USFDA Draft Guidance: Development of Non-Opioid Analgesics for Chronic Pain
- Sharan Murugan
- 26 minutes ago
- 2 min read
The U.S. Food and Drug Administration (FDA) has released a new draft guidance "Development of Non-Opioid Analgesics for Chronic Pain" on September 11, 2025, focused on the development of non-opioid analgesics for chronic pain management. This draft guidance builds upon the mandates of the SUPPORT Act and FDA’s commitment to combating the opioid crisis by supporting the development of safer, effective alternatives.
1. Introduction
The guidance outlines FDA’s vision to:
Foster innovation in non-opioid pain therapies.
Reduce reliance on opioids, thereby minimizing risks of misuse, addiction, and overdose.
Provide clear regulatory pathways for phase 3 clinical trials of non-opioid analgesics targeting chronic pain.
2. Background
Chronic pain, typically defined as pain lasting longer than three months, affects millions worldwide and remains one of the leading causes of disability. Despite available treatments like NSAIDs, gabapentinoids, SNRIs, and topical anesthetics, many patients remain undertreated, leading to inappropriate reliance on opioids.
FDA emphasizes the urgent public health need to expand treatment options through mechanism-driven drug development, focusing on novel therapeutic targets, biomarkers, and patient phenotyping.
3. Development Programs for Non-Opioid Analgesics
A. Establishing Indications
Condition-Specific Indication: Focused on a single chronic pain condition (e.g., diabetic neuropathy).
Group-Specific Indication: Targeting a group of related conditions with shared pathophysiology.
General Chronic Pain Indication: Broadest claim, covering all chronic pain conditions, requiring strong mechanistic evidence and robust trial data.
B. Trial Design Considerations
Randomized, double-blind superiority trials are the gold standard.
12-week treatment periods are typical, but shorter durations may be acceptable in severe pain conditions.
Enriched Enrollment Randomized Withdrawal (EERW) trials may be considered, though they have limitations in generalizability.
Trials should carefully manage rescue medication use and collect robust data on discontinuations.
C. Effectiveness Measures
Primary endpoints should be patient-reported pain intensity scores, typically via an 11-point numerical rating scale.
Secondary endpoints include:
≥30% or ≥50% reduction in pain.
Changes in functional status, sleep quality, or daily living activities.
Rescue medication usage.
D. Evaluating Opioid-Sparing Benefits
The guidance introduces frameworks for demonstrating how non-opioid therapies can:
Avoid opioid initiation.
Eliminate ongoing opioid use.
Reduce opioid dosage while maintaining pain control.
These outcomes, if supported by robust trial data, may be reflected in product labeling.
E. Safety & Statistical Considerations
Sponsors must evaluate abuse potential, especially for CNS-active drugs.
Larger safety databases may be required for new molecular entities.
Analyses should use intent-to-treat principles, adjust for baseline covariates, and handle missing data with robust sensitivity analyses.
F. Expedited Programs
Non-opioid analgesics designed to avoid or reduce opioid use may qualify for expedited programs such as Fast Track, Breakthrough Therapy, Priority Review, or Accelerated Approval—though FDA notes challenges in identifying surrogate endpoints for pain.
4. Innovative Approaches
The FDA encourages sponsors to explore:
Adaptive and Bayesian trial designs.
Decentralized trials and digital health technologies.
Biomarkers to predict treatment response.
Real-world evidence (RWE)Â to complement traditional clinical data.
This draft guidance represents a critical step in advancing the development of safe, effective non-opioid analgesics for chronic pain. By clarifying expectations around trial design, endpoints, and regulatory flexibility, FDA is signaling strong support for industry innovation in tackling one of the most pressing public health challenges—the opioid crisis.
Stakeholders are encouraged to submit comments within 60 days of publication in the Federal Register, helping refine this framework for future drug development. Explore more and access the draft guidance: