Methadone Rapid Restart

Official title

Methadone Rapid Restart Study

Overview

The usual treatment for opioid use disorder (OUD) is opioid agonist therapy (OAT) with either methadone or buprenorphine. These treatments are well-established, reduce the risk of fatal overdoses, and are considered the standard approach. However, current methadone guidelines were developed when most people were using heroin, which is far less potent than today's unregulated/illicit fentanyl supply. As a result, people who use fentanyl often need higher doses to feel stable. Because methadone must be started at low doses and increased slowly, it can take weeks before someone reaches an effective dose. This process becomes even longer when doses are missed, since treatment often needs to be restarted at a lower level. The Methadone Rapid Restart is a newer strategy designed to take ongoing fentanyl use into account. Early clinical experience and modelling suggest that many people who use fentanyl have high opioid tolerance and may be able to return to their previous stable methadone dose even after several missed days, without added safety risk. This approach has shown promise in small clinical settings, but it is not yet known whether it provides better outcomes than the standard methadone titration used today. This study will be testing whether this protocol to help rapidly restart people on Methadone is acceptable for patients and use the learning to guide a subsequent larger clinical trial.

Detailed description

Canada continues to see the ongoing effects of the illicit drug overdose in the last decade. Fentanyl and fentanyl analogues account for the majority illicit drug overdose deaths with the highest rate of opioid-related deaths in Canada occurring in British Columbia (BC). Despite this rapid rise in unregulated fentanyl use, treatment strategies for people who use unregulated fentanyl still rely on the opioid use disorder (OUD) treatment guidelines developed from research conducted in people using heroin, a relatively less potent opioid. Currently, methadone and buprenorphine are the recommended medications for opiate use disorder (MOUD).

Methadone at higher doses (at least 60-120mg/day) has shown to have greater effectiveness and treatment retention as compared to lower dosages, based on studies with patient populations using heroin (Bromley et al. 2021). It therefore stands to reason that in the age of unregulated fentanyl, even higher doses of methadone are likely necessary to achieve optimal efficacy and retention rates. Despite this, the highest recommended starting dose of methadone is currently 40mg with a maximum of 15 mg increase every 3 days, for those with a known very high tolerance. As a result, it takes several weeks for people using unregulated fentanyl to reach an effective dose, which is further compounded by missed doses. It is also recommended that if 4 doses of methadone are missed, patients restart at at 50% of their previous dose or at 30-40mg, whichever is higher; and if 5 or more consecutive doses are missed, patients receive a full re-titration, starting from 30-40mg. However, emerging clinical and pharmacokinetic data suggest that, as long as opioid tolerance remains unchanged, methadone can be safely restarted at the same stable dose after missing 4-8 subsequent doses.

The proposed study aims to determine the safety and efficacy of continuing maintenance dose methadone after 4-8 missed doses in people continuing to use unregulated fentanyl to meet their opioid needs.

Interventions

• Drug Methadone
  Participants who meet study inclusion criteria and have no exclusion criteria, who have missed 4-8 doses of methadone will, be administered methadone according to the stratification below and will continue the same dose for the 7 day follow up. * Arm 1: Previous maintenance treatment with methadone for opioid use disorder at a stable dose for at least 5 consecutive days prior to discontinuing, with allowance for a maximum of 1 missed dose within that 5-day period. These participants will be re-

Primary outcome measures

• Enrollment rate [Time frame: Enrollment]
• Patient Satisfaction [Time frame: Assessed retrospectively at the end of 7 day follow up period.]

Secondary outcome measures (11)

• Recruitment [Time frame: Through study completion, anticipated to be 12 months]
• Level of sedation [Time frame: Baseline, Intervention (1, 2, and 3 hour post-dose) and follow up (Day 1, 3 and 7)]
• Blood Pressure [Time frame: Baseline, intervention (1,2, and 3 hour post methadone dose), and follow up (Day 1, 3, and 7)]
• Oxygen saturation [Time frame: Baseline, intervention (1, 2, and, 3 hour post dose) and follow up (Day 1, 3, and 7)]
• Respiratory rate [Time frame: Baseline, intervention (1, 2 and 3 hour after post methadone dose), and follow up (Day 1, 3, and 7)]
• Heart rate [Time frame: Baseline, intervention (1, 2 and 3 hour after post methadone dose), and follow up (Day 1, 3, and 7)]
• Change in unregulated substance use patterns [Time frame: Baseline and follow up (Day 1, 3, and 7)]
• ECG [Time frame: Baseline and follow up (Day 3 and 7)]
• Adverse events [Time frame: During intervention and follow up]
• OAT retention [Time frame: Follow up]
• Overdose and hospitalization [Time frame: Follow up]

Eligibility criteria

Inclusion criteria

• Age 19 years or older
• Opioid use disorder (OUD) of any severity by DSM-5 TR Clinical Diagnostic criteria \[American Psychiatric Association, 2022\]
• Previously 'stable' on methadone as per the below definitions:

• Previous maintenance treatment with methadone for opioid use disorder at a stable dose for at least 5 consecutive days prior to discontinuing, with allowance for a maximum of 1 missed dose within that 5-day period.
• Participants who were being titrated on methadone for opioid use disorder prior to discontinuation. If participants were on the most recent dose for less than 5 days, they can be restarted on the prior dose providing they cumulatively received 5 consecutive doses (with a maximum of 1 missed dose in that period) between the two most recent dosages.
• Missed 4-8 doses of methadone in a row leading up to intake assessment.
• Participant able to provide baseline opiate use history as per opiate use screening questions in Appendix A. This must provide an estimate of opiate use prior to stopping methadone and change in use since stopping.
• Self-reported increased use of fentanyl since stopping methadone.
• No significant change in opiate withdrawal symptoms as compared to when on methadone, based on self-report and examination.
• Urine drug test (UDT) positive for fentanyl at screening or within 24 hours prior to re-initiating methadone.
• Participant wishes to continue methadone maintenance treatment.
• If applicable the participant must be willing to complete a urine pregnancy test to ensure they are not currently pregnant.
• Participants will require a baseline ECG that demonstrates a QTc < 500ms.
• For participants from VGH study site specifically:

• must be admitted to either psychiatry or CTU, ideally with planned admission of at least 3 days.
• must agree if discharged prior to the completion of the 7 day follow up period, to either return to VGH Diamond Centre for follow up assessments on Days 1/3/7 (+/-2 days).
• must have access to a functioning cell phone to allow for the study team to contact them in case of discharge prior to completion of study follow up period.
• The participants must be willing and able to provide written informed consent for study participation.

Exclusion criteria

• COWS score of 8 or more at the time of clinician assessment
• Self-reported Opioid overdose or naloxone administration since methadone discontinuation or during the 5 days prior to methadone discontinuation
• Self-reported New cardiac disease diagnosis since methadone discontinuation
• Self-reported Intolerable side effects reported when taking methadone
• Individuals who are pregnant (urine pregnancy test) or breast-feeding (self-reported)
• Use of buprenorphine-naloxone (Suboxone®, Sublocade®, Butrans ®) within the previous 3 days (self-reported)
• Participants with a QTc interval >500 msec on the screening ECG

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• Vancouver General Hospital — Vancouver

Identifiers

NCT: NCT07546396 · H25-03989

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗