Data regarding comparative treatment retention among the 3 oral OAT medications is mixed. For example, a 2021 meta-analysis (N=10 RCTs, 3 observational studies; n=5,065) found that retention rates—both length of time retained in study and presence on final day of study—are generally equal for fixed-dose oral OAT with methadone and buprenorphine/naloxone; however, the average retention rate across studies was highly variable and the evidence quality was rated as low.218 Conversely, data from 2012–2018 in BC found that buprenorphine/naloxone was twice as likely as methadone to be discontinued (slow-release oral morphine discontinuation was not reported).124 It is not clear, however, if those individuals discontinuing medication transitioned to another OAT medication or discontinued OAT entirely. In addition, Austrian data from 2011–2012 found that slow-release oral morphine had a significantly higher retention rate compared to both methadone and buprenorphine/naloxone.214 

The partial agonist properties of buprenorphine may be preferable to full agonist options in terms of reduced overdose potential.139 A 2015 study of more than 19 million prescriptions over a six-year period in the United Kingdom found that buprenorphine was six times safer than methadone in terms of overdose risk.219 Other studies have associated methadone with a four-fold higher risk of fatal overdose and a significantly higher risk of unregulated use compared to buprenorphine.220,221 Reports, an expert panel, and a 2017 systematic review have all highlighted the substantial risks of fatal overdose during methadone treatment initiation.111,197,222 Buprenorphine has a lower potential for respiratory depression and standard doses are well below the threshold lethal dose for opioid-naïve adults compared to standard methadone doses, which often exceed the threshold lethal dose.221 Furthermore, methadone has higher potential for adverse drug–drug interactions with many common medications (e.g., antibiotics, antidepressants, antiretrovirals).

Methadone is also associated with an increased risk of QT prolongation; one study estimated that up to 15% of patients receiving methadone may experience QT prolongation.223,224 However, the maximum estimated mortality attributable to QTc prolongation is low: 0.06 per 100 patient-years.223 Research to date has not established a clear association between buprenorphine and QTc prolongation, although some mixed results have been reported in the literature223,225-229 While information on the clinical significance of an association between buprenorphine and QTc prolongation is also limited, available data suggests that effect of buprenorphine formulations on QTc interval does not reach the level of clinical concern and is not associated with increased risk of cardiac arrhythmia.229,230 These findings notwithstanding, the product monograph for buprenorphine/naloxone notes that products containing buprenorphine may be associated with QTc prolongation and warns against the use of buprenorphine/naloxone in individuals with a history of long QT syndrome, as well as those taking certain classes of antiarrhythmic medications.136 Additional guidance on drug-drug interactions that may increase risk of QTc prolongation can be found in the product monograph.136 Guidance on a step-wise approach to assess drug interactions that may impact the QT interval can be found here.231

The traditional method for buprenorphine/naloxone induction requires a period of withdrawal which makes the initiation of buprenorphine/naloxone treatment significantly more challenging than full agonist options (see Appendix 3).232 Newer low-dose induction protocols have been developed that do not require patients to reach moderate withdrawal prior to initiation. Admission to an inpatient treatment facility (i.e., inpatient withdrawal management, bed-based treatment facilities, inpatient monitoring settings) for supervised, medically-managed buprenorphine/naloxone induction may also be considered, as these facilities can provide more intensive monitoring, support, and symptom management to patients during challenging inductions. 

Because of its partial agonist effect and superior safety profile, buprenorphine/naloxone is often prescribed as take-home dosing immediately or soon after initiation, whereas patients on methadone or SROM are required to receive daily witnessed ingestion (DWI) dosing until a stable dose is achieved for a minimum of 4 weeks. Additionally, it is easier to switch from buprenorphine/naloxone to full agonist options than from methadone and SROM to buprenorphine/naloxone.233,234 These are factors that may make buprenorphine/naloxone a preferable option in the absence of contraindications. 

While opioid use is generally more prevalent among men than women,235 there do not appear to be significant sex-based differences in treatment outcomes for buprenorphine/naloxone compared to methadone.236,237 A 2015 systematic review and meta-analysis of sex differences in outcomes of methadone treatment found no significant differences in opioid use, treatment retention, or methadone dosage, but did find male participants more likely to report alcohol use and female participants more likely to use amphetamines.238 A 2019 systematic review concluded that, due to conflicting findings and heterogeneous methods, it is unclear whether there are sex-based differences in treatment retention for men and women being treated with buprenorphine.239

Additional information on sex and gender in relation to opioid use disorder can be found in Sex, Gender, and Sexuality in this document. For guidance on the care of pregnant people with opioid use disorder, consult the Treatment of Opioid Use Disorder During Pregnancy—Guideline Supplement.