November 10, 2025
Food and Drug Administration
Center for Drug Evaluation and Research
Dockets Management Staff (HFA–305)
Re: Docket No. FDA–2025–D–0610
Development of Non-Opioid Analgesics for Chronic Pain- Draft Guidance for Industry The National Center for Health Research (NCHR) appreciates the opportunity to comment on the Food and Drug Administration’s (FDA) draft guidance Development of Non-Opioid Analgesics for Chronic Pain.
NCHR is a nonprofit think tank that bridges scientific evidence and public policy to ensure that medical products and technologies are proven safe and effective through rigorous, unbiased research. We appreciate the FDA’s goal of reducing reliance on opioids for pain management. Our recommendations focus on the core areas FDA identified for comment: clinical trial design features and methodological and ethical considerations relevant to chronic-pain research.
Clinical Trial Design Features
A. Endpoints That Best Demonstrate Meaningful Benefit
FDA’s guidance should ensure that labeling claims for chronic-pain therapies are based on outcomes reflecting patients’ ability to function in daily life in addition to reductions in numeric pain scores.
Pain intensity is a necessary but incomplete measure. As the CDC Clinical Practice Guideline for Prescribing Opioids for Pain emphasized, long-term success in pain care depends on restoring mobility, sleep, and participation. 1 It is important to note that the SPACE Trial demonstrated that non-opioid regimens achieved comparable or better functional outcomes than opioids. 2
Evidence of meaningful functional improvement such as enhanced physical or social activity should therefore be required to establish benefit. The FDA should make clear in the guidance that pain reduction alone is insufficient for FDA approval; pain reduction should be accompanied by evidence of sustained, meaningful improvement in daily function and quality of life.
B. Study Duration Needed to Assess Sustained Effect and Safety
Chronic pain conditions evolve over time, and short-duration trials often fail to reveal whether initial benefit persists or whether adverse effects accumulate.
The SPACE Trial showed that differences between opioid and non-opioid regimens narrowed over extended follow-up, underscoring the importance of long-term evaluation. The FDA should therefore require adequate long-term follow-up in pivotal studies to determine both durability of benefit and delayed safety outcomes—such as renal, hepatic, cardiovascular, or cognitive effects.2
Trials should collect data beyond initial treatment response, including continued adherence, withdrawal rates, and maintenance of function. Follow-up should extend for a minimum of 12 months or longer where clinically appropriate, to capture both the continued effectiveness over time and delayed safety outcomes such as renal, hepatic, cardiovascular, or cognitive effects. This approach aligns with the FDA’s mandate to ensure that approved therapies offer meaningful and sustained benefit in real-world settings.
C. Trial Populations and Inclusion/Exclusion Criteria
The FDA should require that study populations reflect the patients most likely to use these therapies. Chronic pain disproportionately affects older adults, who often have comorbidities and complex medication regimens that may influence safety and efficacy. 3 . In addition, metabolism changes as we age, and this may affect the safety and effectiveness of dosage levels.
Trials that exclude such populations intentionally or unintentionally limit the generalizability of results and risk underestimating real-world adverse events. The FDA should require adequate representation of patients with varying medical profiles, geographic access, age and functional status, particularly older adults who frequently experience chronic pain and polypharmacy yet remain underrepresented in research. Given the longevity of U.S. adults, patients over 70 years of age should be included whenever possible.
This recommendation aligns with FDA’s Enhancing the Diversity of Clinical Trial Populations -Eligibility Criteria, Enrollment Practices, and Trial Designs guidance, 4 which emphasizes inclusion of older adults and avoidance of arbitrary upper-age exclusions in clinical trials. Ensuring that trial demographics mirror the clinical reality of chronic pain will promote the development of therapies that are both effective and safe for the populations most likely to use them.
By aligning patients’ demographics with the clinical reality of chronic pain, FDA can promote the development of therapies that are both effective and safe for the populations who need them most.
D. Use of Background Pain Therapies
Chronic-pain management rarely relies on a single intervention. Trials that restrict the use of background therapies such as physical therapy, cognitive-behavioral therapy, or non-opioid medications fail to reflect how pain is treated in practice.
Therefore, the FDA should allow and encourage multimodal background treatments (e.g., physical therapy, behavioral interventions, and non-opioid OTC medications) within clinical trials. This approach better reflects real-world practice and helps assess how investigational agents perform alongside standard non-opioid care. It will strengthen the external validity of trial findings and facilitate smoother translation into real-world care.
E. Control Groups, Blinding Methods, and Adaptive Designs
FDA should provide additional guidance on control selection, blinding, and innovative methodologies that balance rigor with feasibility.
Appropriate control groups, whether active comparators, placebo arms, or standard-of-care regimens, are essential to isolate treatment effects and ensure unbiased conclusions. Effective blinding is essential in pain trials due to high placebo responsiveness.
Adaptive and platform trial designs are flexible research approaches that allow investigators to modify or add treatment arms based on emerging data within the same study framework. When used in ways that make unbiased analysis possible, these designs could potentially make chronic pain research trials more efficient, reduce patient exposure to ineffective treatments, and better reflect the realities of real-world clinical care while maintaining scientific rigor and regulatory integrity.
By explicitly addressing these design elements, FDA can enhance the reliability and interpretability of data supporting non-opioid analgesic approvals.
Methodological and Ethical Considerations
1. Do Not Initiate Opioid Use in Chronic-Pain Trials
FDA should prohibit the initiation or maintenance of long-term opioid therapy in clinical trials for chronic pain. Extensive evidence from the CDC and National Academies of Sciences 5 demonstrates minimal sustained benefit in pain relief or functional improvement, but substantial risk of dependence, overdose, and other adverse outcomes associated with extended opioid use. Introducing or maintaining such therapy within non-opioid trials contradicts scientific and ethical standards for participant protection.
2. Do Not Use Enriched Enrollment Randomized Withdrawal (EERW) Design Trials
We have previously expressed our opposition to Enriched Enrollment Randomized Withdrawal (EERW) opioid studies because of their bias, so we oppose the proposed use to evaluate maintenance of effect for non-opioid analgesic drugs as well. EERW designs only randomize patients who are shown to tolerate a drug and find it helpful, thereby excluding non-responders. Such designs are biased because they do not accurately estimate real-world responder rates,true effect size in the full population, or long-term safety in non-responders. Since only patients who tolerate the drug will be randomized, safety data are inevitably biased.
3. Evaluating Long-Term Safety and Misuse Potential
FDA should emphasize that non-opioid therapies must demonstrate both durable benefit and safety over extended use. Trials should evaluate not only adverse events but also potential for misuse, dependence, or interaction with other medications.
The National Academies report underscored that inadequate post-market monitoring of pain therapies contributed to the opioid crisis. The FDA should integrate long-term safety endpoints and real-world follow-up into research requirements as an important strategy to prevent similar knowledge and practice gaps for new analgesics.
To ensure that trial findings apply to real-world clinical practice, the FDA should require protocols to include diverse patient populations representative of those who experience chronic pain, including older adults, individuals with comorbidities, and patients receiving multimodal pain
management.
FDA should encourage hybrid or decentralized trial designs that use telehealth visits, community-based enrollment sites, and home-based data collection to improve accessibility and retention. Integrating data from electronic health records, patient registries, wearable devices, and pharmacy claims can provide additional evidence on treatment adherence, long-term safety, and functional outcomes. These strategies will strengthen scientific evidence.
Conclusions
NCHR strongly supports FDA’s initiative to advance non-opioid options for chronic pain. To
ensure that these therapies deliver meaningful, lasting benefit, FDA should:
– Require endpoints that capture functional improvement, not pain reduction alone;
– Define expectations for long-term follow-up to assess durability and safety;
– Ensure trial populations and designs reflect clinical practice and patient needs;
– Permit multimodal background therapies;
– Clarify standards for control selection, blinding, and adaptive methodologies; and
– Maintain strict ethical safeguards against opioid initiation or prolonged exposure in chronic-pain research.
These steps will help ensure that new non-opioid analgesics are developed and evaluated according to principles of scientific rigor, safety, and meaningful clinical value.
Respectfully submitted,
National Center for Health Research
Endnotes
1 Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for
Prescribing Opioids for Pain — United States, 2022. MMWR Recomm Rep 2022;71(No. RR-
3):1–95. DOI: http://dx.doi.org/10.15585/mmwr.rr7103a1
2 Krebs, E. E., Gravely, A., Nugent, S., Jensen, A. C., DeRonne, B., Goldsmith, E. S., Kroenke,
K., Bair, M. J., & Noorbaloochi, S. (2018). Effect of Opioid vs Nonopioid Medications on Pain-
Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The
SPACE Randomized Clinical Trial. JAMA, 319(9), 872–882.
https://doi.org/10.1001/jama.2018.0899
3 Centers for Disease Control and Prevention. Non-Opioid Therapies for Pain Management.
2025. https://www.cdc.gov/overdose-prevention/hcp/clinical-care/nonopioid-therapies-for-pain-
management.html
4 Enhancing the Diversity of Clinical Trial Populations -Eligibility Criteria, Enrollment Practices, and
Trial Designs: Guidance for Industry. 2020 https://collections.nlm.nih.gov/catalog/nlm:nlmuid-
9918249008406676-pdf
5 National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division,
Board on Health Sciences Policy, Committee on Pain Management and Regulatory Strategies to
Address Prescription Opioid Abuse, Phillips, J. K., Ford, M. A., & Bonnie, R. J. (Eds.).
(2017). Pain Management and the Opioid Epidemic: Balancing Academies Press (US).
https://doi.org/10.17226/24781