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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different methadone dosing schedules can manage both pain and opioid use disorder. Participants will either take methadone once in the morning with a placebo in the evening or split their dose into two smaller amounts taken twice daily. It targets individuals who have maintained a stable methadone dose for over a month, have used methadone for more than 90 days, and experience ongoing pain. The study aims to determine if adjusting the methadone schedule improves management of these conditions. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that methadone is generally safe and effective for treating opioid addiction. Studies have found that the usual starting dose is about 20 to 30 milligrams per day, with adjustments as needed to control symptoms and reduce side effects.

Some patients might benefit from split dosing, which involves taking methadone twice a day. This approach can provide steadier symptom control and fewer side effects. While more research is needed, current evidence supports the safety of split dosing.

The FDA has already approved methadone for treating opioid addiction, confirming its safety for this use, although the dosing schedule in this study might differ. Overall, methadone's safety is well understood, making it a reliable option for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for opioid use disorder involve a single daily dose of methadone, aiming to manage withdrawal symptoms and reduce cravings. However, this trial explores a split-dosing method, where methadone is administered in two doses, half in the morning and half in the evening. Researchers are excited about this approach because it could offer more stable blood levels of methadone throughout the day, potentially improving symptom control and reducing the risk of relapse. By experimenting with this dosing schedule, the trial aims to find out if split-dosing can provide better outcomes for patients compared to the traditional single-dose approach.

What evidence suggests that this trial's treatments could be effective for managing opioid use disorder?

Research shows that methadone helps treat opioid addiction by reducing cravings and withdrawal symptoms. Studies indicate that higher doses of methadone can help people stay in treatment longer and use less heroin. In this trial, participants will follow different dosing regimens. One group will receive treatment as usual, with 100% active methadone in the morning and a placebo in the evening. Another group will receive split dosing, with 50% active methadone and a placebo twice daily. Some studies have found that split dosing isn't much different from taking methadone once a day. However, methadone generally results in fewer people stopping treatment compared to other options, like buprenorphine/naloxone, making it a dependable choice for managing opioid addiction. ^{4 6 7 8 9}

Who Is on the Research Team?

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

Principal Investigator

University of Maryland

Denis Antoine, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

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

Willing to comply with study schedule

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

I experience pain.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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 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]

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]

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]

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]

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]

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]

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]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK562216/

Methadone - StatPearls - NCBI Bookshelf - NIH Although a low methadone dose of <30 mg/d can alleviate acute withdrawal, it may not effectively suppress cravings.

2. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2825088

Buprenorphine/Naloxone vs Methadone for the Treatment ... The risk of treatment discontinuation was higher among recipients of buprenorphine/naloxone compared with methadone (88.8% vs 81.5% within 24 months).

3. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ps.201300235

Medication-Assisted Treatment With Methadone Results showed that high doses were associated with better treatment retention and cocaine abstinence, less heroin use during treatment, and fewer withdrawal ...

4. federalregister.gov federalregister.gov/documents/2024/02/02/2024-01693/medications-for-the-treatment-of-opioid-use-disorder

Medications for the Treatment of Opioid Use Disorder There is nothing in the final rule that precludes provision of split doses for take-home doses of methadone. Dosage During Treatment Induction.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2949875923002606

Evaluation of opioid use disorder treatment outcomes in ... Fifty-seven patients (22.8 %) were prescribed once daily dosing and 193 patients (77.2 %) were prescribed split daily dosing. The study found no significant ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/methadone-oral-route/description/drg-20075806

Methadone (oral route) - Side effects & dosage Adults—At first, 20 to 30 milligrams (mg) taken as a single dose per day. Your doctor may adjust your dose as needed.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2949875923001479

Individualizing methadone treatment with split dosing Some patients may benefit from twice-daily (“split”) dosing to produce more stable symptoms and minimize side effects, independent of serum peak-to-trough ...

8. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1111/add.16502

Questioning methadone split‐dosing for analgesia among ... Methadone is hypothesized to provide greater analgesic coverage when split into two or more divided doses. However, empirical data are lacking, ...

9. samhsa.gov samhsa.gov/substance-use/treatment/opioid-treatment-program/methadone-guidance

Methadone Take-Home Flexibilities Extension Guidance From 31 days in treatment, up to 28 unsupervised take-home doses of methadone may be provided to the patient.