A substantial body of evidence has shown methadone to be significantly more effective than non-pharmacological outpatient treatment approaches in terms of treatment retention and suppression of heroin use.164
In terms of treatment retention, a 2022 systematic review and metanalysis (N=79) of randomized controlled trials found that methadone was marginally superior to buprenorphine for treatment retention (RR=1.22; 95% credible interval (CrI)=1.06–1.40).123 Similarly, a 2021 population-based retrospective study utilizing administrative databases of people with who received OAT between 2012 and 2018 in BC (n=37,207) found a lower monthly discontinuation rate among individuals receiving methadone compared to those receiving buprenorphine/naloxone (10% Vs. 21%).124
Methadone at higher doses (i.e., between 60–120mg/day or higher) is more effective than lower doses for treatment retention and reducing heroin during treatment of OUD.165,166 Retention in methadone treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids.111
Methadone-based opioid agonist treatment has been shown to reduce injection risk behaviours and the overall risk of hepatitis C and HIV infection among people who inject drugs.167-169 Furthermore, among HIV-positive individuals, engagement in methadone-based agonist treatment is independently associated with increased adherence to antiretroviral therapy and improved virologic outcomes (e.g., lower HIV viral loads, higher CD4 counts), particularly at higher doses (≥100 mg/day).170-172
Research specifically focused on the effectiveness of methadone for managing OUD among people who use fentanyl is limited. However, a small body of observational data suggests that OAT with methadone is safe and effective in treatment retention and reduction of the risk of overdose mortality among individuals who use fentanyl.117,118 A 2020 retrospective study (n=151) evaluated 12-month methadone treatment outcomes for patients on methadone treatment, 121 (80%) of whom tested positive for fentanyl at intake.118 At 12-month follow-up, there were no significant differences between the fentanyl-exposed participants and other participants in terms of 1-year treatment retention (53% vs. 47% respectively), and short-term and sustained abstinence from unregulated opioid use. Importantly, although return to fentanyl use while in treatment was common, no deaths occurred among participants who were retained in treatment for the full year, while 4 known deaths occurred among participants who left treatment early. The authors concluded that OAT with methadone is safe and effective for people who use fentanyl, and may have some protective effect against drug toxicity death even in the case of continued fentanyl use.118
There is considerable evidence demonstrating methadone’s efficacy and safety for the treatment of opioid use disorder and related harms. However, its unique pharmacological properties compared to other prescription opioids (e.g., narrow therapeutic index, long elimination half-life), and potential for interactions with alcohol and other drugs does increase the relative risk of toxicity and adverse events. For example, in the United States, after controlling for the total number of prescriptions dispensed, methadone-related emergency room visits occur at a rate that is approximately 6 and 23 times higher than the prescription opioids oxycodone and hydrocodone, respectively.173 However, it is important to note that these findings are not free of bias, as methadone is almost exclusively prescribed to people with OUD—a population known to have high rates of ED utilization.155
Moreover, although methadone accounts for fewer than 5% of all opioid prescriptions per year in the US, it is identified in more than a third of prescription-opioid-related overdose deaths.173 This is consistent with a 2015 study in British Columbia that reported that methadone was involved in approximately 25% of prescription-opioid-related deaths in British Columbia.120 A 2017 systematic review of mortality risk during and after OAT found that all-cause mortality for individuals on methadone was almost three times the rate of those on buprenorphine (11.3 per 1,000 person years vs. 4.3 per 1,000 person years, respectively) and overdose mortality was almost double in those in methadone treatment (2.6 per 1,000 years vs. 1.4 per 1,000 person years).111 However, all-cause mortality dropped shortly after the first four weeks of methadone treatment. Data from the BC Provincial Overdose Cohort found that methadone was implicated in far more deaths than buprenorphine (130 cases vs. 2 cases) between 2015 and 2017, appearing in the toxicology results of 6% of the 1,789 of overdose deaths which were analysed.174 It should be noted that these findings are not results of direct comparisons of the medications and are not free from bias.
The significantly increased risk of overdose during early stages of methadone treatment is well described (i.e., during initiation, titration, and dose stabilization). Other factors that have been associated with risk of methadone-involved overdose include175-179:
- Non-prescribed, diverted, and unregulated use (including unregulated use when prescribed methadone dose is insufficient to control withdrawal symptoms)
- Unsupervised or non-witnessed doses
- Combined use with alcohol and benzodiazepines
- Methadone prescribed for pain management, as opposed to treatment of opioid use disorder where doses are witnessed and titration schedules are strictly enforced
To minimize the risk of methadone-involved overdose, particularly in the first weeks of treatment, guidelines typically recommend daily witnessed dosing until patient stability on their methadone dose has been clearly established. However, this practice is based on relatively small body of evidence.176,178,180,181 When considering the safety and utility of daily witnessed dosing, the potential adverse impact of requiring daily office visits on treatment retention—and, in turn, the risks associated with return to unregulated opioid use—should be considered. See Take Home OAT Dosing for a review of evidence on observed versus unobserved dosing.
There are currently 2 methadone options available as regular PharmaCare benefits in BC. Methadose and Metadol-D are covered as regular benefits for those enrolled in PharmaCare Plan C (Income Assistance), Plan B (Licensed Residential Care Facilities), Plan G (Psychiatric Medications), and Plan Z (Assurance). Methadose was introduced in 2014, replacing 1mg/mL pharmacy compounded methadone. Since this formulation change, many patients who had been stable on compounded methadone 1mg/mL have reported return to unregulated opioid use due to inadequate management of withdrawal symptoms.182-185 As a result, Metadol-D was added as a regular benefit in May 2019. In October 2019, compounded methadone became available as a third, last-resort option for individuals who had trialed regular benefit formulations without success. See Appendix 3 for more information.
Initiation dosing
Methadone carries a greater risk of all-cause mortality (adjusted mortality rate ratio [AMRR]: 2.17, 95% CI: 1.29–3.67) and opioid-related overdose related mortality (AMRR: 7.61, 95% CI: 1.81–31.94) during the first 4 weeks of treatment compared to buprenorphine.186 The starting methadone dose will depend on factors that affect the risk of overdose, including the patient’s known opioid tolerance, current opioid use, and co-occurring substance use patterns and other comorbidities. Current guidelines in many Canadian jurisdictions recommend a starting dose range of 10–30mg, with the upper end of this range recommended for individuals with increased opioid tolerance.187,188 However, a number of more recent guidelines have allowed a maximum methadone starting dose of 40mg for patients with established high tolerance to opioids.189-191 For example, Quebec’s dosing standards recommend a maximum starting dose of 40mg based on thorough individualized assessment.187 In the United States, the Substance Abuse and Mental Health Service Administration (SAMHSA) recommends limiting the first day dose to a maximum of 30mg for most patients, but allows a total maximum first day dose of 40mg, administered in divided doses, for patients who experience persisting withdrawal symptoms after receiving 30mg.192 Similarly in its 2020 update, the American Society of Addiction Medicine (ASAM) has endorsed a maximum total first-day dose of 30-40mg as needed, provided that the initial dose does not exceed 30mg.193
The traditional upper limit of 30mg for the initial dose is informed by observational studies that identify the first week of methadone treatment as a high-risk period for methadone toxicity among patients who receive a starting dose higher than 30mg.194-197 However, most of these studies pre-date the infiltration of fentanyl and other highly potent synthetic opioids into the unregulated drug supply and the corresponding increase in the proportion of patients with high tolerance to opioids due to fentanyl use. Although there is a lack of published studies supporting higher first-day doses of methadone, the need for modified induction protocols and higher starting doses in the era of fentanyl are widely acknowledged in clinical practice.198
To address the specific needs of people who use fentanyl, the Ontario-based META-PHI published a series of recommendations for Methadone Treatment for People Who Use Fentanyl.188 A focus group of people with lived experience of methadone/OAT assembled by META-PHI to review the recommendations stated that 30mg is too low to make a significant impact on withdrawal symptoms among people with high opioid tolerance, and favoured starting doses in the range of 40–60mg in an outpatient setting and higher in an inpatient setting, where sedation or overdose can be monitored.188 Although the META-PHI authors endorsed a maximum starting dose of 30mg, the authors of the document acknowledged that there are settings in which 40mg is used as a starting dose and that future updates should seek new evidence for the safety of higher starting doses.188
In keeping with guidelines and accumulating clinical experience in BC and other jurisdictions that support starting doses of up to 40mg,187,189-191 and in recognition of the urgent need to engage and retain individuals who use fentanyl in evidence-based care, this guideline endorses a maximum first day dose of 40mg for individuals who use fentanyl and have established tolerance to methadone. See Appendix 3 for methadone induction guidance.
Efficacy of low dose vs high dose
Adequate methadone dosing (i.e., sufficient dose to control withdrawal symptoms for approximately 24 hours without signs of overmedication) vary significantly between patients due to variability in methadone pharmacokinetics, metabolism, and patient preference. For this reason, methadone dosing should involve careful, individualized dose titration as opposed to standardized dosing regimens.
Results from a 2009 systematic review indicate higher retention rates are associated with methadone doses ≥60mg/day compared to the retention rates at <60mg/day (OR: 1.74, 95% CI: 1.43–2.11). High doses of methadone (i.e., between 60–120mg/day or higher) have been found to be more effective than lower doses for treatment retention and reducing heroin use during OUD treatment.165,166 While methadone dosing should be based on clinical judgment and determined on an individual basis due to differences in individual metabolism, comorbidities (e.g., liver disease, prolonged QTc interval) and drug interactions,199 most studies have suggested that patients who take daily doses of 80mg/day or higher have optimal treatment outcomes143,165 and that doses above 120mg/day may be required to produce full opioid blockade and fully suppress withdrawal.200,201 The optimal methadone dose is generally between 80–150mg/day; however this dose range was established in clinical practice before the dominance of fentanyl in the unregulated drug supply. Some patients, including those who use fentanyl, may require higher doses to achieve therapeutic goals. Once achieved, a sufficient dose of methadone can require little adjustment for up to ten years.202
Despite this, as of 2018, 38% of patients on methadone in BC received doses of less than 60mg per day, the lower limit of what is defined as an optimal daily dose for methadone-based opioid agonist treatment.203 This underscores the need for practice standards that adequately meet patients’ needs by taking into account the increasing toxicity of the unregulated drug supply. This includes addressing barriers to reaching an appropriate individualized dose, such as titration schedules and missed dose protocols.
For induction and dosing guidelines for methadone, refer to Appendix 3.