Perioperative Rectal Methadone in Spine Surgery (PROMISE)

Patients undergoing spinal surgery require pain control medication after their surgery. Investigators have successfully used intravenous Methadone to manage pain after surgery. However, doctors in Canada do not have the intravenous form of Methadone to prescribe to their patients. The investigators in Canada propose a pilot trial to investigate whether Methadone administered rectally could be used to manage pain after spinal surgery.

The main questions are:

1. Are investigators able to recruit participants for this trial and learn from this study to plan a larger trial?
2. Does Methadone administered rectally during surgery, reduce participants' pain intensity, use less pain medication, and have a better recovery after surgery? Investigators will compare Methadone to a placebo (a look-alike substance that contains no drug) to see if Methadone works to manage pain after surgery better than the usual pain management.

Participants will:

• receive either Methadone or placebo during surgery.
• be asked some questions about their pain during days 1 to 3 after surgery
• be contacted by phone to ask about their recovery

At this time, the study aims to recruit 40 participants from St. Michael's Hospital, to learn whether it will be feasible to plan a larger study.

Study Overview

• Status: Recruiting
• Conditions: Spinal Surgery; Post-operative Pain Management; Post-operative Care
• Intervention / Treatment: Drug: Rectal Methadone administer during spinal surgery; Other: Placebo: Rectal saline solution

Detailed Description

Indication: Adult patients undergoing spine surgery Condition: Perioperative pain management Number of participants 40 Primary outcome Feasibility (recruitment success, consent rate, adherence, patient withdrawal, missing data, adverse outcomes) Secondary outcome 1) Average pain intensity; 2) Rate of respiratory depression and postoperative ileus; 3) Use of opioids in morphine equivalents; 4) Quality of recovery Study design

• Interventional trial
• Allocation: Randomized
• Intervention model: 2-Arm Parallel-Group
• Primary purpose: Feasibility
• Phase: Phase IV

Masking Participants and Outcome Assessors

Study Intervention:

• Intervention Arm: Methadone 0.2mg/kg of ideal body weight via rectal administration + standard or care
• Placebo Arm: Saline solution via rectal administration + standard of care

Follow-Up: Postoperative days 1, 2, 3, and 30

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Janneth A Pazmino-Canizares, MSc; Phone Number: 49561 4168646060; Email: Janneth.Pazmino-Canizares@unityhealth.to
• Study Contact Backup: Name: Sergio Pereira, MD PhD; Phone Number: 49308 416-360-4000; Email: Sergio.Pereira@unityhealth.to

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • Recruiting
      • St. Michael's Hospital
      • Contact: Janneth Pazmino-Canizares, MSc; Phone Number: 49561 4168646060; Email: Janneth.Pazmino-Canizares@unityhealth.to
      • Contact: Sergio Pereira, MD. PhD; Phone Number: 49803 416-360-4000; Email: sergio.pereira@unityhealth.to

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18 to 65 years-old.
2. Elective spinal surgery with fusion of one or more sacral, lumbar, thoracic, and/or cervical levels
3. Capacity to provide informed consent
4. For participants of childbearing potential, use of contraception.

Exclusion Criteria:

1. American Society of Anesthesiologists Physical Status > IV
2. Hypersensitivity to the active substance (methadone hydrochloride) or other opioid analgesics or to any ingredient in the formulation
3. Pregnant or nursing participants
4. Known or suspected mechanical gastrointestinal obstruction
5. Acute respiratory depression, elevated carbon dioxide levels in the blood, cor pulmonale, or pulmonary disease necessitating home oxygen therapy
6. Acute alcohol intoxication, delirium tremens, and convulsive disorders secondary to alcohol intoxication
7. Severe central nervous system depression, increased intracranial pressure, or head injury
8. Use of monoamine oxidase (MAO) inhibitors, such as isocarboxazid, phenelzine, selegiline, and tranylcypromine, within 14 days of enrollment
9. Diarrhea associated with pseudomembranous colitis caused by cephalosporins, lincomycins, or penicillins
10. Preoperative renal insufficiency or failure
11. Significant liver disease (cirrhosis or hepatic failure)
12. History of opioid use disorder within the last 3 months
13. Patients taking more than 90 mg of morphine equivalents daily
14. Poor comprehension of the English language
15. Patients who are likely to remain intubated postoperatively
16. QT interval > 500ms on preoperative ECG

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Arm with Methadone; During the spinal surgery intervention, participants receive a single dose of 0.2mg/kg of Methadone rectally, after anesthesia induction.	Drug: Rectal Methadone administer during spinal surgery; Rectal Methadone administered during spinal surgery for post-operative pain management
Placebo Comparator: Placebo arm; During the spinal surgery intervention, participants receive a single dose of saline solution rectally after anesthesia induction.	Other: Placebo: Rectal saline solution; Placebo: Rectal saline solution single dose received during surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility to recruit 40 participants into a trial of methadone and placebo	Recruitment rate (Acceptability and feasibility study)	18 months
Feasibility to recruit 40 participants into a trial of methadone and placebo	Withdrawal rate (Acceptability and feasibility study)	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid reduction	Total morphine equivalent used	At 24, 48, and 72 hours post operative
Pain intensity after surgery	Patient-Reported Outcomes Measurement Information System Pain Interference (PROMIS) Pain Intensity, Pain intensity scale- 0 to 10 (The higher the number the higher the pain intensity)	At 24, 48, and 72 hours post operative
Quality of Recovery	Quality of Recovery (QoR-15) Score, 15 items are rated on a 0-10 scale, with the total possible score ranging from 0 to 150, where higher scores indicate better recovery.	At 24, 48, and 72 hours post operative
Pain interference	Patient-Reported Outcomes Measurement Information System Pain Interference, PROMIS 6 a. 6 items, 5 Likert scale (the higher the score the higher the interference from pain)	Difference between Baseline and 30 days after surgery
Adverse outcomes	Rate of postoperative respiratory depression	At 24, 48, and 72 hours post operative
Adverse outcomes	Rate of postoperative ileus	At 24, 48, and 72 hours post operative

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: AFP Innovation Fund
• Investigators: Principal Investigator: Sergio Pereira, MD PhD, St. Michael's Hospital. Unity Health Toronto

Publications and helpful links

General Publications

• Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid complications and side effects. Pain Physician. 2008 Mar;11(2 Suppl):S105-20.
• 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.
• American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012 Feb;116(2):248-73. doi: 10.1097/ALN.0b013e31823c1030. No abstract available.
• Gerbershagen HJ, Aduckathil S, van Wijck AJ, Peelen LM, Kalkman CJ, Meissner W. Pain intensity on the first day after surgery: a prospective cohort study comparing 179 surgical procedures. Anesthesiology. 2013 Apr;118(4):934-44. doi: 10.1097/ALN.0b013e31828866b3.
• Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Shear TD, Deshur MA, Vender JS, Benson J, Newmark RL. Clinical Effectiveness and Safety of Intraoperative Methadone in Patients Undergoing Posterior Spinal Fusion Surgery: A Randomized, Double-blinded, Controlled Trial. Anesthesiology. 2017 May;126(5):822-833. doi: 10.1097/ALN.0000000000001609.
• Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017 Sep 25;10:2287-2298. doi: 10.2147/JPR.S144066. eCollection 2017.
• 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.
• Machado FC, Palmeira CCA, Torres JNL, Vieira JE, Ashmawi HA. Intraoperative use of methadone improves control of postoperative pain in morbidly obese patients: a randomized controlled study. J Pain Res. 2018 Oct 2;11:2123-2129. doi: 10.2147/JPR.S172235. eCollection 2018.
• Weir S, Samnaliev M, Kuo TC, Ni Choitir C, Tierney TS, Cumming D, Bruce J, Manca A, Taylor RS, Eldabe S. The incidence and healthcare costs of persistent postoperative pain following lumbar spine surgery in the UK: a cohort study using the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). BMJ Open. 2017 Sep 11;7(9):e017585. doi: 10.1136/bmjopen-2017-017585.
• Dale O, Sheffels P, Kharasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol. 2004 Aug;58(2):156-62. doi: 10.1111/j.1365-2125.2004.02116.x.
• 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.
• Elliott K, Kest B, Man A, Kao B, Inturrisi CE. N-methyl-D-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development. Neuropsychopharmacology. 1995 Dec;13(4):347-56. doi: 10.1016/0893-133X(95)00083-P.
• Puvanesarajah V, Liauw JA, Lo SF, Lina IA, Witham TF, Gottschalk A. Analgesic therapy for major spine surgery. Neurosurg Rev. 2015 Jul;38(3):407-18; discussion 419. doi: 10.1007/s10143-015-0605-7. Epub 2015 Feb 14.

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: February 11, 2025
• First Submitted That Met QC Criteria: February 18, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Intraoperative Methadone; Rectal Methadone administration; spinal surgery post-operative pain management
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Postoperative Complications; Pathologic Processes; Pain, Postoperative; Physiological Effects of Drugs; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Methadone
• Other Study ID Numbers: P-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is a feasibility pilot trial only.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No