Association between early methadone dose titration and treatment discontinuation and opioid toxicity: A retrospective cohort study

Ria Garg; Jin Luo; Nikki Bozinoff; Beth Sproule; Tony Antoniou; Jennifer Wyman; Pamela Leece; Charlotte Munro; Jes Besharh; Tara Gomes

doi:10.1371/journal.pmed.1004748

. 2026 Apr 9;23(4):e1004748. doi: 10.1371/journal.pmed.1004748

Association between early methadone dose titration and treatment discontinuation and opioid toxicity: A retrospective cohort study

Ria Garg ^1,^2,^*, Jin Luo ¹, Nikki Bozinoff ^3,⁴, Beth Sproule ^2,^5,⁶, Tony Antoniou ¹, Jennifer Wyman ^4,⁷, Pamela Leece ^4,^8,⁹, Charlotte Munro ¹⁰, Jes Besharh ¹⁰, Tara Gomes ^1,^2,^11,¹²

Editor: Louisa Degenhardt¹³

¹ICES, Toronto, Ontario, Canada

²Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

³Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

⁴Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada

⁵Centre for Addiction and Mental Health, Toronto, Ontario, Canada

⁶Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

⁷Division of Addiction Medicine, Women’s College Hospital, Toronto, Ontario, Canada

⁸Public Health Ontario, Toronto, Ontario, Canada

⁹University of Toronto Dalla Lana School of Public Health, Toronto, Ontario, Canada

¹⁰Ontario Drug Policy Research Network Lived Experience Advisory Group, Toronto, Ontario, Canada

¹¹Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada

¹²Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

¹³University of New South Wales, AUSTRALIA

I have read the journal’s policy and the authors of this manuscript have the following competing interests: N.B. reports receiving personal fees from Ontario College of Family Physicians for moderation of continuing professional development talks, some of which relate to opioid agonist therapy, outside the submitted work. T.G. reports consulting fees from Canada’s Drugs Agency, honoraria from Indigenous Services Canada, and contracts with the Ontario College of Pharmacists and the Auditor General of British Columbia unrelated to this work. She has also been paid for expert testimony in an inquest led by the Ontario Office of the Chief Coroner. J.W. co-authored the methadone prescribing recommendation for people who use fentanyl, officially released by the Mentoring, Education, and Clinical Tools for Addiction – Partners in Health Integration in June 2021.

^✉

* E-mail: ria.garg@mail.utoronto.ca

Roles

Ria Garg: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing

Jin Luo: Formal analysis, Validation, Writing – review & editing

Nikki Bozinoff: Conceptualization, Methodology, Supervision, Visualization, Writing – review & editing

Beth Sproule: Conceptualization, Methodology, Supervision, Visualization, Writing – review & editing

Tony Antoniou: Conceptualization, Methodology, Supervision, Visualization, Writing – review & editing

Jennifer Wyman: Conceptualization, Visualization, Writing – review & editing

Pamela Leece: Conceptualization, Visualization, Writing – review & editing

Charlotte Munro: Conceptualization, Validation, Visualization, Writing – review & editing

Jes Besharh: Conceptualization, Validation, Visualization, Writing – review & editing

Tara Gomes: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing

Louisa Degenhardt: Academic Editor

PMCID: PMC13065010 PMID: 41955210

Abstract

Background

Clinical guidance in Canada and the United States recommends faster methadone dose titration for individuals using fentanyl. An initial dose increase is recommended between days 4 and 6, but the impact on patient outcomes remains unclear, particularly when provided in an outpatient setting. Therefore, we evaluated the association between early methadone dose titration (i.e., within treatment days 4–6) and treatment discontinuation and opioid toxicity.

Methods and findings

We conducted a retrospective propensity-score weighted cohort study of Ontario residents who initiated methadone in an outpatient setting between January 2017 and December 2022. Exposure was defined as provision of a dose titration between treatment days 4–6, with the index date defined as the first date of dose increase. For unexposed individuals, the index date was randomly assigned and followed the same distribution as those exposed. Individuals were followed for up to 181 days following index date for study outcomes. Primary outcomes included methadone discontinuation and opioid toxicity, using an intention-to-treat approach. Secondary outcomes included methadone versus non-methadone-related toxicity while on treatment. We fit a propensity-score model to estimate the probability of dose titration, conditional on baseline demographic and clinical (e.g., comorbidities, past medication use) variables. Propensity score weighted Cox proportional hazard models were then estimated to determine the association between early dose titration and study outcomes. Among 13,560 incident methadone recipients (61.4% [N = 8,322] provided early dose titration), the mean age was 36.5 years old, and approximately one-third were female. Individuals who received an early dose titration had a lower weighted hazard of discontinuation, which was most pronounced during the first seven days of follow-up (weighted hazard ratio [wHR]: 0.55; 95% confidence interval [CI]: 0.51, 0.60), with attenuation towards the null over time. The observed weighted rate of opioid toxicity was lower among those exposed versus unexposed (10.1 versus 12.3 per 100 person-years; wHR: 0.82; [95% CI: 0.69, 0.97]). Early dose titration was not associated with opioid toxicity while on treatment. Most toxicities were attributed to non-methadone opioids (exposed: 3.89 per 100 person-years versus unexposed: 4.06 per 100 person-years; wHR: 1.00; [95% CI: 0.70, 1.44]). Methadone-related toxicity while on treatment remained low and comparable between exposed and unexposed groups (2.02 versus 2.65 per 100 person-years; wHR: 0.80; [95% CI: 0.46, 1.41]). The main study limitation is the lack of information on drug use history and time-varying clinical factors that may influence both dose titration and subsequent outcomes, introducing the potential for residual confounding.

Conclusions

This population-based analysis demonstrated that early methadone dose titration was associated with improved treatment retention and lower hazard of opioid toxicity. Logistical barriers that hinder timely provision of dose increases must be addressed to improve methadone retention among people who use fentanyl.

Author summary

Why was this study done?

Due to persistently low rates of methadone retention—partly attributed to increased opioid tolerance and dissatisfaction with traditional prescribing regimens among people who use fentanyl—clinical guidance in Canada and the United States has evolved to recommend more rapid methadone titration schedules.
However, due to the urgency of the opioid crisis, these recommendations were made in the absence of robust clinical evidence. Ongoing concerns regarding the risk of methadone toxicity due to its highly variable pharmacokinetic profile remain.

What did the researchers do and find?

We used administrative data linked at the individual level to identify a cohort of Ontario residents who initiated methadone in an outpatient setting between January 2017 and December 2022.
We examined associations between provision of an early methadone dose titration, defined as a dose increase between treatment days 4 to 6 and methadone discontinuation and opioid toxicity, compared with no dose change.
In this retrospective propensity score-weighted cohort study of 13,560 incident methadone recipients, provision of an initial dose titration between treatment days four to six was associated with lower rates of methadone discontinuation and opioid toxicity over six months of follow-up, compared with no dose change.

What do these findings mean?

Logistical barriers that prevent people with high opioid tolerance from receiving timely dose titration need to be addressed given the association of early dose titration with improved methadone retention and lower rates of opioid toxicity.
The study’s main limitation was lack of comprehensive data on clinical indicators of opioid use disorder severity such as their drug use history.

Ria Garg and colleagues evaluate how early methadone dose titration between treatment days 4 and 6, as recommended in Canadian and US clinical guidance for individuals using fentanyl, is associated with treatment discontinuation and opioid toxicity.

Introduction

The Canadian and United States’ (US) fentanyl dominated unregulated drug supply has led to a 2-fold increase in the annual number of opioid related deaths between 2016 and 2023, rising from 45,081 to nearly 90,000 [1,2]. An estimated two-thirds of opioid-related deaths occur among people with opioid use disorder (OUD) [3,4]. While opioid agonist treatments (OAT) are safe and effective for people with OUD [5–8], treatment retention in the United States and Canada remains challenging as majority discontinue in the first few months [9–11]. This trend may reflect a mismatch between the high opioid tolerance of individuals exposed to a fentanyl-dominated unregulated drug supply and traditional OAT prescribing practices [9–12]. Recently released clinical guidance recognizes that people who use fentanyl require significantly higher methadone doses than were needed when the unregulated drug supply primarily consisted of heroin. For example, a focus group with people who use fentanyl reported that a minimum methadone dose of 120 mg was needed for adequate suppression of opioid cravings and withdrawal symptoms [13]. Due to requirements for higher methadone doses, evolving clinical guidance in the US and Canada recommends rapid dose titration to reduce time spent receiving a subtherapeutic dose and improve treatment retention [13–16].

In recent years, several US opioid treatment programs have adopted more aggressive titration schedules, with methadone doses increased daily, reaching doses of 70 mg or higher within the first week of treatment [17–19]. In Ontario, Canada, the 2021 guidance by Mentoring, Education, and Clinical Tools for Addition – Partners in Health Integration (META-PHI) recommended initiating methadone at 30 mg rather than 20–30 mg as recommended under the former provincial guidelines [20], with dose increases of 15 mg every 3–5 days until a dose of 75–80 mg per day is reached for people who use fentanyl [13]. Although both US and Canada face a highly potent and volatile unregulated drug supply, their methadone delivery model differs [21]. Specifically, in the US, methadone is exclusively prescribed and dispensed through federally certified opioid treatment programs, whereas in Canada, methadone is provincially regulated, commonly prescribed by outpatient clinicians (e.g., family physicians or nurse practitioners with an addiction medicine-focused practice) and dispensed through community pharmacies [21]. Because methadone prescribing and dispensing typically occur at separate locations in Canada, longstanding guidance recommends that prescribers conduct a follow-up assessment before increasing the dose to ensure lack of adverse effects (e.g., sedation).

Due to the urgency of the opioid crisis in Canada and US, recommendations for faster methadone dose titration were made in the absence of robust clinical evidence. Ongoing concerns remain about methadone accumulation and toxicity due to its highly variable pharmacokinetic profile [22]. Current guidance generally relies on clinical experience and emerging case reports from inpatient settings, where patients receive constant monitoring for toxicity and findings may not be generalizable to community-based care or opioid treatment programs [18,23–25]. Therefore, we investigated the association between provision of early methadone dose titration within an outpatient setting and subsequent methadone discontinuation and opioid related toxicity.

Methods

Study design and setting

We conducted a retrospective, population-based propensity score-weighted cohort study to examine the association between early methadone dose titration (i.e., within the first four to six days of treatment) and methadone discontinuation and opioid toxicity. We accrued Ontario residents who initiated methadone in an outpatient setting between January 1, 2017, and December 31, 2022, in Ontario, Canada. All individuals were observed for 181 days. This study was pre-registered (doi: osf.io/4v5f8) and adheres to STROBE reporting guidelines (S1 Table) [26].

Data sources

We used administrative datasets housed at ICES, an independent, nonprofit research institute in Ontario with legal status that allows for the collection and analysis of administrative healthcare and demographic data without consent, for health system evaluation and improvement. The main data sources included the Narcotics Monitoring System, which captures all controlled substances (including methadone) dispensed from community pharmacies regardless of payer, and the Drug and Drug-Alcohol Related Death (DDARD) database, which provides post-mortem toxicology results for opioid-related deaths. Unique encoded identifiers were used to link the NMS to other datasets (see S2 Table for details on databases) and analyzed at ICES.

Ethics statement

ICES is designated a prescribed entity under Ontario’s Personal Health Information Privacy Act (PHIPA) and the Coroners Act. Section 45 of PHIPA authorizes ICES to collect personal health information without consent for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, the allocation of resources to or planning for all or part of the health system. Data used in this study is authorized under section 45 of Ontario’s Personal Health Information Protection Act and does not require review by a Research Ethics Board.

Cohort

Our study cohort included all incident recipients of methadone meeting our inclusion and exclusion criteria. We defined incident methadone use as no recent dispensing record for OAT or immediate-release hydromorphone (e.g., safer opioid supply [27]) within a predefined lookback period, which varied according to the drug formulation. Specifically, we used a 30-day lookback period to define recent use of shorter-acting OAT (i.e., methadone, sublingual buprenorphine/naloxone, slow-release oral morphine) and immediate-release hydromorphone, and a lookback of 210 and 42 days for longer-acting buprenorphine formulations (i.e., buprenorphine implant and extended-release buprenorphine, respectively).

Exposure definition

We identified all dispense records for methadone during the first six days of treatment. Individuals who received a dose increase during treatment days four to six (i.e., the exposure window) were defined as exposed, with the index date being the first date the dispensed dose exceeded the initiation dose. For unexposed individuals (i.e., received the same dose for the first six days), the index date was randomly assigned and followed the same distribution as the number of days between initiation and index date among the exposed group.

Exclusion criteria

We applied the following exclusion criteria on the date of methadone initiation to ensure incident use: methadone prescribed by an out-of-province practitioner, pharmacist, or dentist; provision of take-home doses; and methadone dose ≥60 mg. Next, we applied the following exclusions on the index date: individuals with missing patient identifiers, non-Ontario residents, recorded death date on or prior to the index date, age <18 or >64 years old, no record for methadone dispensing (for those unexposed), same day dispense record for another OAT product or immediate-release hydromorphone, hospital discharge within 14 days prior to index date, an emergency department (ED) visit on or between the initiation and index dates, provision of take-home doses, methadone prescribed by a non-physician or out-of-province prescriber, pregnancy, and an index date equal to treatment days 2–3 (i.e., before exposure window). Those who may have been prescribed methadone for pain, defined as individuals with a healthcare encounter for palliative care, cancer treatment, or cancer diagnosis in the year prior to the index date were also excluded. People not eligible for early dose titration were also excluded, which included those with a history of decompensated cirrhosis [28] in the prior year to index, those dispensed a lower dose on index versus initiation date, and people with three or more missed doses between the initiation and index dates. Individuals with missing values for any covariates included in our propensity score model were excluded from our analysis. Lastly, individuals could meet eligibility criteria at multiple points over the study period. Therefore, we randomly selected one incident treatment episode per individual to prevent dependence between observations.

Outcomes and follow-up

Our primary outcomes were methadone discontinuation and fatal or non-fatal opioid toxicity. We defined methadone discontinuation as a gap in treatment of six or more days as this would require re-titration of methadone from its starting dose [13]. Coroner-confirmed fatal opioid toxicities were identified using the DDARD database. Nonfatal opioid toxicities were defined as any ED visit or inpatient hospitalization with a diagnosis of opioid toxicity (International Classification of Diseases [ICD] and Related Health Problems, 10th Revision diagnosis codes: T40.0-T40.4 and T40.6). As a secondary outcome, we examined whether the incident opioid toxicity event was attributed to methadone, defined using post-mortem toxicology reports or a healthcare encounter with an ICD-10 T40.3 code. We performed an intention-to-treat analysis for all primary outcomes, following individuals from their index date until the outcome, a non-opioid-related death (for opioid toxicity outcome), death date (for methadone discontinuation outcome), or end of follow-up (181 days or June 30, 2023). A per-protocol analysis for opioid toxicity was conducted to determine the hazard of these events while on treatment. In this analysis, we censored follow-up upon methadone discontinuation (with discontinuation date defined as five days following the last dispense date plus days’ supply; see S3 Table for censorship indication). Finally, we conducted a stratified analysis to compare primary and secondary outcomes among participants who received a dose titration of <15 mg or ≥ 15 mg, relative to those unexposed.

Statistical analysis

We fit a propensity-score model to estimate the probability of dose titration, conditional on baseline demographic (age, sex, income quintile, housing status, urban residence, Northern Ontario residence), clinical (comorbidities, healthcare encounters for alcohol-, benzodiazepine-, stimulant- and opioid-related toxicities, prior medication use), healthcare service use (non-OUD related outpatient visits, ED visits, hospital visits, attachment to primary care), methadone adherence (methadone dispense on the day prior to index, number of missed methadone doses between date of initiation and index, dose dispensed on initiation date, OUD-related outpatient visits between date of initiation and index) and prescriber related variables (physician speciality, prescriber OAT client volume, years in clinical practice) defined on or prior to index date (see S4 Table for covariate definitions). We selected these covariates based on past literature and clinical judgement. We derived stabilized inverse probability of treatment weights (sIPTW) from the propensity score and trimmed the cohort at the 1st and 99th percentiles to reduce the influence of large values. We summarized baseline characteristics using descriptive statistics and compared exposure groups using weighted absolute standardized differences, with values >0.10 indicating imbalance. We used Cox proportional hazards models, weighted by the sIPTW, to compare outcomes between exposed and unexposed individuals. We verified the proportional hazards assumptions using time-varying exposure terms and visual inspection of Schoenfeld residuals. If the assumption was violated, we reported hazard ratios (HRs) over four intervals (0–7, 8–30, 31–90, and 91–181 days). Finally, we calculated sIPTW weighted rates per 100 person-years. We used 95% confidence intervals (CIs) to determine statistical significance, with estimates that crossed 1 considered statistically insignificant. All analyses were conducted at ICES using SAS Enterprise Guide 7.1.

Sensitivity analysis

We conducted several sensitivity analyses to assess the robustness of our intention-to-treat models across different cohorts (i.e., those with no missed doses prior to index date and those whose index date was treatment day 4). Additionally, we redefined methadone discontinuation as a treatment gap of 14 or more days.

Exploratory analysis

In an exploratory analysis (i.e., not included in pre-registered analysis), we examined the prevalence of dose titration after the index date among exposed and unexposed individuals, using the full cohort without application of propensity score trimming methods. We followed each individual for 14 days after their assigned index date to determine time to dose titration, defined as the first dispense date on which the dose exceeded the dose dispensed on index date. Lastly, we reconstructed the study cohort to include each individual’s first continuous use period accrued during the exposure window and reanalyzed the primary study outcomes to test the robustness of our decision to randomly select one incident use period per person.

Results

After application of our exclusion criteria, we included 13,836 individuals in our study cohort (Fig 1). In the primary analysis, following propensity score trimming, the cohort comprised 13,560 individuals, of whom 8,322 (61.4%) had their methadone dose titrated early (i.e., between treatment days four and six; Table 1). The mean age was 36.5 years (standard deviation: 10.3), approximately one-third (34.9%) were female and most (89.7%) resided in urban centers. Before weighting, individuals in the exposed group had a lower prevalence of past methadone use (26.7% versus 40.0%) and a lower mean initiation dose (23.8 mg versus 25.2 mg). Significantly higher measures of methadone adherence were noted among those exposed, as only 7.8% did not receive methadone the day prior to index and 3.2% missed two doses between initiation and index date, compared to 19.1% and 9.0%, respectively, among those unexposed. After propensity-score weighting, all baseline characteristics were balanced between exposure groups with standardized differences of <0.1 (S1 Fig) and good propensity score distributional overlap between those exposed and unexposed was observed (S2 Fig).

Table 1. Unweighted baseline characteristics of incident methadone recipients in Ontario, Canada, January 1, 2017 to December 31, 2022.

	Before weighting		Standardized mean difference
	Unexposed (No dose titration; N = 5,238^a)	Exposed (Dose titration; N = 8,322^a)	Before weighting	After Weighting
Demographic Characteristics ^b
Age (Mean, SD)	36.1 (9.9)	36.8 (10.5)	0.07	0.01
Female	1,817 (34.7%)	2,914 (35.0%)	0.01	0.01
Income Quintile
1	2,042 (39.0%)	3,130 (37.6%)	0.03	0.01
2	1,263 (24.1%)	2,027 (24.4%)	0.01	0.01
3	931 (17.8%)	1,401 (16.8%)	0.02	0.01
4	597 (11.4%)	1,037 (12.5%)	0.03	<0.01
5	405 (7.7%)	727 (8.7%)	0.04	0.01
Hospital flagged homelessness (1 year prior)	483 (9.2%)	539 (6.5%)	0.10	0.01
Low-income or disability support public drug plan	2,694 (51.4%)	4,254 (51.1%)	0.01	0.01
Residence in northern Ontario	592 (11.3%)	828 (9.9%)	0.04	0.02
Urban location of residence	4,705 (89.8%)	7,464 (89.7%)	<0.01	0.01
Year of index date
2017	1,085 (20.7%)	1,964 (23.6%)	0.07	0.01
2018	871 (16.6%)	1,492 (17.9%)	0.03	<0.01
2019	868 (16.6%)	1,365 (16.4%)	0.01	<0.01
2020	877 (16.7%)	1,430 (17.2%)	0.01	0.01
2021	840 (16.0%)	1,239 (14.9%)	0.03	<0.01
2022	690–695	825–830	0.10	<0.01
2023	≤5 (0.1%)	≤5 (0.0%)	0.01	0.01
Comorbidities ^b
Charlson score
No hospital visits	3,566 (68.1%)	5,594 (67.2%)	0.02	0.01
0	1,378 (26.3%)	2,253 (27.1%)	0.02	0.01
1	204 (3.9%)	316 (3.8%)	0.01	0.01
2+	90 (1.7%)	159 (1.9%)	0.01	<0.01
Human Immunodeficiency Virus	44 (0.8%)	65 (0.8%)	0.01	0.01
COPD	346 (6.6%)	699 (8.4%)	0.07	<0.01
Asthma	1,285 (24.5%)	2,121 (25.5%)	0.02	0.01
Chronic Kidney Disease (5 years prior)	44 (0.8%)	95 (1.1%)	0.03	0.01
Liver Disease (1 year prior)	73 (1.4%)	107 (1.3%)	0.01	0.01
COPD related hospital or ED visit (1 year prior)	141 (2.7%)	206 (2.5%)	0.01	<0.01
Asthma related hospital or ED visit (1 year prior)	35 (0.7%)	54 (0.6%)	0.00	0.01
Mental health related hospital or ED visit (3 years prior)	4,288 (81.9%)	6,762 (81.3%)	0.02	<0.01
Psychotic disorders related outpatient visit (3 years prior)	769 (14.7%)	1,071 (12.9%)	0.05	0.01
Behavioral and neuro-developmental disorders related outpatient visit (3 years prior)	287 (5.5%)	429 (5.2%)	0.01	0.01
Other mental health disorders related outpatient visit (3 years prior)	863 (16.5%)	1,264 (15.2%)	0.04	0.01
Alcohol use disorder (3 years prior)	464 (8.9%)	711 (8.5%)	0.01	<0.01
Stimulant harmful use or dependence (3 years prior)	801 (15.3%)	1,025 (12.3%)	0.09	<0.01
Sedative-hypnotic harmful use or dependence (3 years prior)	164 (3.1%)	242 (2.9%)	0.01	<0.01
Hospital or ED visit for injection-related infection (3 years prior)	1,172 (22.4%)	1,601 (19.2%)	0.08	<0.01
Hospital or ED visit for toxicity^b (1 year prior)
Alcohol-related	22 (0.4%)	30 (0.3%)	0.01	<0.01
Benzodiazepine-related	62 (1.1%)	70 (0.8%)	0.03	<0.01
Stimulant-related toxicity	59 (1.1%)	81 (0.9%)	0.01	0.01
Non-fatal opioid toxicity	613 (11.1%)	763 (8.8%)	0.08	<0.01
Healthcare utilization^b (1 year prior)
Non-OUD related outpatient visits	4,522 (86.3%)	7,341 (88.2%)
Mean (SD)	7.5 (10.4)	7.8 (10.7)	0.06	0.01
0	716 (13.7%)	981 (11.8%)
1–4	2,157 (41.2%)	3,406 (40.9%)
5–10	1,195 (22.8%)	1,944 (23.4%)
11+	1,170 (22.3%)	1,991 (23.9%)
ED visits	3,055 (58.3%)	4,841 (58.2%)
Mean (SD)	2.1 (4.0)	2.0 (4.0)	<0.01	0.01
0	2,183 (41.7%)	3,481 (41.8%)
1	1,062 (20.3%)	1,758 (21.1%)
23	1,048 (20.0%)	1,662 (20.0%)
4+	945 (18.0%)	1,421 (17.1%)
Hospital visit	601 (11.5%)	912 (11.0%)
Mean (SD)	0.2 (0.6)	0.2 (0.6)	0.02	0.01
0	4,637 (88.5%)	7,410 (89.0%)
1+	601 (11.5%)	912 (11.0%)
Attachment to Primary Care	4,703 (89.8%)	7,570 (91.0%)	0.04	<0.01
Medication Use History ^b
Controlled Prescription Medication Use (30 days prior)	541 (10.3%)	1,071 (12.9%)	0.08	<0.01
Stimulants	181 (3.5%)	280 (3.4%)	0.01	0.01
Benzodiazepines	430 (8.2%)	889 (10.7%)	0.08	0.01
Non-OAT opioids	0 (0.0%)	0 (0.0%)
Direct acting antivirals (1 year prior)	88 (1.7%)	108 (1.3%)	0.03	<0.01
Opioid Agonist Treatment Use (1 year prior)	2,635 (50.3%)	3,224 (38.7%)	0.23	0.02
Methadone	2,093 (40.0%)	2,222 (26.7%)	0.28	0.01
Buprenorphine/naloxone	960 (18.3%)	1,361 (16.4%)	0.05	0.01
Long-acting buprenorphine	12 (0.2%)	17 (0.2%)	0.01	<0.01
Slow-Release Oral Morphine	89 (1.7%)	94 (1.1%)	0.05	<0.01
Immediate release hydromorphone (1 year prior)	117 (2.2%)	255 (3.1%)	0.05	<0.01
Methadone adherence characteristics following treatment initiation ^b
Dispense record for methadone the day before index date	4,237 (80.9%)	7,673 (92.2%)	0.34	0.01
Missed methadone doses between methadone initiation date and index date
0	3,448 (65.8%)	7,233 (86.9%)	0.51	0.02
1	1,317 (25.1%)	822 (9.9%)	0.41	0.01
2	473 (9.0%)	267 (3.2%)	0.24	0.01
Methadone dose on treatment initiation date
Median (IQR)	25 (20, 30)	20 (20, 30)
Mean (SD)	25.2 (7.5)	23.8 (6.4)	0.19	0.01
Methadone dose on index date
Median (IQR)	25 (20, 30)	35 (30, 45)
Mean (SD)	25.2 (7.5)	37.0 (39.0)
OUD-related outpatient visit between methadone initiation and index date	559 (10.7%)	2,370 (28.5%)	0.46	0.01
Physician Characteristics at Index ^b
Physician Specialty – Family Practitioner	4,081 (77.9%)	6,605 (79.4%)	0.04	0.02
Prescriber OAT Client Volume
Low (lowest 50th percentile)	614 (11.7%)	732 (8.8%)	0.10	<0.01
Moderate (51st to 80th percentile)	1,621 (30.9%)	2,758 (33.1%)	0.05	0.01
High (top 20th percentile)	3,003 (57.3%)	4,832 (58.1%)	0.01	<0.01
Years in Clinical Practice
Mean (SD)	23.3 (10.9)	24.8 (10.7)	0.14	0.01
<10 years	644 (12.3%)	746 (9.0%)	0.11
10–19 years	1,369 (26.1%)	1,818 (21.8%)	0.10
20+ years	3,225 (61.6%)	5,758 (69.2%)	0.16

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^aDerived after applying propensity score trimming to the study cohort.

^bNumbers represent n, (%), unless otherwise specified.

SD, standard deviation; ED, emergency department; OUD, opioid use disorder; OAT, opioid agonist treatment; COPD, chronic obstructive pulmonary disease; IQR, interquartile range.

The provision of an early dose increase was associated with a lower weighted hazard of methadone discontinuation (weighted rate per 100 person-years: 208.9 versus 283.9; Table 2) and a longer median time to methadone discontinuation (109 [interquartile range: 23-inf] versus 63 days [interquartile range: 11-inf]) compared to those unexposed. The difference was most pronounced during the first seven days of follow-up (weighted hazard ratio [wHR] between days 0 and 7: 0.55; 95% CI: 0.51, 0.60) and attenuated towards the null over time (wHR from days 91 to 181: 0.89; 95% CI: 0.81, 0.99). See S5 Table for unadjusted event rates and HRs.

Table 2. Association between early dose titration and study outcomes.

Outcome	Rate^a per 100 person-years (95% CI)		Hazard ratio^a^,^b (95% CI)
Outcome	Unexposed (No dose increase)	Exposed (Dose increase)	Hazard ratio^a^,^b (95% CI)
Methadone Discontinuation	283.9 (270.6, 297.9)	208.9 (201.8, 216.2)	Interval 1^c: 0.55 (0.51, 0.60)
			Interval 2^d: 0.79 (0.73, 0.86)
			Interval 3^e: 0.87 (0.80, 0.95)
			Interval 4^f: 0.89 (0.81, 0.99)
Opioid toxicity
Intention to treat	12.3 (10.9, 14.0)	10.1 (9.0, 11.2)	0.82 (0.69, 0.97)
While on treatment	6.71 (5.18, 8.69)	5.91 (4.94, 7.07)	0.92 (0.68, 1.26)
Methadone toxicity (while on treatment)	2.65 (1.65, 4.28)	2.02 (1.50, 2.73)	0.80 (0.46, 1.41)
Non-methadone toxicity (while on treatment)	4.06 (3.03, 5.42)	3.89 (3.11, 4.86)	1.00 (0.70, 1.44)

Open in a new tab

^aStabilised inverse probability treatment weighting.

^bReference group: Unexposed.

^c0 to 7 days of follow-up.

^d8 to 30 days of follow-up.

^e31 to 90 days of follow-up.

^f91 to 181 days of follow-up.

CI, confidence interval.

In the intention-to-treat analysis, the observed rate of opioid toxicity was lower among exposed individuals (weighted rate per 100 person-years: 10.1 versus 12.3; wHR, 0.82 [95% CI, 0.69,0.97]). In the per-protocol analysis, which censored individuals at treatment discontinuation, respective opioid toxicity rates were lower in both exposure groups (5.91 versus 6.71 per 100-person-years) in comparison to the intention-to-treat analysis, and no association between early dose titration and opioid toxicity was observed (wHR: 0.93; 95% CI: 0.68, 1.26). Among events observed while on treatment, 66.2% (N = 149) were attributed to non-methadone opioids. There was no association between early dose titration and non-methadone toxicity (3.89 versus 4.06 per 100 person-years in exposed versus non-exposed groups, respectively; wHR 1.00; 95% CI 0.70, 1.44) or methadone toxicity (2.02 versus 2.65 per 100 person-years in exposed versus non-exposed groups, respectively; wHR 0.80; 95% CI: 0.46, 1.41).

Stratified analysis

In the stratified analysis, after propensity score trimming, 5,123 individuals received a dose titration of <15 mg (median; interquartile range dose titration [IQR]: 10 mg; 10, 10; S6 Table), while 3,173 were titrated by ≥15 mg (median; IQR dose titration: 15 mg; 15, 15; S7 Table) on index date. While baseline characteristics were generally consistent with the overall analysis, those titrated by <15 mg had significantly lower prevalence of indicators suggestive of substance use disorder severity than those unexposed, including harmful or dependent stimulant use (11.7% versus 15.4%), injection-related infections (18.2% versus 22.3%), and prior opioid toxicity (8.1% versus 10.8%). After propensity-score weighting, baseline characteristics were balanced between exposure groups in each stratified cohort (S1 Fig). Findings were consistent with the overall analyses among individuals titrated by <15 mg compared to those unexposed (S8 Table). Among individuals titrated by ≥15 mg versus those unexposed, the hazard of methadone discontinuation remained significantly reduced (wHR from days 1–7: 0.55, 95% CI: 0.50, 0.61); however, in contrast to our overall findings, we observed no association between early dose titration and opioid toxicity in the intention-to-treat analysis (wHR 0.95, 95% CI: 0.77, 1.16). For the per-protocol analysis, the proportional hazards assumption was violated and therefore we assessed the association at various times over follow-up. In this model, no association between early titration and opioid toxicity was observed in the first 90 days of treatment; however, we observed an elevated hazard of opioid toxicity between treatment days 91 and 181 (wHR 2.23, 95% CI: 1.14, 4.51) compared to unexposed individuals. This finding was driven by non-methadone-related toxicities (wHR from days 91 to 181: 3.29, 95% CI: 1.48, 8.07), whereas no association between methadone-attributed toxicity and dose titration was observed throughout follow-up (wHR 0.88, 95% CI: 0.46, 1.66).

Sensitivity and exploratory analyses

Results from our sensitivity analyses were generally consistent with the main analysis. Findings for time to methadone discontinuation were robust to the application of sensitivity and exploratory analyses (S9 and S10 Tables). While the hazard of opioid toxicity did not significantly differ between exposure groups after application of cohort restrictions and selection of a unique continuous use period at random versus the first incident use period identified over the accrual period, toxicity rates remained lower among those exposed versus unexposed.

Overall, 68.1% of study participants received a dose increase within 14 days of the index date, with a median event time of 4 days (IQR: 3, 6 days) (S11 Table). The crude prevalence of post-index dose titration was significantly higher among those exposed versus unexposed (76.8% versus 54.4%; standardized difference: 0.49).

Discussion

In this population-based study of incident methadone recipients in Ontario, Canada, individuals who received dose titration within an outpatient setting and in alignment with clinical guidance for people who use fentanyl had a lower hazard of methadone discontinuation and a lower or similar hazard of opioid toxicity over six months of follow-up compared to those who did not receive a dose titration during the first six days of treatment. Among individuals who remained on treatment, the rate of opioid toxicity was primarily driven by non-methadone opioids and was comparable between exposure groups.

A key finding of this study was that provision of an early dose titration (i.e., during the first four to six days of treatment) supported methadone retention without increased hazard of opioid toxicity among a cohort of individuals using a fentanyl-dominated unregulated drug supply. The safety and feasibility of rapid methadone titration is further supported by emerging evidence from US outpatient opioid treatment programs, with patients reaching doses up to 70 mg within one week of treatment without significant reports of toxicity and improved 30-day methadone retention [17,18]. Methadone is initiated at subtherapeutic doses due to its highly variable half-life and narrow therapeutic index, which places methadone naïve individuals at risk of bioaccumulation and toxicity [22,29]. Currently, no clinical tools exist to determine the risk of an iatrogenic methadone toxicity at initiation, necessitating cautious titration [29]. However, individuals who use high-potency opioids—such as those in Canada and the US—have a high tolerance to opioids and are partially cross-tolerant to methadone, which may permit higher initiation doses and more rapid titration [13,16,30]. This is in agreement with our study results, conducted within a region where fentanyl dominates the unregulated drug supply, as early methadone dose titration remained safe even when the dose was titrated on treatment day 4 or by 15 mg with a median initiation dose of 30 mg.

A population-based study of methadone initiations in Ontario, Canada between 2015 and 2023 reported that only 40.5% received a dose titration within the first six days of treatment, with the prevalence of dose titration and methadone retention rates significantly declining over time [9,12]. In our study, even when restricted to those with no missed doses during the first six days of treatment, one-third of the cohort was not provided a dose increase. In Canada, methadone dose titration typically requires a follow-up physician visit, as standing orders are uncommon [13,16]. Whereas many opioid treatment programs in the US use standing induction titration orders covering treatment days 1–7, with nursing staff authorized to administer daily doses based on their assessment of sedation and intoxication. Requirements for a physician visit may contribute to many individuals remaining on initiation doses during the first week of treatment. For example, prior to weighting, we found the prevalence of an OUD-related physician visit between the initiation and index dates was significantly higher among those who received an early dose increase versus those unexposed. The first week of treatment with methadone can be challenging, as doses remain subtherapeutic and withdrawal symptoms and cravings persist, making it particularly difficult for patients to attend multiple appointments for dose adjustments [31]. To improve population-level methadone retention, physicians and patients should engage in shared decision-making at treatment initiation 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. Future qualitative research should also explore barriers to dose titration to identify modifiable factors that may be addressed to improve titration rates and support safer, more effective methadone initiation.

Our study has several limitations. First, due to our use of administrative data, we did not have information on clinical factors (e.g., ongoing substance use) that may have evolved during the exposure window and influenced both the likelihood of dose titration and subsequent outcomes. Our findings are thus subject to residual and potentially time-varying confounding. Second, non-fatal opioid toxicities treated in the community without hospital transfer were not captured. Additionally, cases in which an opioid was not identified as the cause of toxicity in the patient’s medical report upon ED or hospital admission may have resulted in missed non-fatal toxicity events. Therefore, our findings may underestimate the overall incidence of non-fatal opioid toxicity in this population. Third, given that defining the cause of a non-fatal toxicity relied on patients’ self-reporting, toxicology testing, or both, there is potential for misclassification of non-fatal opioid toxicities that were attributed to methadone versus non-methadone opioids. Fourth, while we captured provision of the first dose titration, we did not evaluate outcomes related to subsequent dose titrations. Fifth, our study was conducted in a single Canadian province, with a distinct outpatient methadone delivery system, which may limit generalizability of our results to other jurisdictions. Sixth, we excluded treatment episodes initiated at doses ≥60 mg to ensure our cohort reflected true incident use and was aligned with current methadone prescribing guidance. While this may have excluded a small number of people starting methadone at very high doses, Canadian guidelines generally recommend a maximum starting dose of 40 mg in outpatient settings to mitigate the risk of methadone toxicity. Therefore, these cases most likely represent prevalent users whose prior dispensing history was not captured in our dataset (e.g., those transitioning from correctional facilities or moving to Ontario from other provinces). Lastly, as with all observational studies due to the potential for residual confounding, we cannot be certain of a causal association between exposure and study outcomes.

This population-based cohort study suggests that provision of an initial dose titration in alignment with the 2021 treatment guidance for people who use fentanyl in Ontario, Canada is associated with improved treatment retention and reduced opioid toxicity rates. Logistical barriers that prevent people with high opioid tolerance from receiving timely dose titration, despite adequate adherence to methadone, should be addressed to improve treatment retention.

Supporting information

S1 Table. STROBE checklist of items that should be included in reports of cohort studies.

(DOCX)

pmed.1004748.s001.docx^{(21.5KB, docx)}

S2 Table. Descriptions of all linked administrative databases used in the study.

(DOCX)

pmed.1004748.s002.docx^{(18.9KB, docx)}

S3 Table. Censoring criteria applied to each outcome.

(DOCX)

pmed.1004748.s003.docx^{(14.8KB, docx)}

S4 Table. Covariate Definition.

(DOCX)

pmed.1004748.s004.docx^{(22.2KB, docx)}

S5 Table. Crude association between early dose titration and study outcomes.

(DOCX)

pmed.1004748.s005.docx^{(15.5KB, docx)}

S6 Table. Baseline characteristics of incident methadone recipients in Ontario, Canada, January 1, 2017, to December 31, 2022, comparing no dose increase versus provision of a dose increase <15 mg.

(DOCX)

pmed.1004748.s006.docx^{(26.7KB, docx)}

S7 Table. Baseline characteristics of incident methadone recipients in Ontario, Canada, January 1, 2017, to December 31, 2022, comparing no dose increase versus provision of a dose increase ≥15 mg.

(DOCX)

pmed.1004748.s007.docx^{(26.6KB, docx)}

S8 Table. Association between early dose titration and study outcomes, stratified analysis.

(DOCX)

pmed.1004748.s008.docx^{(16.8KB, docx)}

S9 Table. Association between early dose titration and study outcomes, sensitivity analysis.

(DOCX)

pmed.1004748.s009.docx^{(16KB, docx)}

S10 Table. Association between early dose titration and study outcomes, exploratory analysis.

(DOCX)

pmed.1004748.s010.docx^{(15.8KB, docx)}

S11 Table. Characteristics of dose titration following index date.

(DOCX)

pmed.1004748.s011.docx^{(15.1KB, docx)}

S1 Fig. Absolute standardized differences before and after propensity score weighting.

(TIFF)

pmed.1004748.s012.tiff^{(2.5MB, tiff)}

S2 Fig. Propensity score distribution between exposure groups.

(TIFF)

pmed.1004748.s013.tiff^{(6MB, tiff)}

Acknowledgments

This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). Parts of this material are based on data and information compiled and provided by the Ontario Ministry of Health, Ontario Health (OH), and CIHI. Data adapted from the Statistics Canada Postal CodeOM Conversion File was used, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from Canada Post Corporation and Statistics Canada. We thank IQVIA Solutions Canada for use of their Drug Information File.

The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

Abbreviations

CI: confidence interval
DDARD: Drug and Drug-Alcohol Related Death
ED: emergency department
HRs: hazard ratios
ICD: International Classification of Diseases
META-PHI: Mentoring, Education, and Clinical Tools for Addition – Partners in Health Integration
OAT: opioid agonist treatments
OUD: opioid use disorder
PHIPA: Personal Health Information Privacy Act
sIPTW: stabilized inverse probability of treatment weights
wHR: weighted hazard ratio

Data Availability

The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). The full dataset creation plan and underlying analytic code are also available from the ICES via email to das@ices.on.ca upon request to qualified applicants, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

Funding Statement

Author T.G. received grants from the Ontario Ministry of Health (No. 0691) and the Canadian Institutes of Health Research (No. 496563), which supported this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS Med. doi: 10.1371/journal.pmed.1004748.r001

Decision Letter 0

Alexandra Tosun

27 Aug 2025

Dear Dr Garg,

Thank you for submitting your manuscript entitled "Association Between Early Methadone Dose Titration and Treatment Discontinuation and Opioid Toxicity" for consideration by PLOS Medicine.

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PLoS Med. doi: 10.1371/journal.pmed.1004748.r002

Decision Letter 1

Alexandra Tosun

29 Sep 2025

Dear Dr Garg,

Many thanks for submitting your manuscript "Association Between Early Methadone Dose Titration and Treatment Discontinuation and Opioid Toxicity" (PMEDICINE-D-25-02997R1) to PLOS Medicine. The paper has been reviewed by subject experts and a statistician; their comments are included below and can also be accessed here: [LINK]

As you will see, the reviewers find that your study addresses an important research question and is generally well-executed. They mostly ask for clarification and greater detail on treatment guidelines in Canada and the US. After discussing the paper with the editorial team and an academic editor with relevant expertise, I'm pleased to invite you to revise the paper in response to the reviewers' comments. We plan to send the revised paper to some or all of the original reviewers, and we cannot provide any guarantees at this stage regarding publication.

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Alexandra Tosun, PhD

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atosun@plos.org

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Comments from the academic editor:

This is a really interesting manuscript on an important topic for the North American context and must be appropriately framed in that regard. I think a much more global overview and contextualisation of the paper in the introduction and then discussion is necessary given that this is not an issue for all countries and contexts and the authors must be seen to be (and be) clear about that in the paper - this is an issue where highly potent opioids and likely very high opioid tolerance are the norm among illicit opioid users.

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Comments from the reviewers:

Reviewer #1: Statistical review

This paper reports a retrospective analysis using propensity score weighting to investigate whether early methadone dose titration can improve outcomes compared to stable doses. Overall the statistical methods used are appropriate and the study is well reported. I had some comments on the paper, which are provided below:

1. Abstract: I would recommend that the start of follow-up is defined in the abstract.

2. Outcomes and follow-up: can the authors comment on the reliability of the outcome collection methods (especially the non-fatal ones).

3. Statistical analysis: I assume all the variables used in the PS model pre-date the exposure time? Some sounds ambiguous on that (e.g. number of missed methadone doses, hospital visits etc). Later on the results, e.g. table 1, do clarify this is done correctly. I would recommend the text here is updated.

4. Statistical analysis: I noted that it was mentioned missing data was grouped separately but I wasn't entirely sure what this meant. Can more be given on the missing data rates for variables and how these were dealt with in the PS model?

5. Statistical analysis: "A 2-sided type I error rate of 0.05 was used for all comparisons" - since p-values are not reported, I am not sure this statement is needed? It could be replaced by a statement about 95% confidence intervals being used.

6. Results "After propensity-score weighting, all baseline characteristics were balanced between exposure groups (eFigure 1)." - table 1 also shows the SMDs so I would mention here.

7. Results: it would be useful to visualise the propensity score distribution (or weights) by exposed/non-exposed group to demonstrate that there was overlaps, meaning the positivity assumption was met.

James Wason

Reviewer #2: Review of article: Association Between Early Methadone Dose Titration and Treatment Discontinuation and Opioid Toxicity

General comments -

This study examines an important area of methadone treatment that has had little exploration in the past - in spite of methadone being the most effective treatment for OUD for over 50 years, it remains unclear as to what is the most effective way to initiate and titrate the dose. While lower doses may decrease the potential risk of methadone related toxicity and overdose, they may lead to continued use of illicit opioids and early treatment discontinuation. This study is a good study that relates the dose titration early in methadone treatment episodes to outcomes - both retention in treatment and subsequent opioid toxicity, both from methadone and other opioids. This information will be of critical importance to patients and medical providers when they start on methadone. Overall, the study is well done, with a large database composed of many clinical and demographic measures. I would strongly support publication. Below are a few minor comments that might clarify some questions.

1) The paper briefly describes the protocols used in Canada and the US for initial methadone dose determinations in the discussion section. Most US readers will not be familiar with the Canadian system. I would suggest providing a more complete description in the introduction - this will help readers understand why you chose days 4-6 as the exposure window. US readers may not know that a physician visit is required for a dose increase and wonder why there aren't more dose increases in the first week. They may also not be familiar with how dosing is done and how take-home doses are determined.

2) The initial methadone dose on day 1 is given as a median - an average with calculation of standard difference would be more clarifying.

3) In figure 1, there were 93,357 "methadone use periods" - I assume this means this is the number of individuals who received any methadone in the time interval? Although some patients might be listed more than once due to multiple treatment episodes? Patients who were already on methadone (non-incident) were excluded. Why was a methadone dose >60 excluded - is this any dose throughout the period above 60 mg, or just during initiation? While this is mentioned in the text, it would help to put it on the figure as well.

4) Under Exclusion Criteria, you indicate that for individuals with more than one exposure, one of these was chosen randomly. Treatment retention declines with each subsequent treatment episode, so selecting from a group of episodes at random would have the effect of decreasing the average retention compared to the first recorded episode. I would consider selecting the earliest treatment episode rather than a random selection.

5) In Exclusion Criteria, you indicate that a methadone dose >60 mg was excluded (I assume for day 1, but it is not completely clear in the text), but don't indicate why this number was selected - the recommendation is for no more than 30 mg. Under what circumstances in Canada is the initial dose more than 30 mg, or more than 60 mg?

6) An indication of how take-home doses are determined in Canada is necessary to understand why this criterion was used. The exclusion was applied at initiation - does this mean only the initial dose? Over what period of time would a take-home dose be an exclusion? Does Canada allow take-home doses on Sundays and holidays (as in the US)?

7) Is there a good reason to exclude those <18 or >65 years old? This criterion is not indicated in Figure 1. How many were excluded on this basis?

8) You define a methadone discontinuation as missing 6 consecutive days of dosing. Why was this number chosen? Your definition of prior exposure used a 30-day window. Most OTPs in the US discharge patients after a 30-day dosing gap. US OTPs usually institute a dose reduction for a few days for a treatment gap of 6 days but would not consider this to be a readmission.

9) In the statistical analysis, the location of residence was used in the propensity adjustment, but it is not defined further in the text. Table 1 appears to indicate that this means either residence in northern Ontario or not in addition to rural vs. urban. What does it mean to be a resident of northern Ontario and why is it included?

10) In the first sentence of Statistical Analysis, you state that "prior medication use" is a demographic variable - which medication does this refer to?

11) The study uses the number of missed doses and a methadone dose dispensed prior to index in the propensity model. In the US, the likelihood of a dose increase on any day is strongly dependent on whether there have been any recent missed doses. A patient who misses a dose is unlikely to get dose increase on the following day. Patients who miss dosing during the first few days may differ from those who dose every day in important ways that are not completely addressed in the propensity adjustment. Would it be more accurate to simply exclude patients who missed doses prior to the index?

12) In the stratified analysis, for the per-protocol analysis, there was an elevated risk of opioid toxicity between days 91 - 180 for those titrated by 15 or more mg (only related to non-methadone opioids). This is not mentioned in the discussion - what would be a possible reason for this?

13) Under limitations, since this is an observational study, it is not possible to prove a causal connection between a dose titration and retention, only a statistical association after adjustment for all observed parameters. This is an important limitation of all non-randomized studies, and I think should be included in every case.

Reviewer #3: This paper describes a retrospective cohort study of methadone-treated patients, investigating the effects of early titration of the methadone dose. The research question is important, considering the on-going changes in patterns of opioid use, and the need for more data on different approaches to opioid agonist therapy. The manuscript is clearly written and easy to follow, and the basic methodology is sound (in the absence of experimental data). However, I have a couple of comments and questions:

1. The authors mention in the introduction that some treatment providers use a very fast induction schedule, sometimes with daily methadone dose titration. Nevertheless, the authors have chosen to define "early dose titration" as occurring from day four to six. What about the patients who may have received an even earlier dose titration, before day four?

2. I would be interested in knowing a bit more about the treatment of the unexposed patients, i.e. those that did not get any dose titration during the first six days. If I interpret eTable 7 correctly, 54.3% of them got a dose increase within 14 days of the index date (which corresponds to days 18-20 from treatment initiation). Isn't this a bit surprising? Where I work, we rarely wait more than a week before beginning the titration, and in this cohort almost half of the patients had to wait more than 2.5 weeks? Perhaps the requirement to meet a physician in order to change the dose, that is mentioned in the Discussion, might result in a sub-optimal dosing schedule even for some patients with "normal" titration rates? Maybe a comparison between early (<7 days), standard, and late (>14 days) titration starts would be of interest?

3. The authors mention a new guideline that was issued in 2021, recommending an early dose increase for people using fentanyl. However, the study period was from 2017 to 2022, which makes me wonder if the apparent effects of the exposure could be confounded by time, if most early titration cases occurred toward the end of the study period? I am not very familiar with the specific situation in Canada, but I imagine that changes in the drug market, as well as factors related to the covid-19-pandemic etc., could have resulted in different outcomes for this population over different parts of the study period.

In summary, this is an interesting study of an important clinical question. If the authors could clarify the questions above, I believe the manuscript could be suitable for publication.

Any attachments provided with reviews can be seen via the following link: [LINK]

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PLoS Med. 2026 Apr 9;23(4):e1004748. doi: 10.1371/journal.pmed.1004748.r003

Author response to Decision Letter 2

13 Nov 2025

Attachment

Submitted filename: early dose titration_reviewer response letter_2025Nov03.doc

pmed.1004748.s016.doc^{(125KB, doc)}

PLoS Med. doi: 10.1371/journal.pmed.1004748.r004

Decision Letter 2

Alexandra Tosun

18 Dec 2025

Dear Dr Garg,

Many thanks for re-submitting your manuscript "Association Between Early Methadone Dose Titration and Treatment Discontinuation and Opioid Toxicity" (PMEDICINE-D-25-02997R2) to PLOS Medicine. The paper has been seen again by the original subject reviewers and the statistician; their comments are included below and can also be accessed here: [LINK]

As you will see, the changes made to the paper were satisfactory to the reviewers. However, the academic editor provided several suggestions for additional analyses to strengthen the study, and we encourage you to include them in the manuscript. The academic editor also raised a concern about selecting a random treatment episode, and we have consulted the statistical reviewer on this issue. Please see their comments below. After discussing the feedback and the paper with the editorial team, I'm pleased to invite you to revise the paper in response to the editors' comments. We plan to send the revised paper to some or all of the original reviewers, and we cannot provide any guarantees at this stage regarding publication.

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Don't hesitate to contact me directly with any questions (atosun@plos.org).

Best regards,

Alexandra

Alexandra Tosun, PhD

Senior Editor

PLOS Medicine

atosun@plos.org

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Comments from the academic editor:

The authors made a conclusion that high dose methadone (>60mg) should be excluded as a starting dose and yet it is high dose inductions that is the focus of the study - I wonder whether the authors might need to do some additional analysis - albeit post hoc - to consider a) whether inclusion of the high doses they have excluded changes the observed findings, b) whether the high dose initiations look different to the lower dose ones in terms of characteristics of the people or treatment episodes (i.e. any basis for their assumption that these are episodes continued from out of jurisdiction or incarceration) and c) whether there is a time pattern observed whereby proportionally more of these occur in later years of the study - since dose is the object of focus of the study and this is a significant limitation in capture of the dataset. I think it would be helpful to do this additional investigation.

Additionally, the justification for selecting a random treatment episode (rather than the first) does not seem entirely robust. Selecting a random event means that you will randomly usually select a subsequent episode not a first one - at least if you use the first observed episode, you're minimising the number of times where you are using a repeated treatment entry that the authors claim would be at play given the truncation of the observation period?

Editorial note: We consulted the statistical editor regarding the second comment, and they agree with the academic editor's point. They agree that your justification for using random selection instead of an alternative method (e.g., the first eligible visit) is insufficient. They suggest conducting a sensitivity analysis using an alternative method, such as the first visit; we strongly encourage you to perform this analysis.

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Comments from the reviewers:

Reviewer #1: Thank you to the authors for fully addressing my previous review comments. I have no further issues to raise.

Reviewer #2: Thank you for your detailed responses. Thank you also for your contribution to this important area. I have no more comments or revisions at this time.

Reviewer #3: The authors have made a thorough revision of the manuscript, with a number of changes that made it stronger and improved clarity. I agree with the other reviewer comments, that it is important to contextualize the findings, for readers like me that are less familiar with the specifics of the Canadian treatment system. I believe that this version of the manuscript makes this more clear, and I have no further comments to add at this point.

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PLoS Med. 2026 Apr 9;23(4):e1004748. doi: 10.1371/journal.pmed.1004748.r005

Author response to Decision Letter 3

9 Jan 2026

Attachment

Submitted filename: Reviewer response_2025Dec30.docx

pmed.1004748.s017.docx^{(33.1KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004748.r006

Decision Letter 3

Alexandra Tosun

19 Feb 2026

Dear Dr Garg,

On behalf of my colleagues and the Academic Editor, Louisa Degenhardt, I am pleased to inform you that we have agreed to publish your manuscript "Association Between Early Methadone Dose Titration and Treatment Discontinuation and Opioid Toxicity: A retrospective cohort study" (PMEDICINE-D-25-02997R3) in PLOS Medicine.

I appreciate your thorough responses to the reviewers' and editors' comments throughout the editorial process. For transparency, I am sharing the statistical reviewer's feedback on the sensitivity analyses below my signature. We look forward to publishing your manuscript, and editorially there are only a few remaining points that should be addressed prior to publication. We will carefully check whether the changes have been made. If you have any questions or concerns regarding these final requests, please feel free to contact me at atosun@plos.org.

Please see below the minor points that we request you respond to:

* Table 1: Please indicate below the table that the numbers are "n, (%)" unless otherwise specified.

* l.316, “and a longer median time to methadone discontinuation (108 versus 63 days) compared to those unexposed.” – Are these numbers available in a table? Please clarify.

* Sensitivity analyses: We suggest adding a statement explaining that no differences in opioid toxicity were observed for both analyses.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email (including the editorial requests above). Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

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Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Alexandra Tosun, PhD

Senior Editor

PLOS Medicine

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Comments from Reviewers:

Reviewer #1: Thank you to the authors for adding the additional sensitivity analysis looking at choice of eligible visit. It is reassuring that the results are robust to this alternative choice.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. STROBE checklist of items that should be included in reports of cohort studies.

(DOCX)

pmed.1004748.s001.docx^{(21.5KB, docx)}

S2 Table. Descriptions of all linked administrative databases used in the study.

(DOCX)

pmed.1004748.s002.docx^{(18.9KB, docx)}

S3 Table. Censoring criteria applied to each outcome.

(DOCX)

pmed.1004748.s003.docx^{(14.8KB, docx)}

S4 Table. Covariate Definition.

(DOCX)

pmed.1004748.s004.docx^{(22.2KB, docx)}

S5 Table. Crude association between early dose titration and study outcomes.

(DOCX)

pmed.1004748.s005.docx^{(15.5KB, docx)}

S6 Table. Baseline characteristics of incident methadone recipients in Ontario, Canada, January 1, 2017, to December 31, 2022, comparing no dose increase versus provision of a dose increase <15 mg.

(DOCX)

pmed.1004748.s006.docx^{(26.7KB, docx)}

S7 Table. Baseline characteristics of incident methadone recipients in Ontario, Canada, January 1, 2017, to December 31, 2022, comparing no dose increase versus provision of a dose increase ≥15 mg.

(DOCX)

pmed.1004748.s007.docx^{(26.6KB, docx)}

S8 Table. Association between early dose titration and study outcomes, stratified analysis.

(DOCX)

pmed.1004748.s008.docx^{(16.8KB, docx)}

S9 Table. Association between early dose titration and study outcomes, sensitivity analysis.

(DOCX)

pmed.1004748.s009.docx^{(16KB, docx)}

S10 Table. Association between early dose titration and study outcomes, exploratory analysis.

(DOCX)

pmed.1004748.s010.docx^{(15.8KB, docx)}

S11 Table. Characteristics of dose titration following index date.

(DOCX)

pmed.1004748.s011.docx^{(15.1KB, docx)}

S1 Fig. Absolute standardized differences before and after propensity score weighting.

(TIFF)

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S2 Fig. Propensity score distribution between exposure groups.

(TIFF)

pmed.1004748.s013.tiff^{(6MB, tiff)}

Attachment

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Data Availability Statement

[pmed.1004748.ref001] 1.National Institute on Drug Abuse. Drug overdose death rates. National Institute on Drug Abuse. Updated August 29, 2024. [cited 16 June 2025]. Available from: https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates [Google Scholar]

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PERMALINK

Association between early methadone dose titration and treatment discontinuation and opioid toxicity: A retrospective cohort study

Ria Garg

Jin Luo

Nikki Bozinoff

Beth Sproule

Tony Antoniou

Jennifer Wyman

Pamela Leece

Charlotte Munro

Jes Besharh

Tara Gomes

Roles

Abstract

Background

Methods and findings

Conclusions

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Study design and setting

Data sources

Ethics statement

Cohort

Exposure definition

Exclusion criteria

Outcomes and follow-up

Statistical analysis

Sensitivity analysis

Exploratory analysis

Results

Fig 1. Cohort exclusion flow diagram.

Table 1. Unweighted baseline characteristics of incident methadone recipients in Ontario, Canada, January 1, 2017 to December 31, 2022.

Table 2. Association between early dose titration and study outcomes.

Stratified analysis

Sensitivity and exploratory analyses

Discussion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Alexandra Tosun

Roles

Decision Letter 1

Alexandra Tosun

Roles

Author response to Decision Letter 2

Decision Letter 2

Alexandra Tosun

Roles

Author response to Decision Letter 3

Decision Letter 3

Alexandra Tosun

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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