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

Early Phase 1

Not yet recruiting

• Conditions: Brain Injury; Brain Tumors; Craniotomy Surgery; Pain; Postoperative; Postoperative Care
• Interventions: Drug: Remifentanil; Drug: Methadone

• Registration Number: NCT06810336
• Lead Sponsor: University of Virginia

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.

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 Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-01-23
• Study First Submitted QC: 2025-01-30
• Last Update Submitted: 2025-01-30
• Study First Posted: 2025-02-05
• Last Update Posted: 2025-02-05
• Study Start: 2025-03-10
• Primary Completion: 2026-09-10
• Study Completion: 2026-09-10

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 40

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IV Remifentanil	Remifentanil	titratable medication, dosage determined by anesthesia care team.
IV Methadone	Methadone	0.2 mg / kg Intravenous delivery prior to incision

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Morphine Milligram Equivalent	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
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	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".
Overall Benefits of Analgesic Score (OBAS) as noted over post-operative day 0, 1, 2, and 3.	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.
Complications and side effects as noted over post-operative day 0, 1, 2, and 3.	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)
Length of Stay in Post-Anesthesia Care Unit (PACU)	0 hours, 24 hours
Length of Stay in Hospital	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.

Trial Locations

Locations (1)

University of Virginia; 🇺🇸 Charlottesville, Virginia, United States