Intraoperative Methadone for Postoperative Pain Control After Thoracic Surgery

Pain following surgery continues to be an important adverse outcome that may impact postoperative recovery. Opioids like fentanyl and hydromorphone are the primary medications used to provide analgesia, but paradoxically, may actually worsen pain when administered in the operating room. Methadone is a unique opioid which has N-methyl-D-aspartate (NMDA) receptor blocking properties, which may prevent the development of opioid-induced tolerance and hyperalgesia (increased sensitivity to pain induced by a drug). Studies have demonstrated that methadone reduces the need for analgesic medications and decreases pain after surgery. Furthermore, the addition of methadone to a standard anesthetic has been demonstrated to increase patient satisfaction with pain management and reduce the need for opioid analgesic medications during the first month after surgery. Some investigators have described methadone as a "opioid-sparing opioid" and recommended its use as part of a multimodal pain management strategy.

There is a growing interest in reducing the use of traditional opioids in the operating room. The aim of this clinical trial is to compare pain scores and analgesic requirements in two groups of patients; one group will be randomized to receive a small dose of methadone at the start of surgery. The other group will be randomized to receive an equal volume of saline (salt water-control group) at the start of surgery. We hypothesize that patients randomized to be administered methadone at the start of surgery will have less postoperative pain and may require lower doses of pain medications than those given saline-control..

Study Overview

• Status: Terminated
• Conditions: Postoperative Pain
• Intervention / Treatment: Drug: Methadone

Detailed Description

Despite the development of a number of treatment strategies for pain after surgery, many patients continue to experience moderate-to-severe pain in the early postoperative period. Traditionally, opioids are the primary method of providing analgesia in the operating room, postanesthesia care unit (PACU), intensive care unit, and surgical wards. However, a number of potentially life-threatening complications can develop following opioid administration including severe respiratory depression. In addition, studies have demonstrated an association between the dose of opioid used in the operating room and the intensity of pain after following surgery; paradoxically, the greater the dose of opioid administered, the higher the reported pain scores are in the early recovery period. This is likely secondary to two interrelated phenomena: tolerance and opioid-induced hyperalgesia. Tolerance, a pharmacologic concept, can develop acutely after a single dose of opioid in the operating room. This can result in increased requirements for postoperative pain medications. Opioid-induced hyperalgesia (OIH), a clinical concept, involves enhancement of existent pain stimuli (normally minimally painful incisions may feel much worse) and facilitation of chronic pain development. Therefore, it may be beneficial to use lower doses of intraoperative opioids on all surgical patients.

Using a multimodal approach to pain management has been demonstrated to reduce the requirements for postoperative analgesic agents and improve pain scores. A number of different agents have been investigated including gabapentinoids, lidocaine, steroids, and nonsteroidal anti-inflammatory agents. Although it is an opioid, another medication that may be considered as part of a multimodal treatment of pain is methadone. Methadone has several unique properties that may beneficially impact the recovery of the surgical patient. It has been extensively studied as an agent to provide prolonged postoperative analgesia. When larger doses of methadone have been administered intravenously at induction of anesthesia, a median duration of analgesia lasting more than 25 hours has been reported. In patients undergoing abdominal, orthopedic, or gynecologic surgery, the use of a single dose of methadone (20 mg or 0.2-0.3 mg/kg) before surgical incision resulted in improved analgesia for the first 24-48 hours after surgery, when compared to other intraoperative opioids. In these investigations, patients in the methadone groups required significantly less postoperative pain medication and reported lower pain scores during the first or second postoperative days. However, other investigations have demonstrated significant analgesic effects of smaller doses of methadone (0.1 to 0.15 mg/kg). Furthermore, reductions in pain scores and need for oral opioid medications for the first 30 postoperative days have been observed in surgical patients administered 0.15 mg/kg of methadone. In addition to a long plasma half-life, methadone has other properties which may be advantageous in surgical patients. Recent evidence has demonstrated that methadone has the ability to block N-methyl-D-aspartate (NMDA) receptors. NMDA receptors have been implicated in the development of postoperative hyperalgesia (amplification of pain stimuli), and techniques which block NMBA receptors reduce pain. Therefore, methadone may attenuate postoperative pain via this additional mechanism. NMDA receptor stimulation is also thought to play an important role in the development of chronic pain. Although unproven, it has been hypothesized that methadone may reduce the risk of development of chronic postsurgical pain via inhibition of NMDA receptors. No adverse events directly attributable to methadone have been reported in any of the published clinical trials.

The aim of this randomized clinical investigation is to assess two cohorts of patients; one group will receive a dose of methadone at induction of anesthesia (0.15 mg/kg ideal body weight (IBW)-methadone group)). The other group will be randomized to be administered an equal volume of saline in an identical appearing syringe (control group).. The primary endpoint will be pain scores 24 hours after surgery. Secondary endpoints will include pain scores on arrival and discharge from the postanesthesia care unit (PACU), and at 2, 6, 24, 48, and 72 hours (if the patient remains in the hospital) after surgery. Analgesic requirements in the PACU and surgical wards will be assessed. In addition, the incidence of potential methadone-related side effects will be measured (delayed emergence, nausea and vomiting, respiratory depression)). Furthermore, methadone has been documented to potentially reduce the incidence of chronic postsurgical pain. A survey with a self-addressed stamped envelope will be provided to patients at 1, 3, 6, and 12 months after surgery to complete to assess the effect of methadone on this important outcome variable.

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

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Northshore University Healthsystem

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients undergoing any thoracoscopic procedure under general anesthesia

Exclusion Criteria:

• American Society of Anesthesiologists Physical Status 4 or 5, active heart failure, significant liver disease, previous adverse reactions to methadone, preoperative recent history of opioid or alcohol abuse, renal failure, or inability to comprehend the English language

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methadone Group; The methadone group will receive a dose of methadone at induction of anesthesia (0.15 mg/kg ideal body weight (IBW)	Drug: Methadone; The methadone group will receive an intravenous dose of methadone at induction of anesthesia (0.15 mg/kg ideal body weight (IBW)
Placebo Comparator: Control Group; The control group will be administered an equal volume of saline in an identical appearing syringe.	Drug: Methadone; The methadone group will receive an intravenous dose of methadone at induction of anesthesia (0.15 mg/kg ideal body weight (IBW)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Scores	Pain scores 24 hours after the surgical procedure	24 hours after thoracic surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Scores	Pain scores 2 hours after the surgical procedure	2 hours after thoracic surgery
Pain Scores	Pain scores 6 hours after the surgical procedure	6 hours after thoracic surgery
Pain Scores	Pain scores 48 hours after the surgical procedure	48 hours after thoracic surgery
Pain Scores	Pain scores 72 hours after the surgical procedure	72 hours after thoracic surgery
Analgesic requirements	Postoperative opioid needs	At 24 hours
Analgesic requirements	Postoperative opioid needs	At 48 hours
Chronic Pain	Pain intensity after surgical discharge-Pain assessed at rest and with coughing on a 0 to 10 scale with 0=no pain and 10=worst pain imaginable	1 month
Chronic Pain	Pain intensity after surgical discharge-Pain assessed at rest and with coughing on a 0 to 10 scale with 0=no pain and 10=worst pain imaginable	3 months
Chronic Pain	Pain intensity after surgical discharge--Pain assessed at rest and with coughing on a 0 to 10 scale with 0=no pain and 10=worst pain imaginable	6 months
Chronic Pain	Pain intensity after surgical discharge--Pain assessed at rest and with coughing on a 0 to 10 scale with 0=no pain and 10=worst pain imaginable	12 months

Collaborators and Investigators

• Sponsor: NorthShore University HealthSystem

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2019
• Primary Completion (Actual): February 1, 2021
• Study Completion (Actual): February 1, 2021

Study Registration Dates

• First Submitted: February 12, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 25, 2020

Study Record Updates

• Last Update Posted (Actual): December 21, 2021
• Last Update Submitted That Met QC Criteria: December 6, 2021
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Methadone
• Other Study ID Numbers: EH19-031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Data not to be shared

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