Methadone Dosing for Opioid Use Disorder

Overseen By Denis Antoine, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of Maryland, Baltimore

Must be taking: Methadone

Disqualifiers: Pregnant, Acute medical problem, others

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

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: Unknown

Duration: 12 weeks

150 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate whether once versus twice daily dosing of methadone will be an effective method for managing comorbid pain and opioid use disorder.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you must already be on methadone for opioid use disorder and continue with it during the study.

What data supports the effectiveness of the drug Methadone for opioid use disorder?

Research shows that Methadone is effective in reducing illicit opioid use and improving drug-related behavior, with higher doses (like 50 mg) leading to better outcomes compared to lower doses or no methadone. Patients on higher doses had fewer positive drug tests and reported less frequent heroin use. ^{1 2 3 4 5}

Is methadone generally safe for humans?

Methadone is generally safe when used correctly, but it can cause serious side effects like heart rhythm problems (torsades de pointes) and overdose, especially if doses are increased too quickly or if combined with other drugs like benzodiazepines or alcohol. Most methadone-related deaths occur in the early stages of treatment or when the drug is used without a prescription. Careful management and monitoring can help reduce these risks. ^{6 7 8 9 10}

How is the drug methadone unique in treating opioid use disorder?

Methadone is unique because it is considered the gold standard for treating opioid dependence, with flexible dosing that can be adjusted to individual needs, unlike some treatments that have fixed doses. It helps reduce illicit opioid use and improves psychosocial functioning, with higher doses often leading to better outcomes. ^{1 5 11 12 13}

Research Team

Kelly E Dunn, PhD, M.B.A.

Principal Investigator

University of Maryland

Denis Antoine, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for adults over 18 who have been on a stable methadone dose for opioid use disorder (OUD) treatment for at least 90 days. Participants must be willing to follow the study schedule, carry a phone during part of the study, and experience chronic pain. Pregnant individuals or those with acute medical issues, severe mental illness, or conditions that contraindicate split-dosing of methadone are excluded.

Inclusion Criteria

I am 18 years old or older.

Willing to comply with study schedule

I have a cell phone or am willing to carry one provided by the study.

Exclusion Criteria

Presence of a serious and unstable mental illness that interferes with provision of voluntary informed consent and/or adherence to study visits

I am on pain treatment where methadone split-dosing is not suitable.

You do not have a disability that falls within the mild to severe range, as determined by a specific definition that is not disclosed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either treatment as usual with once daily methadone or split dosing with methadone twice daily for 12 weeks

12 weeks

Weekly assessments (virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Methadone

Trial Overview The study is testing if taking methadone once daily versus twice daily can effectively manage both chronic pain and OUD. Participants will receive either their full dose all at once or half the dose twice a day to see which method works better.

Participant Groups

Group I: Split-dosing Experimental Treatment 1 Intervention

Participants in split dosing group will receive 50% active methadone + placebo twice daily.

Group II: Treatment as Usual (TAU) Active Control 1 Intervention

Participants in treatment as usual group will receive 100% active methadone in AM + placebo in PM.

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?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

In a double-blind clinical trial with 95 opioid abusers, those receiving 50 mg of methadone showed significantly better outcomes compared to those on 20 mg or no methadone, indicating a dose-related efficacy in reducing illicit opioid use.

Patients on 50 mg had lower rates of opioid-positive urine tests (36% vs. 60-73%) and reported using heroin less frequently (3 days vs. 11-12 days per month), highlighting the importance of adequate dosing in methadone treatment for opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone dose and treatment outcome. Strain, EC., Stitzer, ML., Liebson, IA., et al.[2022]

In a study involving 131 adults with opioid use disorder, the use of a pharmacologically conditioned open-label placebo (C-OLP) did not significantly change the average methadone dose but improved treatment retention rates, with 77.9% of C-OLP participants remaining in treatment compared to 61.1% in the treatment as usual (TAU) group.

Participants receiving C-OLP also reported better sleep quality, suggesting that this behavioral intervention could enhance the overall treatment experience for individuals undergoing methadone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial. Belcher, AM., Cole, TO., Massey, E., et al.[2023]

In a study of 516 patients on stable methadone treatment, 40.6% were found to be inadequately dosed, with those on inadequate doses averaging 70.6 mg per day compared to 57.8 mg for those adequately dosed.

Patients with inadequate dosing experienced significantly higher addiction-related problems, indicating that higher disease severity may necessitate higher methadone doses for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

When higher doses in opioid replacement treatment are still inadequate - association to multidimensional illness severity: a cohort study. Reimer, J., Boniakowski, E., Bachner, C., et al.[2021]

In a study of 196 heroin-dependent patients undergoing buprenorphine-naloxone treatment, the newly developed BUDAVA questionnaire identified inadequate dosing in 61 patients, highlighting the need for personalized dosage adjustments in opioid dependence therapy.

After modifying the dosages for 48 patients deemed inadequately treated, 50% of them reported adequate dosing after one week, suggesting that the BUDAVA tool can effectively guide treatment adjustments for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of buprenorphine dosage adequacy in opioid receptor agonist substitution therapy for heroin dependence: first use of the BUprenorphine-naloxone Dosage Adequacy eVAluation (BUDAVA) questionnaire. D'Amore, A., Romano, F., Biancolillo, V., et al.[2021]

In a study of 85 patients monitored for up to 8 years, treatment-resistant chronic psychosis patients (PSY-HUD) showed similar retention rates in methadone treatment (36%) compared to those without dual disorders (HUD) (34%), indicating that enhanced methadone maintenance is effective for both groups.

PSY-HUD patients had significantly better outcomes in terms of clinical severity and functioning, and they required less time to stabilize on methadone, suggesting that tailored treatment approaches can lead to positive results even in complex cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The long-term outcome of patients with heroin use disorder/dual disorder (chronic psychosis) after admission to enhanced methadone maintenance. Maremmani, AGI., Pallucchini, A., Rovai, L., et al.[2022]

Methadone, used for treating opiate addiction, can cause dose-dependent QT prolongation, which may lead to severe heart arrhythmias like torsades de pointes, particularly at high doses (100 mg to 400 mg/day).

The risk of torsades de pointes increases with rapid dose escalation and when methadone is combined with CYP 3A4 inhibitors, highlighting the importance of monitoring patients for predisposing factors such as bradycardia and hypokalemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Torsades de pointes with methadone. [2013]

Between 2001 and 2005, there were 206 reported methadone-associated deaths in Victoria, Australia, primarily due to drug toxicity, highlighting the risks associated with methadone use, especially when combined with other CNS depressants.

A significant number of deaths (25%) occurred within 14 days of starting opioid replacement therapy with methadone, often linked to high starting doses and rapid dose increases, suggesting that better management during the induction phase could help reduce mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of methadone deaths between 2001 and 2005 in Victoria, Australia. Pilgrim, JL., McDonough, M., Drummer, OH.[2013]

Methadone maintenance treatment (MMT) has been shown to provide significant health, social, and legal benefits for individuals with opioid dependency, but it also poses risks, particularly during the early stabilization period and for those abusing other substances.

Individualizing methadone dosages is crucial for treatment efficacy, as some patients may require higher doses to achieve therapeutic goals, but this must be balanced with the risk of serious side effects like torsade de pointes and increased mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone death, dosage and torsade de pointes: risk-benefit policy implications. Latowsky, M.[2013]

Buprenorphine, when administered sublingually, shows a ceiling effect on its physiological and subjective responses, with maximal effects observed at doses between 4 and 8 mg, which may enhance its safety and reduce potential for abuse compared to methadone.

Both buprenorphine and methadone effectively attenuate the effects of subsequent opioid challenges, indicating that they can block opioid effects after acute administration, which is important for treating opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute administration of buprenorphine in humans: partial agonist and blockade effects. Walsh, SL., Preston, KL., Bigelow, GE., et al.[2014]

Esmethadone, a low-affinity NMDA receptor antagonist, demonstrated rapid and sustained antidepressant effects in a Phase 2 trial, indicating its potential as a new treatment for depression.

In studies assessing abuse potential, esmethadone showed significantly lower 'Drug Liking' scores compared to oxycodone and ketamine, suggesting it has no meaningful abuse potential at therapeutic and higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users. Shram, MJ., Henningfield, JE., Apseloff, G., et al.[2023]

In a 12-month study involving 515 patients undergoing methadone maintenance treatment, the use of the Opiate Dosage Adequacy Scale (ODAS) helped increase the frequency of adequate methadone dosing from 60.9% at baseline to 85.3% by month 12.

Patients with inadequate methadone doses showed greater improvements in their ODAS scores and addiction severity, suggesting that the ODAS may be a valuable tool for optimizing methadone treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The opiate dosage adequacy scale for identification of the right methadone dose--a prospective cohort study. Walcher, S., Koc, J., Reichel, V., et al.[2019]

In a study of 54 opioid-dependent individuals at a methadone maintenance clinic, those exhibiting symptoms of Cluster B personality pathology were prescribed significantly higher doses of methadone compared to those without such symptoms.

This suggests that personality traits may play a role in determining methadone dosing, highlighting the need for personalized treatment approaches in opioid dependence management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personality factors associated with methadone maintenance dose. Murray, H., McHugh, RK., Behar, E., et al.[2014]

The literature review of 24 studies, including 12 clinical trials, suggests that the optimal methadone dosing for maintenance therapy should generally be between 60 to 100 mg daily.

For patients still using illicit opiates while on this dosing range, higher doses above 100 mg may be considered, although this is not widely accepted and should be evaluated on a case-by-case basis due to potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone maintenance dosing guideline for opioid dependence, a literature review. Fareed, A., Casarella, J., Amar, R., et al.[2022]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Methadone dose and treatment outcome. [2022]

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

Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial. [2023]

3. England pubmed.ncbi.nlm.nih.gov

When higher doses in opioid replacement treatment are still inadequate - association to multidimensional illness severity: a cohort study. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Evaluation of buprenorphine dosage adequacy in opioid receptor agonist substitution therapy for heroin dependence: first use of the BUprenorphine-naloxone Dosage Adequacy eVAluation (BUDAVA) questionnaire. [2021]

5. England pubmed.ncbi.nlm.nih.gov

The long-term outcome of patients with heroin use disorder/dual disorder (chronic psychosis) after admission to enhanced methadone maintenance. [2022]

6. France pubmed.ncbi.nlm.nih.gov

Torsades de pointes with methadone. [2013]

7. Ireland pubmed.ncbi.nlm.nih.gov

A review of methadone deaths between 2001 and 2005 in Victoria, Australia. [2013]

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

Methadone death, dosage and torsade de pointes: risk-benefit policy implications. [2013]

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

Acute administration of buprenorphine in humans: partial agonist and blockade effects. [2014]

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

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users. [2023]

11. England pubmed.ncbi.nlm.nih.gov

The opiate dosage adequacy scale for identification of the right methadone dose--a prospective cohort study. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Personality factors associated with methadone maintenance dose. [2014]

13. England pubmed.ncbi.nlm.nih.gov

Methadone maintenance dosing guideline for opioid dependence, a literature review. [2022]