Pain Control and Quality of Recovery After Intravenous Methadone Versus Intravenous Remifentanil in Craniotomy Surgery

NCT06810336 | Recruiting Early Phase 1 FDA Drug

• 1 other identifier: HSR240122
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Postoperative pain is prevalent after intracranial surgery. Patients undergoing craniotomy are typically managed with short acting opioids to enable early and reliable post-operative neurological exam as well as avoid the risk of respiratory depression. However, a plethora of studies have shown that a majority of these patients experience moderate to severe pain in first 48 hours after surgery. Suboptimal pain control can lead to complications such as arterial hypertension and post-operative intracranial hemorrhage, and hence, increased morbidity and mortality. Intravenous (IV) methadone has a long analgesic half-life and has N-methyl-D-aspartate (NMDA) receptor antagonist and serotonin and norepinephrine reuptake inhibitor (SNRI) properties. It has previously been shown to reduce postoperative opioid requirements, postoperative nausea and vomiting (PONV), and postoperative pain scores in patients that underwent orthopedic, abdominal, complex spine, and cardiac surgery. Similar findings have been shown in obstetric patients that underwent caesarean delivery under general anesthesia as well as patients that underwent gynecologic surgery and received IV methadone intraoperatively. In a recently published retrospective study, a single intraoperative dose of IV methadone was well tolerated with lower pain scores as well as MME (oral morphine milligram equivalents) requirements for up to 72 hours after elective intracranial surgery. IV methadone has, however, never been compared with conventional management via IV remifentanil for functional recovery in patients undergoing elective intercranial surgery. The investigator's hypothesis is that intravenous (IV) methadone is non-inferior to IV remifentanil in patients who undergo elective intracranial surgery. It offers the advantage of being a single dose noninvasive analgesic modality that may contribute to decreasing MME consumption during the first 72 hours postoperatively, controlling postoperative pain, and improving quality of recovery after surgery.

Conditions

Brain Injury; Brain Tumors; Craniotomy Surgery; Pain; Postoperative; Postoperative Care

Keywords

craniotomy

Outcome Measures

Primary Outcomes (1)

• Quality of recovery after surgery on postoperative day 1,2,3 using QoR-15 psychometrical questionnaire (range 0-150).

  The Quality of Recovery-15 (QoR-15) scale is a patient-reported outcome measurement of the quality of recovery after surgery and anesthesia. The scale ranges from 0 to 150, with a higher score indicating a better quality of recovery. A score of 0 indicates extremely poor quality of recovery, while a score of 150 indicates excellent quality of recovery. The QoR-15 score can be classified into four severity classes: excellent, good, moderate, and poor recovery.

  24 hours, 48 hours, 72 hours

Secondary Outcomes (6)

• Morphine Milligram Equivalent

  24 hours, 48 hours, 72 hours

• Numeric Rating scale (NRS) pain scores (0-10) as noted over post-operative day 0, 1, 2, and 3.

  24 hours, 48 hours, 72 hours

• Overall Benefits of Analgesic Score (OBAS) as noted over post-operative day 0, 1, 2, and 3.

  24 hours, 48 hours, 72 hours

• Complications and side effects as noted over post-operative day 0, 1, 2, and 3.

  24 hours, 48 hours, 72 hours

• Length of Stay in Post-Anesthesia Care Unit (PACU)

  0 hours, 24 hours

Study Arms (2)

IV Remifentanil

ACTIVE COMPARATOR

titratable medication, dosage determined by anesthesia care team.

Drug: Remifentanil

IV Methadone

EXPERIMENTAL

0.2 mg / kg Intravenous delivery prior to incision

Drug: Methadone

Interventions

Remifentanil DRUG

Intravenous Remifentanil

IV Remifentanil

Methadone DRUG

Intravenous Methadone

IV Methadone

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult Patients between ages 18 and 65 years old.
• Undergoing supratentorial intracranial surgery
• American Society of Anesthesiologists (ASA) physiological status I-III
• Body Mass Index (BMI) between 18.5 and 45
• Ability to understand and read English

You may not qualify if:

• Being unable or unwilling to sign a consent
• Anticipated discharge within 24 hours after surgery
• Patients requiring Emergent Surgery
• Preoperative usage of Methadone, or allergy to it.
• Patients with chronic pain, requiring daily opioid use at the time of surgery, MME \>60 as FDA defines opioid tolerant as 60 MME, long-acting forms of opioids such as fentanyl patch, oxycontin
• Active or Prior Substance Use Disorder, undergoing active treatment with Medication of Opioid Use Disorder including methadone (once daily dosing), Buprenorphine (any formulation) and Naltrexone
• Preoperative chronic renal insufficiency or failure (defined as a serum creatinine more than 2 mg/dl),
• Pregnancy
• Significant liver disease (cirrhosis or hepatic failure)
• QTc \>450 on preoperative electrocardiogram
• Pulmonary disease necessitating home oxygen therapy
• Inability to speak or read the English language

Sponsors & Collaborators

• University of Virginia: lead

Study Sites (1)

University of Virginia

Charlottesville, Virginia, 22908-0710, United States

RECRUITING

Related Publications (14)

• Russell T, Mitchell C, Paech MJ, Pavy T. Efficacy and safety of intraoperative intravenous methadone during general anaesthesia for caesarean delivery: a retrospective case-control study. Int J Obstet Anesth. 2013 Jan;22(1):47-51. doi: 10.1016/j.ijoa.2012.10.007. Epub 2012 Dec 7.

  PMID: 23219678 BACKGROUND

• Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Marymont JH, Shear T, Parikh KN, Patel SS, Gupta DK. Intraoperative Methadone for the Prevention of Postoperative Pain: A Randomized, Double-blinded Clinical Trial in Cardiac Surgical Patients. Anesthesiology. 2015 May;122(5):1112-22. doi: 10.1097/ALN.0000000000000633.

  PMID: 25837528 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.

  PMID: 20418538 BACKGROUND

• Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982 Dec;57(6):458-67. doi: 10.1097/00000542-198212000-00005. No abstract available.

  PMID: 6128949 BACKGROUND

• Mancini I, Lossignol DA, Body JJ. Opioid switch to oral methadone in cancer pain. Curr Opin Oncol. 2000 Jul;12(4):308-13. doi: 10.1097/00001622-200007000-00006.

  PMID: 10888415 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.

  PMID: 21173206 BACKGROUND

• Basali A, Mascha EJ, Kalfas I, Schubert A. Relation between perioperative hypertension and intracranial hemorrhage after craniotomy. Anesthesiology. 2000 Jul;93(1):48-54. doi: 10.1097/00000542-200007000-00012.

  PMID: 10861145 BACKGROUND

• Molnar L, Simon E, Nemes R, Fulesdi B, Molnar C. Postcraniotomy headache. J Anesth. 2014 Feb;28(1):102-11. doi: 10.1007/s00540-013-1671-z. Epub 2013 Jul 12.

  PMID: 23846599 BACKGROUND

• Tsaousi GG, Logan SW, Bilotta F. Postoperative Pain Control Following Craniotomy: A Systematic Review of Recent Clinical Literature. Pain Pract. 2017 Sep;17(7):968-981. doi: 10.1111/papr.12548. Epub 2017 Feb 23.

  PMID: 27996204 BACKGROUND

• Mordhorst C, Latz B, Kerz T, Wisser G, Schmidt A, Schneider A, Jahn-Eimermacher A, Werner C, Engelhard K. Prospective assessment of postoperative pain after craniotomy. J Neurosurg Anesthesiol. 2010 Jul;22(3):202-6. doi: 10.1097/ANA.0b013e3181df0600.

  PMID: 20479664 BACKGROUND

• Flexman AM, Ng JL, Gelb AW. Acute and chronic pain following craniotomy. Curr Opin Anaesthesiol. 2010 Oct;23(5):551-7. doi: 10.1097/ACO.0b013e32833e15b9.

  PMID: 20717011 BACKGROUND

• De Benedittis G, Lorenzetti A, Migliore M, Spagnoli D, Tiberio F, Villani RM. Postoperative pain in neurosurgery: a pilot study in brain surgery. Neurosurgery. 1996 Mar;38(3):466-9; discussion 469-70. doi: 10.1097/00006123-199603000-00008.

  PMID: 8837797 BACKGROUND

• Gottschalk A, Berkow LC, Stevens RD, Mirski M, Thompson RE, White ED, Weingart JD, Long DM, Yaster M. Prospective evaluation of pain and analgesic use following major elective intracranial surgery. J Neurosurg. 2007 Feb;106(2):210-6. doi: 10.3171/jns.2007.106.2.210.

  PMID: 17410701 BACKGROUND

• Vandse R, Vacaru A, Propp D, Graf J, Sran JK, Pillai P. Retrospective Study of the Safety and Efficacy of Intraoperative Methadone for Pain Management in Patients Undergoing Elective Intracranial Surgery. World Neurosurg. 2023 Jul;175:e969-e975. doi: 10.1016/j.wneu.2023.04.053. Epub 2023 Apr 19.

  PMID: 37084845 BACKGROUND

MeSH Terms

Conditions

Brain Injuries; Brain Neoplasms; Pain

Interventions

Remifentanil; Methadone

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propionates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ketones

Central Study Contacts

Jennifer Phillips, RN

CONTACT

434-297-8136; JVP8A@virginia.edu

Lauren Dunn, M.D.

CONTACT

434-924-2283; lak3r@uvahealth.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Anesthesiology

Model Details: a single blind study

Study Record Dates

• First Submitted: January 23, 2025
• First Posted: February 5, 2025
• Study Start: March 10, 2025
• Primary Completion (Estimated): September 10, 2027
• Study Completion (Estimated): September 10, 2027
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)