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

April 27, 2026 updated by: Lauren Dunn, MD, University of Virginia

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Early Phase 1

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

Study Contact Backup

Study Locations

  • United States
    • Virginia
      • Charlottesville, Virginia, United States, 22908-0710
        • Recruiting
        • University of Virginia
        • Contact:
        • Contact:
        • Principal Investigator:
          • Lauren K Dunn, MD
        • Sub-Investigator:
          • Priyanka Singla, MD

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

No

Description

Inclusion Criteria:

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

Exclusion Criteria:

  1. Being unable or unwilling to sign a consent
  2. Anticipated discharge within 24 hours after surgery
  3. Patients requiring Emergent Surgery
  4. Preoperative usage of Methadone, or allergy to it.
  5. 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
  6. 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
  7. Preoperative chronic renal insufficiency or failure (defined as a serum creatinine more than 2 mg/dl),
  8. Pregnancy
  9. Significant liver disease (cirrhosis or hepatic failure)
  10. QTc >450 on preoperative electrocardiogram
  11. Pulmonary disease necessitating home oxygen therapy
  12. Inability to speak or read the English language

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: Health Services Research
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: IV Remifentanil
titratable medication, dosage determined by anesthesia care team.
Drug: Remifentanil
Intravenous Remifentanil
Experimental: IV Methadone
0.2 mg / kg Intravenous delivery prior to incision
Drug: Methadone
Intravenous Methadone

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of recovery after surgery on postoperative day 1,2,3 using QoR-15 psychometrical questionnaire (range 0-150).
Time Frame: 24 hours, 48 hours, 72 hours
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Morphine Milligram Equivalent
Time Frame: 24 hours, 48 hours, 72 hours
morphine milligram equivalent is a measurement of a given analgesic effect standardized to a milligram of morphine. In other words, agent X has the same effect as Y milligrams of morphine
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.
Time Frame: 24 hours, 48 hours, 72 hours
The numeric rating scale (NRS) is a pain screening tool, commonly used to assess pain severity at that moment in time using a 0-10 scale, with zero meaning "no pain" and 10 meaning "the worst pain imaginable".
24 hours, 48 hours, 72 hours
Overall Benefits of Analgesic Score (OBAS) as noted over post-operative day 0, 1, 2, and 3.
Time Frame: 24 hours, 48 hours, 72 hours
The overall benefit of analgesic score (OBAS) is a daily survey that assesses a patient's satisfaction with analgesia, pain intensity, and adverse effects. To compute score, add all scores in items 1-7. Range: [0 - 28]. A low score indicates high benefit.
24 hours, 48 hours, 72 hours
Complications and side effects as noted over post-operative day 0, 1, 2, and 3.
Time Frame: 24 hours, 48 hours, 72 hours

Complications and side-effects:

(a) Ability to extubate patient in the operating room (yes or no) (i) If no, Documented Time to Extubation (b) Incidence of hypoxia (requiring >2l NC O2 to maintain SpO2 > 90), respiratory depression (RR<8), and reintubation during the hospital stay after surgery (c) Time to ambulation, passing flatus, bowel movement (d) Incidence of pruritus, antiemetic medication administered - both as needed and scheduled (surrogate for PONV)
24 hours, 48 hours, 72 hours
Length of Stay in Post-Anesthesia Care Unit (PACU)
Time Frame: 0 hours, 24 hours
0 hours, 24 hours
Length of Stay in Hospital
Time Frame: From day of surgery to hospital discharge, expected to range from 5 to 10 days
Length of stay will be recorded from the calendar day of surgery through the calendar day of hospital discharge.
From day of surgery to hospital discharge, expected to range from 5 to 10 days

Collaborators and Investigators

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

Sponsor

University of Virginia

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)

March 10, 2025

Primary Completion (Estimated)

September 10, 2027

Study Completion (Estimated)

September 10, 2027

Study Registration Dates

First Submitted

January 23, 2025

First Submitted That Met QC Criteria

January 30, 2025

First Posted (Actual)

February 5, 2025

Study Record Updates

Last Update Posted (Actual)

May 4, 2026

Last Update Submitted That Met QC Criteria

April 27, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSR240122

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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.

No

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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