As the tragic consequences of the opioid epidemic continue to mount, some experts are focusing on a creative new approach to treating opioid use disorder (OUD). At a planning meeting held in November 2019, experts met to consider strategies for evaluating medications that have not yet been used to treat OUD. Sponsoring the meeting was the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), a public-private entity, in partnership with the US Food and Drug Administration.
This article summarizes the results of that meeting, specifically clinical trial considerations for studying emerging treatments for OUD. These treatments address targets beyond the μ (mu)opioid receptor (MOR), a key component of the receptor system responsible for regulating the body’s everyday response to pain, among other functions.
Opioid Agonists and Antagonists
The current standard of care for OUD includes using one of three approved medications: either methadone or buprenorphine, the two MOR agonists used therapeutically; or the MOR antagonist, naltrexone.
Opioid agonists and antagonists act in opposite ways. Opioid agonists, such as methadone, bind to and activate an opioid receptor. The receptor responds to various agonists in ways that are similar, but not identical. An opioid antagonist, such as naloxone, blocks a receptor, preventing the receptor from responding to another opioid, such as heroin.
The illicit attraction of opioids stems from their action on the major receptor for opioids the body produces on its own; endogenous opioids that lead to pain relief and feelings of pleasure.
The illicit attraction of opioids stems from their action on the major receptor for opioids the body produces on its own; endogenous opioids that lead to pain relief and feelings of pleasure
Problems With Current Treatment Approaches to OUD
Researchers are looking for new drugs to treat OUD because of drawbacks with currently available MOR-based medications:
- Induction and dosing procedures differ for each medication
- Policy and regulatory barriers exist, as do barriers related to patients
- Many patients find it difficult to access treatment and to stay in it
So, it’s not surprising that more than half of patients receiving MOR-based treatment discontinue their medication, or relapse, or both, within six months.
Options in Clinical Trials
To expand OUD treatment options would mean either adding to existing MOR-based programs, or coming up with novel stand-alone treatments. But developing any new treatment would require randomized clinical trials (RCTs)—and the design of these trials for novel treatments would likely need to differ from the design of existing trials involving medications for opioid use disorder (MOUDs).
Participants in the November 2019 meeting discussed a trial design far afield indeed from those used in current trials. For an eyebrow-raising group is being considered for investigation: cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutic agents, such as vaccines.
A radical approach? Some might think so. But the publication points out that novel treatments 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 ACTTION Consortium for Addiction Research on Efficacy and Safety (CARES) included participants who were working at universities and government agencies, and who had relevant expertise. No pharmaceutical company participated directly.
The Core Stages
The first step in study planning, according to the group’s participants, is to specify the target of the interventions—the exact core stage OUD treatment and recovery. Each stage has unique treatment needs that would influence study design.
- Current active use of opioids
- Acute abstinence, nonmedically supervised withdrawal, and/or supervised medical withdrawal
- Early recovery (eg, less than six months of abstinence with or without opioid agonist or antagonist treatment)
- Sustained recovery (eg, abstinence from illicit opioid use for at least 6 months)
Important planning considerations include whether the novel treatment would be adjunctive to an existing MOUD that has been approved by a regulatory agency. Patients with physical dependence and withdrawal symptoms may need this. Adjunctive treatment, including harm-reduction strategies (such as naloxone training to prevent fatal overdose) would be essential for clinically unstable patients.
Critical Design Elements
In evaluating the design of trials for novel OUD treatments, participants identified four key items:
Stage of treatment to target
Will it be when the patient is seeking treatment? During early abstinence/detoxification? During long-term recovery?
Role of treatment
Will it be adjunctive, within existing OUD treatment? Or independent?
What will determine primary outcomes (ie, the measure to indicate whether treatment was beneficial)—patient preferences that assess opioid use, including changes in patterns of use? Treatment retention? Global functioning? Quality of life?
The adverse-event category should include the potential for opioid-related relapse or overdose—especially for patients who are not taking a MOR medication.
Additional Comments and Recommendations
This review paper, which has 27 authors, includes a Table with useful details about each of the four atypical medications: rationale for use, key challenges, potential exclusion criteria, and outcomes. A Box summarizes key recommendations and considerations for clinical trials for evaluating emerging non-MOR treatments for OUD.
Some important points:
- Some patients may need adjunctive treatment, such as naloxone training
- Some may need a MOUD that has been approved by a regulatory agency
- People with lived experience may be useful in helping planners guide the choice of primary and secondary outcomes
- Registering the prospective trial in publicly accessible databases
- Including in the registration primary and secondary outcomes, hypotheses, and study objectives, before starting data collection
- Giving priority to specifying the stage in OUD treatment that the intervention will target
- Measuring abstinence and patterns of opioid use, with clear responder criteria specified for each
- In trials, especially early treatment trials, frequently assessing opioid-related adverse events
- Determining whether the emerging treatment will be adjunctive to, or independent of, existing OUD treatments
Ideally, the study should be double-blind and randomized, with placebo group (when ethically appropriate) or an active control comparison, or both. Stand-alone interventions should be compared to an existing evidence-based OUD treatment (eg, MOUD).
- Participants should be a representative, diverse population
- Exclusion criteria should not be too restrictive
- A standard placebo-controlled trial may be inappropriate (the publication discusses alternatives)
The opioid crisis continues to escalate, and this review paper emphasizes the need for research and new answers. The authors comment:
Promoting a unifying structure of best research practices as described in the present review will help the field build consensus as to the appropriate methodological strategies, and prevent otherwise promising targets from languishing or being abandoned because of problematic study designs rather than true lack of efficacy or lack of uptake. In the context of a continually evolving and escalating opioid crisis, research must prioritize both innovation and efficiency. The field and the patients with whom we work will be best served by maintaining an open dialogue to develop a consistent methodological framework for the assessment and treatment of OUD.
The meeting and resulting review paper were funded through a partnership between ACTTION and the U.S. Food and Drug Administration (FDA).
Kiluk BD, Kleykamp BA, Comer SD, et al. Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review. JAMA Psychiatry. 2023;80(1):84-92. doi:10.1001/jamapsychiatry.2022.4020