Identifying optimal dosage regimes under safety constraints: An application to long term opioid treatment of chronic pain

Stat Med. 2018 Apr 30;37(9):1407-1418. doi: 10.1002/sim.7566. Epub 2018 Feb 21.


There is growing interest and investment in precision medicine as a means to provide the best possible health care. A treatment regime formalizes precision medicine as a sequence of decision rules, one per clinical intervention period, that specify if, when and how current treatment should be adjusted in response to a patient's evolving health status. It is standard to define a regime as optimal if, when applied to a population of interest, it maximizes the mean of some desirable clinical outcome, such as efficacy. However, in many clinical settings, a high-quality treatment regime must balance multiple competing outcomes; eg, when a high dose is associated with substantial symptom reduction but a greater risk of an adverse event. We consider the problem of estimating the most efficacious treatment regime subject to constraints on the risk of adverse events. We combine nonparametric Q-learning with policy-search to estimate a high-quality yet parsimonious treatment regime. This estimator applies to both observational and randomized data, as well as settings with variable, outcome-dependent follow-up, mixed treatment types, and multiple time points. This work is motivated by and framed in the context of dosing for chronic pain; however, the proposed framework can be applied generally to estimate a treatment regime which maximizes the mean of one primary outcome subject to constraints on one or more secondary outcomes. We illustrate the proposed method using data pooled from 5 open-label flexible dosing clinical trials for chronic pain.

Keywords: Q-learning; chronic pain; flexible dosing trials; policy-search; precision medicine; treatment dosing regimes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / therapeutic use
  • Chronic Pain / drug therapy*
  • Drug Dosage Calculations*
  • Humans
  • Long-Term Care
  • Models, Statistical
  • Precision Medicine / methods
  • Statistics as Topic
  • Statistics, Nonparametric


  • Analgesics, Opioid