Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder

Abstract

ImportanceNovel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines.ObservationsConsensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications.Conclusions and RelevanceApplying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

From Taboo to Treatment: The Emergence of Psychedelics in the Management of Pain and Opioid Use Disorder

“…117 Kiluk and colleagues also reviewed clinical trial design challenges and opportunities for emerging treatments in OUD. 118,119 Addressing the existing methodological limitations is imperative for improved study design and a better understanding of the various possible uses for psychedelic medications for chronic pain and OUD, conditions with limited treatment options.…”

“…146 Guidance suggests additional measurement of long term follow up for return to use or later overdose events which would shed light on other possible risks for psychedelics. 119 Notably, rigorous reporting of adverse events across psychedelic studies has varied and deserves attention in future trial design. 143 Other serotonergic psychedelics have cardiovascular risks, including QTc prolongation and possible valvular disease, warranting adequate screening and monitoring of participants with OUD, whose QTc interval may be prolonged at baseline, and who may have underlying cardiac disorders as a consequence of intravenous drug use.…”

Vaccines to Treat Substance Use Disorders: Current Status and Future Directions

“…However, these medications have not been fully successful in addressing the alarming increase in opioid abuse in recent times. Moreover, they can be associated with significant side effects, limiting their overall effectiveness and acceptance in some cases [ 50 , 51 ]. A vaccine-mediated pharmacokinetic strategy could combat the deadly and addictive effects of opioids.…”

Will the promise of translational neuropsychopharmacology research ever deliver? The lion’s roar; the kitten’s purr

“…Esketamine is another revolutionary example; it is a fast-acting antidepressant with fundamentally different underlying mechanisms of action than the decades-old, delayed-action drugs based on inhibiting serotonin or norepinephrine uptake [8]. For people suffering from opioid use disorder (OUD), several drugs that target the endogenous μ-opioid receptor system [9], such as buprenorphine, naltrexone, and methadone, have been approved. Moreover, neuromodulatory approaches such as transcranial magnetic stimulation, transcranial direct current stimulation, focused ultrasound, and deep-brain stimulation have a promising future for treating neuropsychiatric disorders [10,11].…”