• Emiliano Tognoli, Paolo L Proto, Giuliana Motta, Carlotta Galeone, Luigi Mariani, and Franco Valenza.
• From the Department of Anesthesiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (ET, PLP, FV), the Department of Anesthesiology ASST Vimercate Monza-Brianza, Italy (GM), the Department of Clinical Science and Comunity, University of Milan, Milano, Italy (CG), the Unit of Clinical epidemiology and Trial organization, Fondazione IRCCS Istituto nazionale dei Tumori, Milano, Italy (LM), and the Department of Oncology and Onco-Hematology, University Of Milan, Milano, Italy (FV).
• Eur J Anaesthesiol. 2020 Oct 1; 37 (10): 934-943.

BackgroundOver the past number of years, N-methyl-D-aspartate (NMDA) inhibitory drugs, like ketamine, have been introduced as adjuvant treatments for postoperative acute pain, within a multimodal approach. A further extension of this strategy could be the use of opioids with NMDA receptor (NMDAr) antagonism activity for control of postoperative pain. Methadone has a unique pharmacodynamic profile: it is both a μ-agonist and an NMDAr-blocker.ObjectiveWe designed this study to investigate the precise contribution of NMDAr antagonism in methadone-induced analgesia.DesignSingle-centre, prospective, randomised, double-blind study.SettingNational Cancer Center - Fondazione IRCCS Istituto Nazionale Tumori Milano; patients were recruited between March 2010 and June 2012.PatientsNinety-six patients scheduled for an open laparotomy for anterior resection of the rectum.InterventionsWe randomly assigned patients to four groups: 0-Mo (placebo and morphine), K-Mo [S(+)-ketamine and morphine], 0-Me (placebo and methadone), K-Me [S(+)-ketamine and methadone].Main Outcome MeasuresThe primary end-point was the extent of mechanical static (punctuate) hyperalgesia to von Frey hair stimulation lateral to the surgical incision.ResultsPeri-incisional hyperalgesia was 8.4 cm (95% confidence interval, 1.5 to 15.41) lower in the treatment group (K-Me) compared with the control group (0-Mo) at 24 h after surgery (P = 0.02). No significant differences were observed between the groups at 48 h after surgery (P = 0.88). Both groups treated with methadone had significantly lower pain during rest and movement, as measured with a Numerical Rating Scale at 24 h. At 48 h, only the movement Numerical Rating Scale was significantly lower. No difference occurred in opioid consumption.ConclusionMethadone provides effective control of acute postoperative pain, independently, by modulation of the hyperalgesia mechanism.Clinical Trial RegistrationClinicalTrials.gov, no.: NCT01594047.

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