Methadone-Based Analgesia for Scoliosis Surgery

(PRECISE Trial)

Overseen By Carly Riedmann, MPH

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Senthil Sadhasivam

Must not be taking: Opioids

Disqualifiers: Adults, Pregnancy, Severe sleep apnea, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Up to 1 week post-operative

500 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but it excludes those who are already using opioids before surgery.

What data supports the effectiveness of the drug methadone for pain management in scoliosis surgery?

Research shows that using methadone during scoliosis surgery can reduce the need for other pain medications and improve pain control. It has been found to help manage pain effectively after surgery, leading to shorter hospital stays and better recovery outcomes. ^{1 2 3 4 5}

Is methadone safe for use in humans during scoliosis surgery?

Methadone has been used safely in humans for pain management during major spine surgeries, including scoliosis surgery, with studies showing it can reduce the need for other opioids. However, caution is advised due to potential risks like heart rhythm issues at high doses, so it is generally considered safer at lower doses. ^{1 2 4 5 6}

How is the drug methadone unique for scoliosis surgery pain management?

Methadone is unique for scoliosis surgery pain management because it acts as both a mu-opioid agonist (a type of pain reliever) and an NMDA antagonist (which can help reduce pain and prevent chronic pain development), allowing it to reduce the need for additional opioids and improve pain control after surgery. ^{1 2 5 7 8}

What is the purpose of this trial?

The purpose of this study is to look at a standardized methadone-based enhanced recovery after surgery protocol following pediatric spinal surgery. This study will consist of randomly assigning children to receive the methadone-based recovery procedures or to receive current standard of care recovery procedures. Randomly assigning means that there is a 50/50 chance, like a coin flip, of being assigned to either research group.

Research Team

Senthilkumar Sadhasivam, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for children undergoing elective spine fusion surgery to correct scoliosis, including idiopathic scoliosis. Specific eligibility criteria are not provided, but typically include a certain age range and health status.

Inclusion Criteria

ASA physical status 1&2

I am between 10 and 17 years old.

I am having surgery for scoliosis not caused by other conditions.

Exclusion Criteria

Baseline prolonged QTc

Developmental delay

I have a neurological condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either methadone-based ERAS or standard-of-care non-methadone-based analgesia during and after spinal fusion surgery

Up to 1 week post-operative

Inpatient hospital stay

Follow-up

Participants are monitored for safety and effectiveness, including pain scores, opioid use, and adverse events

3 months

Week 1 post-discharge, Month 1, and Month 3

Long-term monitoring

Participants are assessed for chronic persistent surgical pain and opioid dependence

3 months

Treatment Details

Interventions

• Methadone

Trial Overview The study compares two post-surgery recovery protocols: one using methadone (a strong painkiller) and another with standard care that doesn't use methadone. Children will be randomly placed in either group by chance.

Participant Groups

Group I: Methadone-Based ERAS Group Experimental Treatment 1 Intervention

Children randomized to the methadone arm will receive standardized perioperative care and analgesia, including intraoperative intravenous methadone (0.1 mg/kg up to a maximum of 5 mg before incision and 0.05 mg at the end of surgery) and postoperatively, up to 4 oral doses of methadone every 12 hours before discharge as part of standardized multimodal analgesia in the hospital setting.

Group II: SOC Non-Methadone-Based Group Active Control 1 Intervention

Children randomized to the standard-of-care arm will receive standard opioid analgesia protocol without intra- and post-operative methadone per the current site standards.

Methadone is already approved in United States, European Union, Canada, Japan, Switzerland for the following indications:

Approved in United States as Dolophine for:

• Pain management
• Opioid use disorder

Approved in European Union as Methadose for:

• Pain management
• Opioid dependence

Approved in Canada as Physeptone for:

• Pain management
• Opioid use disorder

Approved in Japan as Heptadon for:

• Pain management

Approved in Switzerland as Heptanon for:

• Pain management
• Opioid dependence

Who Is Running the Clinical Trial?

Senthil Sadhasivam

Lead Sponsor

Trials

7

Recruited

4,200+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

A protocol using scheduled postoperative methadone significantly reduced opioid usage by 45% compared to a patient-controlled analgesia (PCA) strategy in patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis, with 22 patients in the methadone group consuming only 0.18 mg/kg of hydromorphone equivalents.

Both pain and sedation scores were similar across all groups, indicating that the reduction in opioid use did not compromise pain management effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scheduled methadone reduces overall opioid requirements after pediatric posterior spinal fusion: A single center retrospective case series. Mok, V., Sweetman, S., Hernandez, B., et al.[2022]

The implementation of a methadone-based multimodal analgesia protocol in 122 idiopathic scoliosis patients significantly reduced the length of hospital stay from a median of 3 days to 2 days compared to the conventional pain management regimen.

Patients on the new protocol experienced lower total opioid consumption and improved pain control by postoperative day 2, along with a quicker return to bowel function, indicating enhanced recovery outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone-based Multimodal Analgesia Provides the Best-in-class Acute Surgical Pain Control and Functional Outcomes With Lower Opioid Use Following Major Posterior Fusion Surgery in Adolescents With Idiopathic Scoliosis. Ye, J., Myung, K., Packiasabapathy, S., et al.[2022]

In a study of 1010 patients undergoing spine surgery, oral methadone was found to be a feasible alternative to intravenous methadone, showing non-inferior pain scores and opioid consumption by postoperative day 3.

While the intravenous group required a higher preoperative and total opioid dose, there were no significant differences in adverse effects like QTc prolongation or arrhythmias between the two groups, suggesting that oral methadone is a safe option for postoperative pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of oral versus intravenous methadone on postoperative pain and opioid use after adult spinal deformity surgery: A retrospective, non-inferiority analysis. Esfahani, K., Tennant, W., Tsang, S., et al.[2023]

In a study of 1,478 patients undergoing major spine surgery, 36.8% experienced respiratory depression and 79.8% had hypoxemia after receiving intravenous methadone, indicating a significant risk of respiratory issues post-surgery.

Despite the high incidence of respiratory depression, the overall in-hospital mortality rate was low at 0.14%, suggesting that while methadone can lead to mild to moderate respiratory complications, it can be managed effectively with proper monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of intraoperative methadone for analgesia after major spine surgery: An observational study of 1,478 patients. Dunn, LK., Yerra, S., Fang, S., et al.[2020]

Methadone is a unique opioid that not only acts on mu receptors but also has effects on delta receptors and NMDA receptors, making it a complex option for pain management, especially in cases of uncontrolled pain or when other opioids cause toxicity.

While methadone can be safer at lower doses, there are significant risks associated with high doses, including prolonged QT interval and potential for serious heart issues, highlighting the need for more research through randomized controlled trials to better understand its safety and efficacy compared to other opioids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone for treatment of cancer pain. Bryson, J., Tamber, A., Seccareccia, D., et al.[2019]

Patients who received a single intraoperative dose of methadone during complex spine surgery reported significantly lower weekly frequency of chronic pain at 3 months post-surgery compared to those who received hydromorphone, indicating methadone's potential for long-term pain management.

In cardiac surgery patients, those who received methadone also experienced less frequent postsurgical pain at 1 month compared to those who received fentanyl, suggesting methadone's efficacy in reducing early postoperative pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative Pain and Analgesic Requirements in the First Year after Intraoperative Methadone for Complex Spine and Cardiac Surgery. Murphy, GS., Avram, MJ., Greenberg, SB., et al.[2023]

References

1. France pubmed.ncbi.nlm.nih.gov

Scheduled methadone reduces overall opioid requirements after pediatric posterior spinal fusion: A single center retrospective case series. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Methadone-based Multimodal Analgesia Provides the Best-in-class Acute Surgical Pain Control and Functional Outcomes With Lower Opioid Use Following Major Posterior Fusion Surgery in Adolescents With Idiopathic Scoliosis. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Comparison of oral versus intravenous methadone on postoperative pain and opioid use after adult spinal deformity surgery: A retrospective, non-inferiority analysis. [2023]

4. England pubmed.ncbi.nlm.nih.gov

In-hospital opioid usage following posterior spinal fusion for adolescent idiopathic scoliosis: Does methadone offer an advantage when used with an ERAS pathway? [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Safety profile of intraoperative methadone for analgesia after major spine surgery: An observational study of 1,478 patients. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Methadone for treatment of cancer pain. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Postoperative Pain and Analgesic Requirements in the First Year after Intraoperative Methadone for Complex Spine and Cardiac Surgery. [2023]

8. India pubmed.ncbi.nlm.nih.gov

The role of methadone in cancer pain treatment--a review. [2015]