The effect of methadone and ketamine on quality of recovery in patients undergoing laparoscopic cholecystectomy: a prospective cohort study
Keywords:
Methadone, Analgesia, Anesthesia, Ketamine, Multimodal analgesiaAbstract
BACKGROUND AND OBJECTIVES: Acute pain following laparoscopic cholecystectomy is most intense in the first 24 h. The use of shorter-acting opioids for pain management may contribute to increased postoperative morbidity. The combination of methadone and ketamine has been associated with lower postoperative pain scores and less opioid use. We aimed to determine whether the combination of ketamine and methadone improves the quality of recovery.
METHODS: This prospective cohort study included patients undergoing laparoscopic cholecystectomy. Patients who received either methadone alone or a combination of methadone and ketamine (0.3 mg/kg) were followed up for 24 h after surgery. The primary outcome was the quality of recovery, measured using the quality of recovery-40 (QoR-40) questionnaire. Secondary outcomes included postoperative pain intensity, opioid consumption, and the incidence of nausea and vomiting.
RESULTS: The QoR-40 scores were higher in patients who received methadone and ketamine than in those who received methadone alone [197 (194.7–198) versus 195 (189–197), P = 0.01]. Postoperative pain scores, the incidence of postoperative nausea and vomiting, and postoperative opioid use were similar between the groups. The combination of methadone and ketamine was not associated with lower incidence of moderate-to-severe pain in propensity score analysis.
CONCLUSION: Although the combination of methadone and ketamine showed a slight increase in QoR-40 scores at 24 h postoperatively, the observed difference between the groups was not clinically significant. Moreover, the absence of a reduction in postoperative pain intensity and similar perioperative opioid consumption between the groups further support the hypothesis that small, isolated doses of ketamine may not be effective in improving recovery quality compared with methadone alone.
Downloads
References
Bisgaard T, Warltier DC. Analgesic treatment after laparoscopic cholecystectomy. Anesthesiology. 2006;104(4):835–46. https://doi.org/10.1097/00000542-200604000-00030.
Murphy GS, Szokol JW. Intraoperative methadone in surgical patients. Anesthesiology. 2019;131(3):678–92. https://doi.org/10.1097/ALN.0000000000002755.
Madsen MR, Jensen KE. Postoperative pain and nausea after laparoscopic cholecystectomy. Surg Laparosc Endosc. 1992;2(4):303–5.
Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011;14(2):145–61.
Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153–93. https://doi.org/10.2165/00003088-200241140-00003.
Brinck E, Tiippana E, Heesen M, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018;12(12):CD012033. https://doi.org/10.1002/14651858.CD012033.pub4.
Machado FC, Vieira JE, De Orange FA, Ashmawi HA. Intraoperative methadone reduces pain and opioid consumption in acute postoperative pain: a systematic review and meta-analysis. Anesth Analg. 2019;129(6):1723–32. https://doi.org/10.1213/ANE.0000000000004404.
Komen H, Brunt LM, Deych E, Blood J, Kharasch ED. Intraoperative methadone in same-day ambulatory surgery: a randomized, double-blinded, dose-finding pilot study. Anesth Analg. 2019;128(4):802–10. https://doi.org/10.1213/ANE.0000000000003464.
Kharasch ED, Brunt LM, Blood J, Komen H. Intraoperative methadone in next-day discharge outpatient surgery: a randomized, double-blinded, dose-finding pilot study. Anesthesiology. 2023;139(4):405–19. https://doi.org/10.1097/ALN.0000000000004663.
Nunn KP, Velazquez AA, Bebawy JF, et al. Perioperative methadone for spine surgery: a scoping review. J Neurosurg Anesthesiol. 2025 Jan 1;37(1):31–9. PMID: 38624227; https://doi.org/10.1097/ANA.0000000000000966.
Von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9. https://doi.org/10.1016/j.jclinepi.2007.11.008.
Sznejder H, Amand C, Stewart A, Salazar R, Scala WAR. Real world evidence of the use of metamizole (dipyrone) by the Brazilian population. A retrospective cohort with over 380,000 patients. Einstein (Sao Paulo). 2022;20:eAO6353. https://doi.org/10.31744/einstein_journal/2022AO6353.
Höhener D, Blumenthal S, Borgeat A. Sedation and regional anaesthesia in the adult patient. Br J Anaesth. 2008;100(1):8–16. https://doi.org/10.1093/bja/aem342.
Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability of a postoperative quality of recovery score: the QoR-40. Br J Anaesth. 2000;84(1):11–5. https://doi.org/10.1093/oxfordjournals.bja.a013366.
Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34(28):3661–79. https://doi.org/10.1002/sim.6607.
Myles PS, Reeves MD, Anderson H, Weeks AM. Measurement of quality of recovery in 5672 patients after anaesthesia and surgery. Anaesth Intensive Care. 2000;28(3):276–80. https://doi.org/10.1177/0310057X0002800304.
Guimarães-Pereira L, Costa M, Sousa G, Abelha F. Quality of recovery after anaesthesia measured with QoR-40: a prospective observational study. Braz J Anesthesiol. 2016;66(4):369–75. https://doi.org/10.1016/j.bjane.2014.11.010.
Myles PS, Myles DB, Galagher W, et al. Minimal clinically important difference for three quality of recovery scales. Anesthesiology. 2016;125(1):39–45. https://doi.org/10.1097/ALN.0000000000001158.
Moro ET, Feitosa IMPSS, Oliveira RG, et al. Ketamine does not enhance the quality of recovery following laparoscopic cholecystectomy: a randomized controlled trial. Acta Anaesthesiol Scand. 2017;61(7):740–8. https://doi.org/10.1111/aas.12919.
Kwok RFK, Lim J, Chan MTV, Gin T, Chiu WKY. Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery. Anesth Analg. 2004;98(4):1044–9. https://doi.org/10.1213/01.ANE.0000105911.66089.59.
Mion G. Ketamine stakes in 2018: right doses, good choices. Eur J Anaesthesiol. 2019;36(1):1–3. https://doi.org/10.1097/EJA.0000000000000902.
Gerbershagen HJ, Aduckathil S, Van Wijck AJM, et al. Pain intensity on the first day after surgery. Anesthesiology. 2013;118(4):934–44. https://doi.org/10.1097/ALN.0b013e31828866b3.
Riddell JM, Trummel JM, Onakpoya IJ. Low-dose ketamine in painful orthopaedic surgery: a systematic review and meta-analysis. Br J Anaesth. 2019;123(3):325–34. https://doi.org/10.1016/j.bja.2019.05.043.
Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621–60. https://doi.org/10.1124/pr.117.015198.
Ates I, Aydin ME, Celik EC, Gozeler MS, Ahiskalioglu A. Perioperative intravenous low-dose ketamine infusion to minimize pain for septorhinoplasty: a prospective, randomized, double-blind study. Ear Nose Throat J. 2021;100(4):254–9. https://doi.org/10.1177/0145561320974860.
Rivat C, Laulin JP, Corcuff JB, et al. Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methyl-D-aspartate receptor antagonist ketamine. Anesthesiology. 2002;96(2):381–91. https://doi.org/10.1097/00000542-200202000-00025.
Avidan MS, Maybrier HR, Abdallah AB, et al. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet. 2017;390(10091):267–75. https://doi.org/10.1016/S0140-6736(17)31467-8.
Maheshwari K, Avitsian R, Sessler DI, et al. Multimodal analgesic regimen for spine surgery. Anesthesiology. 2020;132(5):992–1002. https://doi.org/10.1097/ALN.0000000000003143.
Faiz HR, Rahimzadeh P, Visnjevac O, et al. Intravenous acetaminophen is superior to ketamine for postoperative pain after abdominal hysterectomy: results of a prospective, randomized, double-blind, multicenter clinical trial. J Pain Res. 2014;7:65–70. https://doi.org/10.2147/JPR.S53234.
Moro ET, Lambert MF, Pereira AL, et al. The effect of methadone on postoperative quality of recovery in patients undergoing laparoscopic cholecystectomy: a prospective, randomized, double blinded, controlled clinical trial. J Clin Anesth. 2019;53:64–9. https://doi.org/10.1016/j.jclinane.2018.09.031.
Pelissier T, Laurido C, Kramer V, Hernández A, Paeile C. Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats. Eur J Pharmacol. 2003;477(1):23–8. https://doi.org/10.1016/S0014-2999(03)02192-7.
Murphy GS, Avram MJ, Greenberg SB, et al. Perioperative methadone and ketamine for postoperative pain control in spinal surgical patients: a randomized, double-blind, placebo-controlled trial. Anesthesiology. 2021;134(5):697–708. https://doi.org/10.1097/ALN.0000000000003743.
Kharasch ED, Clark JD. Methadone and ketamine: boosting benefits and still more to learn. Anesthesiology. 2021;134(5):676–9. https://doi.org/10.1097/ALN.0000000000003752.
Buckner Petty SA, Raynor G, Verdiner R, et al. The use of methadone and ketamine for intraoperative pain management in cardiac surgery: a retrospective cohort study. J Cardiothorac Vasc Anesth. 2025;39(2):414–9.
Macrae WA. Chronic pain after surgery. Br J Anaesth. 2001;87(1):88–98. https://doi.org/10.1093/bja/87.1.88.
Perkins FM, Kehlet H. Chronic pain as an outcome of surgery: a review of predictive factors. Anesthesiology. 2000;93(4):1123–33. https://doi.org/10.1097/00000542-200010000-00038.
Murphy GS, Avram MJ, Greenberg SB, et al. Postoperative pain and analgesic requirements in the first year after intraoperative methadone for complex spine and cardiac surgery. Anesthesiology. 2020;132(2):330–42. https://doi.org/10.1097/ALN.0000000000003025.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 São Paulo Medical Journal
This work is licensed under a Creative Commons Attribution 4.0 International License.
