What is the ideal time to begin tapering opioid agonist treatment? A protocol for a retrospective population-based comparative effectiveness study in British Columbia, Canada.

INTRODUCTION: Opioid agonist treatment (OAT) tapering involves a gradual reduction in daily medication dose to ultimately reach a state of opioid abstinence. Due to the high risk of relapse and overdose after tapering, this practice is not recommended by clinical guidelines, however, clients may still request to taper off medication. The ideal time to initiate an OAT taper is not known. However, ethically, taper plans should acknowledge clients' preferences and autonomy but apply principles of shared informed decision-making regarding safety and efficacy. Linked population-level data capturing real-world tapering practices provide a valuable opportunity to improve existing evidence on when to contemplate starting an OAT taper. Our objective is to determine the comparative effectiveness of alternative times from OAT initiation at which a taper can be initiated, with a primary outcome of taper completion, as observed in clinical practice in British Columbia (BC), Canada. METHODS AND ANALYSIS: We propose a population-level retrospective observational study with a linkage of eight provincial health administrative databases in BC, Canada (01 January 2010 to 17 March 2020). Our primary outcomes include taper completion and all-cause mortality during treatment. We propose a 'per-protocol' target trial to compare different durations to taper initiation on the likelihood of taper completion. A range of sensitivity analyses will be used to assess the heterogeneity and robustness of the results including assessment of effectiveness and safety. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

A New Look at P Values for Randomized Clinical Trials.

BACKGROUND: We have examined the primary efficacy results of 23,551 randomized clinical trials from the Cochrane Database of Systematic Reviews. METHODS: We estimate that the great majority of trials have much lower statistical power for actual effects than the 80 or 90% for the stated effect sizes. Consequently, "statistically significant" estimates tend to seriously overestimate actual treatment effects, "nonsignificant" results often correspond to important effects, and efforts to replicate often fail to achieve "significance" and may even appear to contradict initial results. To address these issues, we reinterpret the P value in terms of a reference population of studies that are, or could have been, in the Cochrane Database. RESULTS: This leads to an empirical guide for the interpretation of an observed P value from a "typical" clinical trial in terms of the degree of overestimation of the reported effect, the probability of the effect's sign being wrong, and the predictive power of the trial. CONCLUSIONS: Such an interpretation provides additional insight about the effect under study and can guard medical researchers against naive interpretations of the P value and overoptimistic effect sizes. Because many research fields suffer from low power, our results are also relevant outside the medical domain. (Funded by the U.S. Office of Naval Research.)

Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

Why Stating Hypotheses in Grant Applications Is Unnecessary.

This Viewpoint argues that a hypothesis-centric approach to writing grant applications is problematic and instead suggests that funding applications should be evaluated by their relevance and methodological quality rather than by qualitative assertions before the study is conducted.