In May 2026, FDA issued two draft guidances regarding the development of non-opioid analgesics for acute pain (Development of Non-Opioid Analgesics for Acute Pain) and chronic pain (Development of Non-Opioid Analgesics for Chronic Pain). While the first guidance is a revision of a previous guidance issued in 2022, the latter is a new guidance.
For Sponsors working on analgesic therapeutics, especially treatments that can potentially be used instead of opioid analgesics, these new guidances are welcome additions. They outline the required studies and data necessary to demonstrate efficacy and safety of new analgesics in both the acute and chronic pain settings.
While this is the good news, it becomes increasingly clear in reading the guidances that the development of analgesics is not straightforward, especially when they are being developed for multiple or more generalized pain indications.
Both guidances recommend that each indication be developed separately, and both provide guidance on when a more generalized pain indication may be appropriate and what data are necessary to support this.
While the new standard for approval at FDA may be one adequate and well controlled study with confirmatory evidence, both guidelines clearly state that, for pain indications, the general requirement is two adequate and well controlled studies for the first indication. If the mechanism of action of the approved therapeutic is the same in additional indications, follow-on indications may include one adequate and well controlled study with the prior approval providing the supporting evidence.
As an example, where the therapeutic has a well-established mechanism of action in acute pain and the mechanism is applicable to multiple pain indications, it may be possible to obtain a general acute pain indication with at least two clinical trials, each in a different pain indication. For a therapeutic with a novel mechanism of action, it is anticipated that studies in more than two pain indications would be required for an acute generalized pain indication.
Chronic Pain Indications
Chronic pain is defined as pain that persists longer than 3 months. The guidance recognizes that chronic pain can be caused by many different conditions and distinct mechanisms. Mechanistic descriptors can characterize chronic pain. The most commonly used descriptors are nociceptive, neuropathic and nociplastic.
Nociceptive pain is due to the activation of receptors associated with the detection of potentially tissue-damaging noxious stimuli and can be visceral or somatic. Examples include burns, contusions, sprains, osteoarthritis, and postoperative (surgical) pain.
Neuropathic pain is caused by damage or disease affecting the somatosensory nervous system, leading to misfired pain signals, and can be further divided into peripheral neuropathic pain or central neuropathic pain. Common symptoms include burning, shooting, or electric shock-like stabs, tingling, numbness, and extreme touch sensitivity (allodynia). Diabetes, infections such as shingles or HIV, trauma or surgery, or medical treatments such are chemotherapy are common causes of neuropathic pain.
Nociplastic pain is chronic pain caused by altered nervous system processing rather than ongoing tissue damage or nerve injury. Fibromyalgia, irritable bowel syndrome (IBS) and tension-type headaches and migraines are common conditions involving nociplastic pain. (Thapa, R; Ang, D; Nociplastic pain: a practical guide to chronic pain management in the primary care setting CLINIC JOURNAL OF MEDICINE VOLUME 92 • NUMBER 4 APRIL 2025)
To further complicate matters, many chronic pain conditions may have more than one mechanism and are considered to be of a mixed pain origin.
Chronic pain indications can target a specific pain condition (condition-specific), a group of chronic pain conditions (group-specific), or all chronic pain (general chronic pain) as described in more detail in the guidance.
As the guidance points out, historically, chronic pain indications have been condition-specific (e.g., painful diabetic peripheral neuropathy [pDPN]). If two adequate and well controlled studies are conducted in pDPN and the therapeutic is approved for pDPN, it is possible that a second indication for which the mechanism is similar, such as post-herpetic neuralgia (PHN) could be approved based on one adequate and well controlled study in PHN with supporting evidence from the pDPN program. It is also possible that the development program could include one adequate and well controlled study in each indication and each study would provide supportive evidence for the other. For a potential approval in both indications, both studies would need to be positive and convincing.
For therapeutics being developed for group-specific indications or chronic pain, the development program is more complex, and pain pathology also plays a role. For chronic pain indications with shared pain pathology, it may be possible to obtain a group-specific indication (e.g., neuropathic pain) for a therapeutic with a well-established mechanism of action and at least two adequate and well controlled studies, each in a different pain indication. Obtaining a general chronic pain indication may be very challenging and will require building upon data in condition-specific and group-specific indications.
Reduction or Replacement of Opioid Analgesics
As the focus of the development of new therapeutics for the treatment of pain may be to reduce or replace the use of opioid analgesics, it is important to understand these sections of the guidances and how data on the reduction of opioid use might be presented in product labeling. Both guidances discuss the decrease and elimination of opioid use. The important take home message here is that there needs to be a statistically significant difference from the control group in order for the finding of decrease and/or elimination to be part of a labeling claim.
Clinical Program and Long-Term Safety Considerations
Also of interest is the statement in the guidances that, depending on the safety profile of the therapeutic and the study design, it may be necessary to have more patient exposure than is recommended in the current ICH guideline E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of 670 Non-Life-Threatening Conditions (March 1995). While this statement and the statement that these types of products are generally not approved using accelerated approval pathways may be met with some negativity, I, for one, congratulate FDA on being up front regarding these challenges. While we in industry may need to plan for a larger clinical program, knowing this at the clinical plan development stage is a great benefit.
The guidances are in agreement with the recommendation that pain intensity should be the primary efficacy endpoint. Both guidances discuss study designs, recommended designs, and the pros and cons of each alternate. While this points out some of the challenges in conducting these studies, it is also helpful to know that FDA realizes that there is no perfect study design, there are pros and cons to each, and we as drug developers need to pick the designs that are fit for purpose for the therapeutic we are developing.
Last but not least, both guidances invite Sponsors to interact with FDA to discuss and achieve agreement on the development programs. This is one of the most important take home messages. Early communication, gaining input on study design, and discussing results and next steps with regulators will aid in timely product development.
We at PROMETRIKA are uniquely poised to help our clients develop their analgesic products with services including study design, regulatory interactions, and clinical trial execution.
