Methadone for Postoperative Analgesia: Contribution of N-methyl-d-aspartate Receptor Antagonism

BACKGROUND Over 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. OBJECTIVE We designed this study to investigate the precise contribution of NMDAr antagonism in methadone-induced analgesia. DESIGN Single-centre, prospective, randomised, double-blind study. SETTING National Cancer Center – Fondazione IRCCS Istituto Nazionale Tumori Milano; patients were recruited between March 2010 and June 2012. PATIENTS Ninety-six patients scheduled for an open laparotomy for anterior resection of the rectum. INTERVENTIONS We 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 MEASURES The primary end-point was the extent of mechanical static (punctuate) hyperalgesia to von Frey hair stimulation lateral to the surgical incision. RESULTS Peri-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. CONCLUSION Methadone provides effective control of acute postoperative pain, independently, by modulation of the hyperalgesia mechanism. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, no.: NCT01594047.