at rest (MD, 1.09; 95% confdence 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, addition- ally 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. CONCLUSIONS: Intraoperative use of methadone reduced postoperative pain scores compared to other opioids, and Trial Sequential Analysis suggested that no more trials are required to con- frm 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 postopera- tively compared to other opioids. (Anesth Analg 2019;129:1723–32) Intraoperative Methadone Reduces Pain and Opioid Consumption in Acute Postoperative Pain: A Systematic Review and Meta-analysis Felipe C. Machado, MD, PhD,* Joaquim E. Vieira, PhD,* Flávia A. de Orange, PhD,† and Hazem A. Ashmawi, PhD* See Editorial, p 1456 From the *Anesthesia Department, Universidade de Sao Paulo, São Paulo, Brazil; and †Anesthesia Department, Institute of Integral Medicine Prof. Fernando Figueira (IMIP), Recife, Brazil. Accepted for publication July 23, 2019. Funding: None. The authors declare no conficts of interest. E META ANALYSIS KEY POINTS • Question: How effective is intraoperative methadone administration in reducing postoperative pain scores and opioid consumption compared to other opioids? • Findings: Pain scores until 72 hours postoperatively, postoperative opioid consumption, and patient satisfaction favor methadone over other opioids, and the incidence of opioid-related side effects was not increased with methadone use. • Meaning: Intraoperative methadone is effective in reducing postoperative pain scores and opioid consumption. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). Reprints will not be available from the authors. Address correspondence to Felipe C. Machado, MD, PhD, Anesthesia De- partment, Universidade de Sao Paulo, Av Dr Eneas de Carvalho Aguiar, 155, Prédio dos Ambulatórios 8 andar, Setor Azul, CEP (zip): 05403-000, Cerqueira César, São Paulo, Brazil. Address e-mail to felipe.chiodini@hotmail.com. Copyright © 2019 International Anesthesia Research Society Chronic Pain Medicine Section Editor: Honorio T. Benzon