Written By: Pharmacally Medically News Desk
The U.S. Food and Drug Administration released draft guidance this week published in the Federal Register and announced by the agency on September 10, 2025 laying out its current thinking on how sponsors should design late-stage (phase 3) trials of prescription non-opioid analgesics for chronic pain. The goal is clear to accelerate development of safe, effective non-opioid options while making sure new products are evaluated for both analgesic benefit and potential for misuse.
Why this matters
Chronic pain affects millions of people worldwide and has been a reason for decades of opioid prescribing. The FDA’s guidance aims to lower barriers to bringing alternatives specially non-opioids to market by clarifying expectations about trial population, endpoints, comparators, safety evaluation, and how to account for misuse and abuse potential in product development. For sponsors, clinicians, and patients, clearer regulatory expectations should shorten development uncertainty and ideally speed access to safer treatment options.
What the guidance recommends
Scope: The document focuses on prescription non-opioid analgesics for chronic pain and provides nonbinding, practical recommendations for phase 3 trials. It is a draft: comments from industry and other stakeholders are expected during the public comment period.
Patient population and diagnoses: Trials should enroll patients with well-characterized chronic pain conditions and use clear diagnostic and baseline pain-severity criteria to limit heterogeneity. Enrichment strategies such as prior responsiveness to mechanism-based treatments are discussed as options to improve signal detection.
Primary endpoints and measurement: The FDA emphasizes patient-reported pain intensity and pain interference as primary outcomes, measured with validated instruments and analyzed using pre-specified, clinically meaningful thresholds. The guidance recommends co-measuring function and quality of life to capture broader benefit. Rescue-medication rules and how to handle missing data receive specific attention.
Safety and abuse/misuse assessment: evaluate abuse, misuse, diversion and dependence potential early and across development. The FDA asks sponsors to include preclinical assessments, human abuse-liability studies where relevant, and post-approval risk-management planning. Importantly, the agency wants safety evaluations to consider the product’s risk profile relative to available opioid alternatives.
Statistical considerations and multiplicity: The guidance details analytic plans for primary and secondary endpoints, multiplicity control, handling of rescue medication effects, and sensitivity analyses to support robust conclusions of efficacy and safety.
Expedited programs: The FDA states how existing expedited programs (fast track, breakthrough, accelerated approval) might apply, and what evidence would be needed to support more rapid development pathways while maintaining patient safety.
Practical implications for sponsors
Expect to design trials with clear, patient-centered endpoints and robust safety/abuse assessments up front. Early engagement with the FDA (pre-IND, end-of-phase-2 meetings) is likely to reduce later surprises.
Mechanism-specific enrichment and well-defined diagnostic criteria can make trials more efficient but must be justified and replicable.
If a candidate shows lower misuse potential than opioids, sponsors should document that advantage with both clinical and abuse-liability data that comparative framing may influence both label language and payer uptake.
Trial design and comparators
Sponsors are encouraged to use randomized, controlled designs with placebo and/or active comparators depending on the condition and standard of care. The guidance outlines when an active-comparator trial may be preferable and how to select appropriate doses and duration for chronic use. Parallel-group designs remain the standard for registration-directed trials.
What clinicians and patients should know
The draft guidance signals a regulatory push to diversify pain-management options beyond opioids. That doesn’t mean changes overnight: draft guidances shape development pathways but must be followed by successful trials and approvals.
For patients, the long-term promise is more choices that balance pain relief and lower addiction risk. The guidance also underlines that any new therapy will need careful post-market monitoring to confirm real-world safety and misuse profiles.
Context: recent FDA activity on pain therapies
This draft follows a series of FDA actions aimed at addressing overdose and opioid misuse, including recent labeling changes and guidance on opioid formulations and abuse-deterrence. It also complements approvals in the non-opioid space like Journavx and Tonmya earlier this year, as regulators and developers look for alternatives to traditional opioids. Together, these steps reflect a broader policy push to reduce opioid-related harms while maintaining effective pain care.
Limitations and next steps
The guidance is draft and nonbinding. Stakeholders have the opportunity to comment during the public comment period listed in the Federal Register. Sponsors should review the full FDA text for technical details (statistical plans, exact endpoint definitions, recommended study durations) and plan early engagement with regulators.
The FDA’s draft guidance clarifies how to design registrational chronic-pain trials for non-opioid analgesics, with a strong emphasis on patient-reported outcomes, rigorous safety and abuse potential assessment, and trial designs that can show clinically meaningful benefit compared with current care. If followed, the recommendations should make it easier for developers to generate the evidence needed for approval and for clinicians and patients to get safer alternatives to opioids.
Reference
Development of Non-Opioid Analgesics for Chronic Pain; Draft Guidance for Industry, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, September 2025. Content as of 09/11/2025, Docket No. FDA-2025-D-0610, Comment period ends November 10, 2025.
Press Announcement: FDA Issues New Guidance to Expand Non-Opioid Options for Chronic Pain, Curb Misuse, U.S. FDA, September 10, 2025