Methadone-Based Recovery for Pediatric Cardiac Surgery

(PRECISE Trial)

Overseen By Amy Monroe, MPH, MBA

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Senthil Sadhasivam

Must not be taking: Opioids

Disqualifiers: Adults, Pregnancy, ASA 3, 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: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new recovery method using methadone, an opioid medication, for children after heart surgery. It compares methadone-based recovery procedures to usual care to determine which aids better recovery. Eligible children have undergone specific heart surgeries and experience significant pain afterward. Participants have a 50/50 chance of receiving either methadone treatment or standard care. This trial suits children whose surgeries often result in significant pain and who are not currently using opioids or have conditions like severe sleep apnea. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are using opioids before the surgery, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that methadone can be safe for children recovering from heart surgery. Studies have found that using methadone during and after surgery reduces the need for other painkillers without increasing side effects. Specifically, one study found that methadone reduced the use of other opioids early in recovery, benefiting children post-surgery.

Another study indicated that methadone use allowed for the early removal of breathing tubes without complications. However, methadone was sometimes associated with longer hospital stays, necessitating further research to understand the reasons.

Overall, current evidence suggests methadone is a well-tolerated option for managing pain in children after heart surgery. Discussing potential risks and benefits with healthcare providers is important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using methadone for pediatric cardiac surgery recovery because it offers a potentially more effective pain management approach. Unlike standard opioid treatments that may require frequent dosing, methadone's long-acting nature allows for fewer doses, potentially reducing the risk of side effects and dependency. Additionally, methadone's dual action as both a pain reliever and an NMDA receptor antagonist could provide more comprehensive pain control, targeting multiple pain pathways simultaneously. This approach not only aims to improve comfort for young patients but also enhances overall recovery experiences in the hospital setting.

What evidence suggests that this methadone-based protocol is effective for pediatric cardiac surgery recovery?

Research has shown that methadone can help manage pain after surgery. In this trial, participants in the Methadone-Based ERAS Group will receive methadone during surgery. Studies suggest this might reduce the need for other pain relief drugs afterward, potentially leading to a quicker recovery by lowering pain levels and reducing medication use. Methadone has also been associated with helping patients breathe independently sooner after surgery. While methadone is generally effective, limited information exists about its use in children. This study aims to learn more about its benefits in heart surgeries for kids. ^{1 2 4 6 7}

Who Is on the Research Team?

Senthilkumar Sadhasivam, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for children undergoing elective cardiac surgery. Specific eligibility details are not provided, but typically participants must meet certain health criteria and have parental consent.

Inclusion Criteria

ASA physical status 1&2

I am having heart surgery that will cause a lot of pain right after.

Exclusion Criteria

Baseline prolonged QTc

Methadone/oxycodone allergy

I have been diagnosed with severe sleep apnea.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Children undergo cardiac surgery and receive either methadone-based or standard-of-care analgesia protocols

1 week

Inpatient hospital stay

Follow-up

Participants are monitored for safety, effectiveness, and adverse events post-surgery

3 months

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

What Are the Treatments Tested in This Trial?

Interventions

• Methadone

Trial Overview The study compares a methadone-based enhanced recovery after surgery (ERAS) protocol with the current standard of care in pediatric cardiac surgery. Children will be randomly assigned to either group.

How Is the Trial Designed?

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

The methadone-based standardized analgesia intervention arm will include standardized perioperative care and analgesia, including intraoperative intravenous methadone (1st dose: 0.1 mg/kg up to a maximum of 5 mg before incision; 2nd dose: 0.1 mg/kg up to a maximum of 5 mg 4 hours after 1st dose) and postoperatively, up to 4 oral or IV doses of methadone (0.1 mg/kg up to a maximum of 5 mg) every 12 hours before discharge as part of standardized multimodal analgesia in the hospital setting.

Group II: 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+

Published Research Related to This Trial

In a meta-analysis of 10 studies involving 617 surgical patients, those who received methadone had significantly lower postoperative opioid consumption compared to those who received other opioids, with a mean difference of -15.22 mg in oral morphine equivalents.

Patients receiving methadone also reported lower pain scores and higher satisfaction with their pain management, although the use of methadone carries risks such as respiratory depression and arrhythmia that need to be considered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative methadone administration and postoperative pain control: a systematic review and meta-analysis. D'Souza, RS., Gurrieri, C., Johnson, RL., et al.[2021]

Methadone may be an effective option for postoperative pain control in children and adolescents, potentially reducing pain, opioid consumption, and the length of hospital stays, while also minimizing some side effects associated with traditional opioids.

Despite its benefits, methadone carries risks such as nausea, sedation, and QTc prolongation, highlighting the need for careful dosing protocols and further research to establish its safety and efficacy in various surgical contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What we know and what we don't know about the perioperative use of methadone in children and adolescents. Boisvert-Plante, V., Poulin-Harnois, C., Ingelmo, P., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12109820/

Intraoperative Methadone Versus Non- ... Conclusions: Intraoperative methadone-based analgesia had comparable effectiveness in postoperative opioid use, pain, and antiemetic use ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06626035

Evaluation of Analgesia for Cardiac Elective Surgery in ... The purpose of this study is to look at a standardized methadone-based enhanced recovery after surgery protocol following pediatric cardiac surgery.

3. journals.lww.com journals.lww.com/aoca/fulltext/2020/23010/enhanced_recovery_and_early_extubation_after.13.aspx

Enhanced Recovery and Early Extubation after Pediatric... Methadone may offer advantages in facilitating early extubation after cardiac surgery, but very few data are available in the pediatric population.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41201594/

Opioid and Methadone Prescribing for Infants with Surgical ... Methadone was independently associated with longer LOS, ventilator days, and TPN days. Higher RACHS-2 scores were associated with increased ...

5. www2.ccasociety.org www2.ccasociety.org/newsletters/2020summer/chip/chao%20commentary.html

CCAS E-News The results showed that intraoperative methadone was associated with a decrease of total opioid exposure during the early postoperative period with comparable ...

6. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2806477

Opioid and Methadone Use for Infants With Surgically ... Methadone use was associated with 21.41 (95% CI, 10.81-32.02) more days of postoperative length of stay, 10.80 (95% CI, 3.63-17.98) more ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31929251/

Enhanced recovery and early extubation after pediatric ... A methadone-based multimodal regimen facilitated early extubation without appreciable adverse events. Further investigations are needed to confirm efficacy ...