Early methadone dose titration (a boost between treatment days 4 and 6) is associated with better treatment retention and reduced risk for opioid toxicity among patients using fentanyl over 6 months of follow-up, according to new data.

In response to poor methadone retention rates, clinical guidance in Canada and the US recommends rapid methadone dose titration for patients using fentanyl. With the rapid rise of more potent fentanyl in Canada and the US in recent years, the “low and slow” dosing increase approach had become less effective. The loss of efficacy has prompted some patients to stop treatment as withdrawal symptoms and cravings became intolerable.

“It could take weeks to months before a therapeutic dose was reached,” lead author Ria Garg, a pharmacist and PhD student at the University of Toronto, Toronto, told Medscape News Canada.

The paper also noted, “In Canada, methadone dose titration typically requires a follow-up physician visit as standing orders are uncommon….Requirements for a physician visit may contribute to many individuals remaining on initiation doses during the first week of treatment.”

The data were published on April 9 in PLOS Medicine.

Better Adherence, Less Toxicity

To help patients reach stable therapeutic doses rapidly and safely, clinical guidance shifted to early titration (a boost of about 10 mg to 15 mg in the first week), Garg explained. But with clinical evidence coming mostly from case reports, the effect on patient outcomes has been unclear, particularly when the doses are given in the outpatient setting, where patients receive minimal monitoring, she said.

Her team conducted a retrospective, propensity-score weighted cohort study of 13,560 Ontario residents who started on methadone in an outpatient setting between January 2017 and December 2022. The exposure group (61.4% of the patients) included participants who received a dose titration between treatment days 4 and 6, with the index date defined as the first date of dose increase. For the unexposed group, the index date was randomly assigned because there was no change in dose in the first 6 days.

The study’s primary outcomes included methadone discontinuation and opioid toxicity, using an intention-to-treat analysis. Secondary outcomes included methadone vs nonmethadone-related toxicity while on treatment.

Patients who received early dose titration had a lower weighted hazard ratio (wHR) of stopping the treatment (wHR, 0.55). Only 7.8% of participants in the exposed group did not receive methadone the day before the index date, and 3.2% missed two doses between initiation and index date compared with 19.1% and 9.0%, respectively, among participants in the unexposed group.

The observed weighted rate of opioid toxicity was also lower among participants in the exposure group vs those not given the early dose (10.1 vs 12.3 per 100 person-years; wHR, 0.82). Most toxicities were attributed to nonmethadone opioids (exposed, 3.89 per 100 person-years vs unexposed, 4.06 per 100 person-years; wHR, 1.00).

Some patients may not be eligible for early titration because of the severity of their opioid use disorder or other factors, Garg said. But for eligible users, these data show that rapid titration is effective and safe.

The main study limitation is that information was lacking on patients’ drug use history, the authors wrote.

Provincial Variations

“We can and should increase methadone titrations early within the first few days, without needing to worry about overdose or methadone toxicity,” S. Monty Ghosh, MD, MPH, an internist, addiction medicine specialist, and associate professor at the University of Alberta in Edmonton, told Medscape News Canada. “Not only will this help improve opioid agonist treatment retention but it also can help with the overall wellness of the individual.”

Ghosh, who did not participate in the research, pointed out that the study was conducted in Ontario. “Ontario has stricter, and some would say restrictive, prescribing. Individuals need to be assessed by the prescriber prior to dose increase.” The paper mentions that in the US, prescribers sometimes initiate automatic titration orders without requiring a visit with a physician.

“We do the same in Alberta with titrations > 15 mg at a time sometimes and have had good experience with this,” Ghosh said.

The study authors encourage physicians and patients to engage in shared decision-making at the start of treatment “to develop a titration plan that allows for flexible reassessment, accounts for potential missed doses, and incorporates preplanned dose increases based on the patient’s reported opioid tolerance — particularly for individuals who may be unable to see a physician for a dose increase during the first week of treatment, when discontinuation rates are highest.”

This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. Garg and Ghosh reported having no relevant financial relationships.

Marcia Frellick is an independent healthcare journalist and a regular contributor to Medscape.