Methadone to Reduce Chronic Opioid Use After Major Spine Surgery: The MEND Pilot Feasibility Study

Summary

The investigators propose a randomized, triple-blinded (patients, investigators, outcomes assessors), placebo-controlled pilot feasibility trial (Methadone to End Narcotic Dependence, MEND trial) to assess the feasibility and safety of postoperative oral methadone in patients undergoing spine surgery and collect preliminary data to inform a larger clinical trial that will test the opioid-sparing effects of methadone at 3 months after spine surgery.

Timeline

Start

2025-11-15

Primary completion

2027-10

Completion

2028-10

Publications

• Background Berardino K, Carroll AH, Kaneb A, Civilette MD, Sherman WF, Kaye AD. An Update on Postoperative Opioid Use and Alternative Pain Control Following Spine Surgery. Orthop Rev (Pavia). 2021 Jun 22;13(2):24978. doi: 10.52965/001c.24978. eCollection 2021.
• Background Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, Bohnert ASB, Kheterpal S, Nallamothu BK. New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg. 2017 Jun 21;152(6):e170504. doi: 10.1001/jamasurg.2017.0504. Epub 2017 Jun 21.
• Background Dunn LK, Yerra S, Fang S, Hanak MF, Leibowitz MK, Alpert SB, Tsang S, Durieux ME, Nemergut EC, Naik BI. Safety profile of intraoperative methadone for analgesia after major spine surgery: An observational study of 1,478 patients. J Opioid Manag. 2018 Mar/Apr;14(2):83-87. doi: 10.5055/jom.2018.0435.
• Background Martin BI, Turner JA, Mirza SK, Lee MJ, Comstock BA, Deyo RA. Trends in health care expenditures, utilization, and health status among US adults with spine problems, 1997-2006. Spine (Phila Pa 1976). 2009 Sep 1;34(19):2077-84. doi: 10.1097/BRS.0b013e3181b1fad1.
• Background Luby AO, Alessio-Bilowus D, Hu HM, Brummett CM, Waljee JF, Bicket MC. Trends in Opioid Prescribing and New Persistent Opioid Use After Surgery in the United States. Ann Surg. 2025 Mar 1;281(3):347-352. doi: 10.1097/SLA.0000000000006461. Epub 2024 Aug 1.
• Background Kharasch ED. Intraoperative methadone: rediscovery, reappraisal, and reinvigoration? Anesth Analg. 2011 Jan;112(1):13-6. doi: 10.1213/ANE.0b013e3181fec9a3. No abstract available.
• Background Banks ML, Roma PG, Folk JE, Rice KC, Negus SS. Effects of the delta-opioid agonist SNC80 on the abuse liability of methadone in rhesus monkeys: a behavioral economic analysis. Psychopharmacology (Berl). 2011 Aug;216(3):431-9. doi: 10.1007/s00213-011-2235-2. Epub 2011 Mar 3.
• Background Davidson EM, Coggeshall RE, Carlton SM. Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test. Neuroreport. 1997 Mar 3;8(4):941-6. doi: 10.1097/00001756-199703030-00025.
• Background Stubhaug A, Breivik H. Long-term treatment of chronic neuropathic pain with the NMDA (N-methyl-D-aspartate) receptor antagonist ketamine. Acta Anaesthesiol Scand. 1997 Mar;41(3):329-31. doi: 10.1111/j.1399-6576.1997.tb04693.x. No abstract available.
• Background Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE. Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009 Oct;60(4):284-90. doi: 10.1016/j.phrs.2009.04.002. Epub 2009 Apr 11.
• Background Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther. 1999 May;289(2):1048-53.
• Background Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995 Sep;62(3):259-274. doi: 10.1016/0304-3959(95)00073-2.
• Background Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. doi: 10.1097/00000542-200603000-00025.
• Background Kreek MJ, Borg L, Ducat E, Ray B. Pharmacotherapy in the treatment of addiction: methadone. J Addict Dis. 2010 Apr;29(2):200-16. doi: 10.1080/10550881003684798.
• Background Kreutzwiser D, Tawfic QA. Methadone for Pain Management: A Pharmacotherapeutic Review. CNS Drugs. 2020 Aug;34(8):827-839. doi: 10.1007/s40263-020-00743-3.
• Background Gottschalk A, Durieux ME, Nemergut EC. Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery. Anesth Analg. 2011 Jan;112(1):218-23. doi: 10.1213/ANE.0b013e3181d8a095. Epub 2010 Apr 24.
• Background Fons RA, Hainsworth KR, Michlig J, Jablonski M, Czarnecki ML, Weisman SJ. Perioperative methadone for posterior spinal fusion in adolescents: Results from a double-blind randomized-controlled trial. Paediatr Anaesth. 2024 May;34(5):438-447. doi: 10.1111/pan.14843. Epub 2024 Jan 30.
• Background Murphy GS, Avram MJ, Greenberg SB, Shear TD, Deshur MA, Dickerson D, Bilimoria S, Benson J, Maher CE, Trenk GJ, Teister KJ, Szokol JW. Postoperative Pain and Analgesic Requirements in the First Year after Intraoperative Methadone for Complex Spine and Cardiac Surgery. Anesthesiology. 2020 Feb;132(2):330-342. doi: 10.1097/ALN.0000000000003025.
• Background 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 Dec;129(6):1723-1732. doi: 10.1213/ANE.0000000000004404.
• Background D'Souza RS, Gurrieri C, Johnson RL, Warner N, Wittwer E. Intraoperative methadone administration and postoperative pain control: a systematic review and meta-analysis. Pain. 2020 Feb;161(2):237-243. doi: 10.1097/j.pain.0000000000001717.
• Background Esfahani K, Tennant W, Tsang S, Naik BI, Dunn LK. Comparison of oral versus intravenous methadone on postoperative pain and opioid use after adult spinal deformity surgery: A retrospective, non-inferiority analysis. PLoS One. 2023 Jul 21;18(7):e0288988. doi: 10.1371/journal.pone.0288988. eCollection 2023.
• Background Eldridge SM, Lancaster GA, Campbell MJ, Thabane L, Hopewell S, Coleman CL, Bond CM. Defining Feasibility and Pilot Studies in Preparation for Randomised Controlled Trials: Development of a Conceptual Framework. PLoS One. 2016 Mar 15;11(3):e0150205. doi: 10.1371/journal.pone.0150205. eCollection 2016.
• Background Moore CG, Carter RE, Nietert PJ, Stewart PW. Recommendations for planning pilot studies in clinical and translational research. Clin Transl Sci. 2011 Oct;4(5):332-7. doi: 10.1111/j.1752-8062.2011.00347.x.
• Background Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, Lancaster GA; PAFS consensus group. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot Feasibility Stud. 2016 Oct 21;2:64. doi: 10.1186/s40814-016-0105-8. eCollection 2016.
• Background Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986 Dec;51(6):1173-82. doi: 10.1037//0022-3514.51.6.1173.
• Background Mascha EJ, Dalton JE, Kurz A, Saager L. Statistical grand rounds: understanding the mechanism: mediation analysis in randomized and nonrandomized studies. Anesth Analg. 2013 Oct;117(4):980-994. doi: 10.1213/ANE.0b013e3182a44cb9. Epub 2013 Sep 10.
• Background Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009 Nov 10;28(25):3083-107. doi: 10.1002/sim.3697.

Drugs

Indications

No indication recorded.