The challenges facing patients and providers in managing ongoing opioid analgesic therapy for chronic pain are complex. Benefit of long-term opioid therapy, for which there are scant data, must be balanced against myriad potential undesired outcomes, including safety problems, ranging from mild toxicities to overdose and death; inadequate efficacy, which may mean continued patient suffering and unwarranted exposure to toxicities; and misuse of these potent medications. To help patients and providers navigate these challenges and optimize therapy, we present a research agenda in which we first characterize appropriate ongoing opioid prescribing and then describe three areas where quality improvement work is needed: 1) developing brief validated measures of patient-reported safety, efficacy, and misuse that improve outcomes; 2) designing evidence-based algorithms to guide changes in therapy when issues related to safety, efficacy or misuse are identified; and 3) promoting use of patient-centered, multi-modal treatment plans.