Individualized Methadone Restart Protocol May Improve Care, Maintain Safety

A novel, patient-centered methadone restart protocol for individuals with opioid use disorder could potentially improve care without compromising safety, according to a study published in JAMA Network Open.¹ The individualized approach, which considered interim opioid tolerance during a gap in treatment, was associated with higher restart doses and similar safety and treatment retention.

“This study shows that we can safely tailor methadone treatment to better meet patients where they are,” Paul Christine, MD, PhD, assistant professor of internal medicine at the University of Colorado Anschutz, physician at Denver Health, and part of the team that developed and tested the protocol, said in a statement.² “It’s a step toward more responsive, effective care.”

The new study evaluated a novel, patient-centered methadone restart protocol incorporating patient-reported, non-prescribed opioid use. | image credit: M.Rode-Foto - stock.adobe.com

Methadone use is associated with a 50% reduction in mortality, the authors noted.¹ However, standard guidelines for initiating methadone treatment after a gap usually require large dose reductions of at least 50% after 4 or more missed dosing days, which often overlooks individual patient needs.

“These recommendations are based on pharmacologic concepts of tolerance, yet most do not distinguish between individuals with loss of tolerance from opioid abstinence vs maintenance of tolerance from interim use of other prescribed or non-prescribed opioids,” the authors explained. “This approach can lead to substantial underdosing of opioid-tolerant individuals, resulting in ongoing illicit opioid use to alleviate withdrawal symptoms and further clinical instability.”

The new study evaluated a novel, patient-centered methadone restart protocol incorporating patient-reported, nonprescribed opioid use. It was conducted at a public, safety-net opioid treatment program in Colorado and compared outcomes prior to and after implementing the new, individualized restart protocol in 2022. The study cohorts were treated in 2021 and 2023, and the study focused on patients who had missed 4 or more consecutive dosing days—a common cutoff point in clinical practice that triggers the need for a restart protocol.

With the new protocol, clinicians conducted a patient interview to determine recent nonprescribed opioid use, then adjusted the methadone restart dose based on that information and a comprehensive clinical assessment. This more nuanced approach aims to provide a dose that is high enough to prevent withdrawal but not so high as to pose a significant overdose risk. The main outcomes were patient safety, defined as emergency department (ED) visits within 7 days of restarting methadone, and all-cause mortality at both 7 and 90 days after restart. The secondary outcome was treatment retention measured at 90 days, defined as no continuous gap in dosing greater than 30 days.

A total of 786 patients were included in the preimplementation cohort, and 780 were included in the postimplementation cohort. Prior to implementation, 202 patients had a total of 464 methadone restart episodes; after implementation, 195 patients had a total of 489 restart episodes. Most patients were insured by Medicaid.

In the preimplementation cohort, restart doses were 32.8% lower than the last dose prior to restart (95% CI, 30.8%-34.7%), whereas in the postimplementation cohort, restart doses were 3.4% lower than the last received dose (95% CI, 1.5%-5.3%).

Regarding safety, 9.5% of restarts were followed by ED visits within 7 days in the preimplementation cohort, compared with 6.1% in the postimplementation cohort (adjusted risk ratio [aRR], 0.61; 95% CI, 0.37-0.98). In both cohorts, there were 4 restarts followed by death within 90 days. The cohorts also showed similar treatment retention (aRR, 0.88; 95% CI, 0.73-1.05). Based on survey responses, there was high acceptance and satisfaction with the protocol.

The study had several limitations, including its observational nature and pre-post design that lacks an external control group, the authors noted. The differences in outcomes could be caused by multiple factors, not solely due to the new protocol. Observed decreases in methadone doses in the preimplementation period were also smaller than recommended guidelines, meaning many clinicians were already using higher restart doses in the preimplementation period. The effects of the new protocol may therefore be muted, the authors explained. The study may also be underpowered because ED visits for nonfatal overdose and all-cause mortality are rare, and larger studies would help clarify the safety of higher restart doses.

“In this cohort study of individuals with opioid use disorder restarting methadone after a gap in treatment, an individualized methadone restart protocol that relied on patient self-report and clinician assessments of interval opioid use and maintenance of tolerance was associated with higher restart doses without compromising safety or treatment retention,” the authors concluded. “Our findings suggest that traditional methadone restart protocols that recommend substantial dose reductions may fail to address important individual heterogeneity in restart dosing needs, although additional studies powered to detect small changes in safety outcomes are needed.”

References

1. Christine PJ, Blum J, Tillman AR, et al. Evaluation of a novel patient-centered methadone restart protocol. JAMA Netw Open. Published online August 28, 2025. doi:10.1001/jamanetworkopen.2025.29393

2. Study proposes new, more personalized methadone restart approach for opioid use disorder. News release. University of Colorado Anschutz. August 28, 2025. Accessed August 28, 2025. https://news.cuanschutz.edu/news-stories/study-proposes-new-more-personalized-methadone-restart-approach-for-opioid-use-disorder