[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"trial:NCT07222072":3,"trial-entities:NCT07222072":209,"trial-summary:NCT07222072":214},{"id":4,"nct_id":4,"org_study_id":5,"brief_title":6,"official_title":6,"overall_status":7,"completion_date":8,"status_verified_date":9,"last_update_date":10,"start_date":11,"sponsor_name":12,"lead_sponsor_class":13,"has_dmc":14,"brief_summary":15,"detailed_description":16,"conditions":17,"keywords":20,"study_type":24,"primary_purpose":13,"phases":25,"enrollment_info":27,"interventions":30,"primary_outcomes":45,"secondary_outcomes":64,"sex":74,"minimum_age":75,"maximum_age":76,"healthy_volunteers":77,"eligibility_criteria":78,"std_ages":89,"locations":92,"central_contacts":114,"overall_officials":119,"references":125,"see_also_links":208},"NCT07222072","The MEND Study pilot","Methadone to Reduce Chronic Opioid Use After Major Spine Surgery: The MEND Pilot Feasibility Study","RECRUITING","2028-10","2025-12","2025-12-17","2025-11-15","The Cleveland Clinic","OTHER",false,"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.","The Centers for Disease Control and Prevention reports a nearly 10-fold increase in the number of deaths from all types of drug overdose over the past 20 years, including 82,000 deaths that occurred in 2022 alone. Prescription opioid medications contribute to drug overdose deaths. In fact, nearly 294,000 people in the US died from a drug overdose involving prescription opioid medications between 1999 and 2022 - a 4-fold increase in prescription drug overdose deaths. Surgery is often the first exposure to opioid medications for many patients. Severe pain after surgery requires potent opioid medications which control pain but includes risk of long-term opioid-dependence. Long-term opioid use and abuse may lead to opioid addiction, overdose and even death.\n\nPatients undergoing spine surgery experience severe postoperative back pain immediately after surgery, which requires treatment with potent opioid medications. Severe pain in the first 1 to 3 days after surgery often develops into chronic back pain, which increases risk for long-term use and abuse of prescription opioid drugs. Importantly, compared with all other surgical procedures, back and spine surgery is associated with the highest risk of long-term use and abuse of prescription opioid medications. Certainly, chronic back pain requires opioid use in approximately 50% of patients at three months after surgery, 40% at six months, 30% at one year, and 17% at two years. A financial burden exists as well. Over the past 10 years, annual prescription opioid expenditures for pain after spine-related surgery increased 660% from $246 million in 1997 to $1.9 billion in 2006. Monthly direct and indirect costs associated with the treatment of postoperative persistent and chronic back pain totaled an average US $3,455 per patient. These data indicate that new approaches that provide effective, long-lasting, and safe treatment of postoperative pain after complex spine surgery while reducing risk of persistent and chronic postoperative pain and prolonged opioid use and reducing cost are needed.\n\nMultiple randomized clinical trials in patients undergoing a variety of surgical procedures have demonstrated that intraoperative methadone significantly reduces postoperative analgesic requirements in the immediate postoperative period, compared to shorter-acting opioids. Methadone is a unique long-acting opioid medication that demonstrates rapid onset and prolonged duration of action with a half-life of 24-36 hours and pain relief lasting 8-12 hours. Like other opioids, methadone activates the mu-opioid receptor, but it also has additional effects on the brain, such as blocking NMDA receptors and reducing reuptake of serotonin and norepinephrine. These actions may help improve recovery by reducing pain sensitivity, preventing tolerance to the medication with euphoric effects, preventing opioid-induced hyperalgesia and opioid tolerance. One investigation studied the impact of methadone on persistent and chronic post-surgical pain in a small randomized controlled trial (RCT) with 66 patients. Participants were randomized to receive either a single intraoperative intravenous dose of methadone (0.2 mg\u002Fkg) or intravenous hydromorphone (2 mg). Methadone not only reduced the incidence of post-surgical pain in the study group. but also the percentage of patients who required opioid analgesics at three months (10 versus 41%), suggesting a protective effect against prolonged opioid consumption. Pilot data from another investigation using preoperative oral methadone in patients undergoing cardiac surgery showed reduction in postoperative morphine consumption in the first 24 hours. If acute postoperative pain is reduced, the development of chronic pain may also decrease, as well as the need for long-term opioid therapy, dependence, and abuse.\n\nAlthough methadone provides effective analgesia for major surgery, a thorough safety assessment of perioperative intravenous methadone is needed. A large retrospective study of 1,478 patients after major spine fusion surgery who received IV methadone (0.13 mg\u002Fkg) along with other analgesics, including lidocaine, ketamine, and hydromorphone noted respiratory depression in one-third of patients and hypoxia in nearly 80%. Other concerns include a nearly 60% incidence of electrocardiographic QTc prolongation and 1.1% experienced myocardial infarction (MI) postoperatively. However, there is limited data on the impact of a single perioperative dose of methadone on QTc prolongation. Additional potential complications such as respiratory depression requires further investigation.\n\nIf proven safe and effective, postoperative pain therapy with methadone could offer a simple, practical strategy to improve long-term outcomes in this high-risk population undergoing spine surgery. This investigation will the safety and efficacy of postoperative methadone treatment in patients undergoing spine surgery and the opioid-sparing effects of methadone at 3 months after surgery.",[18,19],"Post Operative Pain","Spinal Surgery",[21,22,23],"Methadone","non-opioid","spinal surgery","INTERVENTIONAL",[26],"PHASE4",{"count":28,"type":29},120,"ESTIMATED",[31,38],{"type":32,"name":21,"description":33,"armGroupLabels":34,"otherNames":36},"DRUG","Patients randomized to receive (blinded) methadone: 5 mg twice daily on postoperative (post-op) days 1 and 2 followed by 5 mg daily on postop days 3, 4, and 5.",[35],"Methadone Group",[37],"Methadone (Blinded) Group",{"type":32,"name":39,"description":40,"armGroupLabels":41,"otherNames":43},"Placebo","Patients randomized to receive (blinded) placebo will receive placebo twice daily on day 1 and day 2 and once daily on day 3, 4 and 5. Patients taking preoperative opioids will return to baseline opioid schedule after surgery.",[42],"Patients randomized to receive (blinded) placebo",[44],"Placebo (Blinded) Group",[46,50,53,56,60],{"measure":47,"description":48,"timeFrame":49},"Feasibility and Acceptability-Participant Willingness\u002FRecruitment","Willingness of participants to be randomized Indicates acceptability of randomization among eligible patients Outcome Measure: % of eligible patient consenting to randomization","7 days",{"measure":51,"description":52,"timeFrame":49},"Feasibility and Acceptability-Provider Engagement","Feasibility, acceptability and execution of clinical protocol based on the use of intraoperative IV methadone followed by a postoperative oral methadone regimen following spine surgery will be assessed by yes\u002Fno response to the following: Willingness of neurosurgeons\u002Fanesthesiologists to buy in to the trial Reflects institutional buy-in and clinical integration potential Outcome Measure: % of surgeons permitting patient enrollment and supporting protocol adherence",{"measure":54,"description":55,"timeFrame":49},"Feasibility and Execution-Protocol Compliance and Execution","Feasibility of clinical protocol based on the use of intraoperative IV methadone followed by a postoperative oral methadone regimen following spine surgery will be assessed by yes\u002Fno response to the following:\n\nCompliance with the protocol, including specific study related procedures and timepoints specific to medication administration, adverse event reporting and data collection. Demonstrates deliverability and data reliability Outcome Measure: % adherence to all major protocol steps (drug administration, ECGs, AE reporting, opioid data)",{"measure":57,"description":58,"timeFrame":59},"Acceptability and Execution-Baseline Stratification Data","Outcome Measure: % of enrolled patients with prior chronic opioid use","18 months",{"measure":61,"description":62,"timeFrame":63},"Feasibility and Execution-Follow-Up Completion","Ability to assess primary endpoint (opioid use at 3 months).Measured by response rates to the telephone survey at 3 months","90 days",[65,68,71],{"measure":66,"description":67,"timeFrame":59},"Execution-Collection of Cardiac Rhythm Abnormalities","1\\) ECG collected on postoperative days 1, 2 and 3. Presence of cardiac arrhythmias (frequent premature ventricular contractions, ventricular arrhythmias) requiring treatment will be collected. An increase in QTc interval \\>500 ms or \\>25% from baseline will be compared to baseline ECG,",{"measure":69,"description":70,"timeFrame":59},"Execution-Collection of Respiratory Adverse Events","Respiratory depression indicators will be measured every 6 hours.\n\n1\\) The presence of any of the following will be considered respiratory depression:\n\n1. Respiratory rate \\\u003C8 or oxygen saturation \\\u003C90% for longer than 5 minutes\n2. Increased oxygen requirement by ≥ 2 L O2 for 15 min\n3. naloxone use. Patients who are receiving\n4. supplemental oxygen",{"measure":72,"description":73,"timeFrame":63},"Estimate Reduction in Opioid Use","To estimate reduction in opioid use (Morphine Milligram Equivalents, MME) in the acute postoperative period as a mechanistic indicator for decrease in opioid usage at 3 months.\n\nPostoperative 5-day opioid requirements assessed by total MME (5 days duration or length of hospitalization, whichever is earlier) will be compared between methadone and placebo groups","ALL","18 Years","72 Years",true,{"inclusion":79,"exclusion":82,"raw_text":88},[80,81],"Adult ≥ 18 years of age","Scheduled for multilevel lumbar and\u002For thoracic spine fusion (primary or revision)",[83,84,85,86,87],"\\\u003C18 or \\>72 Years of age","Body Mass Index \\>40","Known allergy to methadone","Pregnant females","Non-English-speaking patients","Inclusion Criteria:\n\n* Adult ≥ 18 years of age\n* Scheduled for multilevel lumbar and\u002For thoracic spine fusion (primary or revision)\n\nExclusion Criteria:\n\n* \\\u003C18 or \\>72 Years of age\n* Body Mass Index \\>40\n* Known allergy to methadone\n* Pregnant females\n* Non-English-speaking patients",[90,91],"ADULT","OLDER_ADULT",[93],{"facility":94,"status":7,"city":95,"state":96,"zip":97,"country":98,"contacts":99,"geoPoint":111},"Cleveland Clinic","Cleveland","Ohio","44195","United States",[100,105,108],{"name":101,"role":102,"phone":103,"email":104},"Stephanie Stoianoff, MBA","CONTACT","216-444-0231","stoians@ccf.org",{"name":106,"role":102,"email":107},"Sandra Durbin, CLPN, CCRP","durbins@ccf.org",{"name":109,"role":110},"Shobana Rajan, M","PRINCIPAL_INVESTIGATOR",{"lat":112,"lon":113},41.4995,-81.69541,[115,117],{"name":101,"role":102,"phone":116,"email":104},"12164440231",{"name":106,"role":102,"phone":118,"email":107},"216-269-4073",[120,122],{"name":121,"affiliation":12,"role":110},"Shobana Rajan, MD",{"name":123,"affiliation":12,"role":124},"Andra Duncan, MD","STUDY_CHAIR",[126,130,133,136,139,142,145,148,151,154,157,160,163,166,169,172,175,178,181,184,187,190,193,196,199,202,205],{"pmid":127,"type":128,"citation":129},"34745473","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\u002F001c.24978. eCollection 2021.",{"pmid":131,"type":128,"citation":132},"28403427","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\u002Fjamasurg.2017.0504. Epub 2017 Jun 21.",{"pmid":134,"type":128,"citation":135},"29733094","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\u002FApr;14(2):83-87. doi: 10.5055\u002Fjom.2018.0435.",{"pmid":137,"type":128,"citation":138},"19675510","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\u002FBRS.0b013e3181b1fad1.",{"pmid":140,"type":128,"citation":141},"39087325","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\u002FSLA.0000000000006461. Epub 2024 Aug 1.",{"pmid":143,"type":128,"citation":144},"21173206","Kharasch ED. Intraoperative methadone: rediscovery, reappraisal, and reinvigoration? Anesth Analg. 2011 Jan;112(1):13-6. doi: 10.1213\u002FANE.0b013e3181fec9a3. No abstract available.",{"pmid":146,"type":128,"citation":147},"21369752","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\u002Fs00213-011-2235-2. Epub 2011 Mar 3.",{"pmid":149,"type":128,"citation":150},"9141069","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\u002F00001756-199703030-00025.",{"pmid":152,"type":128,"citation":153},"9113174","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\u002Fj.1399-6576.1997.tb04693.x. No abstract available.",{"pmid":155,"type":128,"citation":156},"19717013","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\u002Fj.phrs.2009.04.002. Epub 2009 Apr 11.",{"pmid":158,"type":128,"citation":159},"10215686","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.",{"pmid":161,"type":128,"citation":162},"8657426","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\u002F0304-3959(95)00073-2.",{"pmid":164,"type":128,"citation":165},"16508405","Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. doi: 10.1097\u002F00000542-200603000-00025.",{"pmid":167,"type":128,"citation":168},"20407977","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\u002F10550881003684798.",{"pmid":170,"type":128,"citation":171},"32564328","Kreutzwiser D, Tawfic QA. Methadone for Pain Management: A Pharmacotherapeutic Review. CNS Drugs. 2020 Aug;34(8):827-839. doi: 10.1007\u002Fs40263-020-00743-3.",{"pmid":173,"type":128,"citation":174},"20418538","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\u002FANE.0b013e3181d8a095. Epub 2010 Apr 24.",{"pmid":176,"type":128,"citation":177},"38288667","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\u002Fpan.14843. Epub 2024 Jan 30.",{"pmid":179,"type":128,"citation":180},"31939849","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\u002FALN.0000000000003025.",{"pmid":182,"type":128,"citation":183},"31743194","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\u002FANE.0000000000004404.",{"pmid":185,"type":128,"citation":186},"31613867","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\u002Fj.pain.0000000000001717.",{"pmid":188,"type":128,"citation":189},"37478144","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\u002Fjournal.pone.0288988. eCollection 2023.",{"pmid":191,"type":128,"citation":192},"26978655","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\u002Fjournal.pone.0150205. eCollection 2016.",{"pmid":194,"type":128,"citation":195},"22029804","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\u002Fj.1752-8062.2011.00347.x.",{"pmid":197,"type":128,"citation":198},"27965879","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\u002Fs40814-016-0105-8. eCollection 2016.",{"pmid":200,"type":128,"citation":201},"3806354","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\u002F\u002F0022-3514.51.6.1173.",{"pmid":203,"type":128,"citation":204},"24023021","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\u002FANE.0b013e3182a44cb9. Epub 2013 Sep 10.",{"pmid":206,"type":128,"citation":207},"19757444","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\u002Fsim.3697.",[],{"nct_id":4,"conditions":210,"biomarkers":213},[211,212],"Post-Operative Pain","Spinal surgery",[],{"nct_id":4,"found":77,"summary":215,"prompt_version":225},{"design":216,"status":217,"heading":218,"summary":219,"follow_up":220,"word_count":221,"commitments":222,"compensation":223,"drugs_mentioned":224},"This is a randomized, triple-blinded (you, your doctors, and the people analyzing results won't know if you're getting methadone or placebo), placebo-controlled study with 120 participants.","completed","Methadone for Pain After Spine Surgery","This study is looking at whether a medication called methadone can help reduce the need for other strong pain medicines (opioids) after major spine surgery. Researchers want to see if giving methadone for a few days after surgery is practical and safe. You could be eligible if you are an adult between 18 and 72 years old and are scheduled for certain types of spine fusion surgery. The study will compare methadone to a placebo (a pill with no medicine) to see how well it works. The main goal for this first study is to check if it's possible to recruit enough participants and if the study procedures can be followed easily. This information will help plan a larger study in the future.","The main goals for this study are measured at 7 days after surgery.",123,"You would receive either methadone or a placebo twice daily for two days after surgery, then once daily for three more days.","Not stated in the trial record.",[21,39],"v2"]