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

December 15, 2025 updated by: The Cleveland Clinic
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Patients 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.

Multiple 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/kg) 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.

Although 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/kg) 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.

If 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.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Stephanie Stoianoff, MBA
  • Phone Number: 12164440231
  • Email: stoians@ccf.org

Study Contact Backup

  • Name: Sandra Durbin, CLPN, CCRP
  • Phone Number: 216-269-4073
  • Email: durbins@ccf.org

Study Locations

  • United States
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic
        • Contact:
          • Stephanie Stoianoff, MBA
          • Phone Number: 216-444-0231
          • Email: stoians@ccf.org
        • Contact:
        • Principal Investigator:
          • Shobana Rajan, M

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Adult ≥ 18 years of age
  • Scheduled for multilevel lumbar and/or thoracic spine fusion (primary or revision)

Exclusion Criteria:

  • <18 or >72 Years of age
  • Body Mass Index >40
  • Known allergy to methadone
  • Pregnant females
  • Non-English-speaking patients

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Methadone Group
Patients randomized to receive post operative methadone
Drug: Methadone
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.
Other Names:
  • Methadone (Blinded) Group
Placebo Comparator: Patients randomized to receive (blinded) placebo
Patients will receive post operative placebo
Drug: 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.
Other Names:
  • Placebo (Blinded) Group

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Feasibility and Acceptability-Participant Willingness/Recruitment
Time Frame: 7 days
Willingness of participants to be randomized Indicates acceptability of randomization among eligible patients Outcome Measure: % of eligible patient consenting to randomization
7 days
Feasibility and Acceptability-Provider Engagement
Time Frame: 7 days
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/no response to the following: Willingness of neurosurgeons/anesthesiologists 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
7 days
Feasibility and Execution-Protocol Compliance and Execution
Time Frame: 7 days

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/no response to the following:

Compliance 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)
7 days
Acceptability and Execution-Baseline Stratification Data
Time Frame: 18 months
Outcome Measure: % of enrolled patients with prior chronic opioid use
18 months
Feasibility and Execution-Follow-Up Completion
Time Frame: 90 days
Ability to assess primary endpoint (opioid use at 3 months).Measured by response rates to the telephone survey at 3 months
90 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Execution-Collection of Cardiac Rhythm Abnormalities
Time Frame: 18 months
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,
18 months
Execution-Collection of Respiratory Adverse Events
Time Frame: 18 months

Respiratory depression indicators will be measured every 6 hours.

1) The presence of any of the following will be considered respiratory depression:

  1. Respiratory rate <8 or oxygen saturation <90% for longer than 5 minutes
  2. Increased oxygen requirement by ≥ 2 L O2 for 15 min
  3. naloxone use. Patients who are receiving
  4. supplemental oxygen
18 months
Estimate Reduction in Opioid Use
Time Frame: 90 days

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.

Postoperative 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
90 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Development of and effective study design
Time Frame: 24 months
To estimate key design parameters (variability and effect size) of a large clinical trial which will evaluate the reduction in chronic opioid use at 3 months post-surgery. Focusing on estimating parameters that will be needed to appropriately calculate the sample size for a larger trial.
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Cleveland Clinic

Investigators

  • Principal Investigator: Shobana Rajan, MD, The Cleveland Clinic
  • Study Chair: Andra Duncan, MD, The Cleveland Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 15, 2025

Primary Completion (Estimated)

October 1, 2027

Study Completion (Estimated)

October 1, 2028

Study Registration Dates

First Submitted

October 21, 2025

First Submitted That Met QC Criteria

October 24, 2025

First Posted (Estimated)

October 29, 2025

Study Record Updates

Last Update Posted (Actual)

December 17, 2025

Last Update Submitted That Met QC Criteria

December 15, 2025

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • The MEND Study pilot

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The investigator plans to share information by presenting abstract/journal materials pending results.

IPD Sharing Time Frame

De-identified data will be available post-analysis in abstract/journal articles.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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