Divided or Single Exposure (DOSE) Study

Divided or Single Exposure (DOSE) Study: Randomized Controlled Trial for Pain in Persons Receiving Methadone Treatment

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.

Study Overview

• Status: Recruiting
• Conditions: Chronic Pain; Opioid Use Disorder; Methadone
• Intervention / Treatment: Drug: Methadone (100% dose); Drug: Methadone (50% dose)

Detailed Description

This study follows a successfully completed project (NCT03254043) to now pursue the investigators overarching goal of optimizing methadone dosing as a method for managing comorbid chronic pain and opioid use disorder (OUD) among persons receiving methadone for the treatment of OUD. Up to 62% of persons maintained on methadone for OUD experience clinically significant pain, versus 31% in the general population. Pain in methadone-maintained persons (MMP) is associated with poor OUD treatment outcomes and severe distress. No effective treatment for comorbid pain and OUD currently exists; though preclinical and human data suggest divided methadone dosing may be a more optimal strategy for managing pain than once daily dosing, this has never been empirically examined. This study will evaluate an intervention for comorbid chronic pain among MMP using a Phase II double-blind, randomized, placebo-controlled comparison of treatment as usual (TAU) versus split daily methadone dosing for 12-weeks. Methadone will be remotely managed via an electronic pillbox. Outcomes will include weekly assessments of pain and OUD outcomes, ecological momentary assessment of pain before and after dosing, and point-prevalence measures of laboratory-induced pain to explore mechanism of effects. If effective, this approach could transform the care of MMP with pain because it would be feasible to implement within the operational structure of a methadone clinic and would impose low provider burden. Results could provide a high magnitude treatment for the substantial number of MMP who experience daily pain with no reliable form of treatment.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Kelly E Dunn, PhD, M.B.A.; Phone Number: 802-922-1682; Email: kelly.dunn@som.umaryland.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Recruiting
      • Addiction Treatment Services (ATS)
      • Contact: Denis Antoine, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged 18 years of age or older
• Currently receiving methadone for treatment of OUD for >90 days and have been consuming the same dose for >30 days
• Have previously received a take-home dose of methadone as part of routine care
• Willing to comply with study schedule
• Report pain (specific definition blinded)
• Have a cellular phone or be willing to carry phone provided by the study during one phase of the study

Exclusion Criteria:

• Pregnant
• Presence of acute medical problem that requires immediate and intense medical management
• Presence of a serious and unstable mental illness that interferes with provision of voluntary informed consent and/or adherence to study visits
• Plans to leave methadone treatment during the study period
• Maintained on a dose of methadone that would prevent effective splitting of doses
• Currently receiving split doses of methadone
• Currently receiving treatment for pain for which the split-dosing of methadone is judged by medical staff to be contraindicated or otherwise interfere with study conduct or integrity
• Does not meet criteria for mild-severe disability (definition blinded)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment as Usual (TAU); Participants in treatment as usual group will receive 100% active methadone in AM + placebo in PM.	Drug: Methadone (100% dose); Methadone for the treatment of opioid use disorder
Experimental: Split-dosing; Participants in split dosing group will receive 50% active methadone + placebo twice daily.	Drug: Methadone (50% dose); Methadone for the treatment of opioid use disorder

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in worst pain rating- past 24 hour as assessed by the Brief Pain Inventory scale	Using the Brief Pain Inventory rating of "Worst Pain" in the past 24 hours, rated on a scale of 1-10, collected once weekly during weeks 1 through 12 of the intervention.	Week 1 up to week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pain Tolerance Latency	Time in seconds (0-300) to removal of hand from cold pressor measure of laboratory-induced pain, collected point-prevalence during weeks 1, 6, and 12 of the intervention.	Weeks 1, 6, and 12
Change in Pain Interference- past 7 days as assessed by Pain-related Disability Scale Total Score	Past 7 day Pain-related Disability Scale Total Score (range 0-70), collected once weekly during weeks 1 through 12 of the intervention.	Week 1 up to 12
Change in Opioid Withdrawal Severity- past 24 hours as assessed by the Subjective Opioid Withdrawal Scale	Past 24 hour total score (range 0-64) for the Subjective Opioid Withdrawal Scale (SOWS), collected once weekly during weeks 1 through 12 of the intervention.	Week 1 up to 12

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Kelly E Dunn, PhD, M.B.A., University of Maryland; Principal Investigator: Denis Antoine, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: July 12, 2022
• First Submitted That Met QC Criteria: July 12, 2022
• First Posted (Actual): July 15, 2022

Study Record Updates

• Last Update Posted (Actual): February 3, 2026
• Last Update Submitted That Met QC Criteria: January 30, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Pain; Neurologic Manifestations; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Opioid-Related Disorders; Chronic Pain; Organic Chemicals; Ketones; Methadone
• Other Study ID Numbers: IRB00318642; 1R01DA056045 (U.S. NIH Grant/Contract); 1R01DA056045-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No