FDA issues guidance on non-opioid drug development for chronic pain

The US Food and Drug Administration (FDA) on Tuesday issued draft guidance to promote the development of non-opioid pain medications for chronic pain. The document addresses key topics, including trial design, participant enrollment criteria, and how sponsors can prove their pain medication helps reduce opioid use.

The guidance specifically details the agency’s thinking on indications that such analgesics could target, potential clinical trial designs, the drugs' ability to reduce reliance on opioids, and how sponsors can use expedited programs to get their drugs through the premarket review process.

“Physicians need more alternatives to opioid medications for patients suffering from chronic pain,” said FDA Commissioner Marty Makary in a statement. “FDA can help by providing clear guidance like this, which makes regulatory pathways more predictable for innovators and drug developers, enabling effective, lower-risk therapies to quickly reach the millions of Americans living with chronic pain.”

FDA notes that drugmakers typically consider indications that target specific pain conditions when developing their drugs, but they can look for broader indications. The agency said that sponsors can develop their drug for a specific condition and group before looking to have their drug approved for a broader population.

While FDA generally wants at least two well-controlled trials to evaluate a drug's safety and effectiveness, in certain circumstances, it said it is willing to consider a single well-controlled trial if the sponsor is able to provide additional confirmatory data and provided several examples of when a single trial may be sufficient.

“Sponsors intending to establish substantial evidence of effectiveness using one adequate and well-controlled clinical investigation plus confirmatory evidence should consult FDA in advance to discuss the appropriateness of such an approach for their development program,” said the agency.

FDA also acknowledged that its understanding of pain pathophysiology and analgesic mechanisms is limited, which limits its ability to leverage information across patients suffering from chronic pain.

“Although pain classification systems are based on data suggesting similar pain pathophysiology across conditions within a particular pain category, these systems alone may not provide sufficient justification for the use of mechanistic data as confirmatory evidence of effectiveness, as in the case of mixed pain conditions (e.g., chronic low back pain, chronic post-surgical pain) or for drugs that act on pathophysiology present in multiple pain categories (e.g., central sensitization, inflammation),” said FDA. “Furthermore, based on existing knowledge, even within well-defined mechanistic categories, such systems have not been sufficiently reliable to predict the analgesic response to a drug across all conditions within a category.

“This may, in part, relate to the common occurrence of mixed pain mechanisms, even for conditions within a category, or to differences in susceptibility to a drug’s specific mechanism(s) of action for conditions within a category,” the agency added.

In terms of general trial design, FDA stated that sponsors should aim to conduct at least one randomized, controlled, double-blind, parallel group superiority trial, and an additional randomized study. It said the design and number of additional randomized studies required will depend on the indication of the drug.

FDA also emphasized that the clinical trial populations enrolled by sponsors should reflect the patient population that the drugs are intended to treat and should consider that when determining trial eligibility criteria.

“Sponsors should leverage established diagnostic criteria, when available, to identify participants with the chronic pain condition of interest (e.g., American College of Rheumatology criteria for fibromyalgia, osteoarthritis of the hip, and osteoarthritis of the knee),” said FDA. “When such diagnostic criteria do not exist, sponsors should provide scientific justification for the enrollment criteria defining the study population.

“Additionally, the enrollment criteria should select participants with pain of appropriate intensity and chronicity (e.g., at least 3 months) to minimize the potential impact of factors such as the spontaneous resolution of pain or excessive fluctuation in pain, which may complicate the detection of a treatment effect,” the agency added.

The guidance addresses several other key topics such as Safety and effectiveness considerations, and how to evaluate whether the drug has been able to reduce opioid use.

FDA noted that the guidance fulfills requirements under the Substance Use–Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act.

Stakeholders can comment on the guidance on www.regulations.gov under docket no. FDA-2025-D-0610 through 10 November.

Draft guidance

FDA issues guidance on non-opioid drug development for chronic pain

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