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.