Treatment of Pain in Persons With Opioid Use Disorder

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Opioid Use Disorder, Chronic Pain, Methadone

Intervention / Treatment
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* Drug: Methadone (100% dose)
* Drug: Methadone (50% dose)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be enrolled for a 14-week Phase II between-group intervention period followed by a 6-month follow-up period with once monthly visits. All participants will be transitioned from liquid to tablet methadone within a 1 to 2-week period before being randomized to treatment as usual versus split daily methadone dosing for a 12-week period. Participants will complete monthly follow-up visits during months 4 - 9.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 |