FDA Issues Guidance for Non-Opioid Acute Pain Relief

(Arek Socha, Pixabay)

10 Feb. 2022. The Food and Drug Administration released for comment review processes for new non-opioid drugs to relieve acute or temporary pain episodes. The draft regulatory guidance aims to provide drug makers with the agency’s latest thinking on development, product labeling, and expedited review programs for non-opioid pain relief drugs.

FDA’s document defines acute pain as “pain, lasting up to 30 days, typically in response to some form of tissue injury, such as trauma or surgery.” Opioid drugs are still prescribed for acute pain in many cases, which can lead to dependence or abuse. In the U.S., abuse of opioid pain drugs continues at rates reaching emergency levels, along with heroin and fentanyl sold on the street. Overdose deaths from opioids, according to National Institute on Drug Abuse, reached nearly 50,000 in 2019, with the economic burden from abuse of prescription pain drugs totaling $78.5 billion a year. In addition, a 2018 law calls for FDA to develop regulatory guidance addressing the need for non-opioid pain drugs.

“Preventing new addiction through fostering the development of novel non-opioid analgesics is an important priority for the FDA,” says Patrizia Cavazzoni, director of the Center for Drug Evaluation and Research, in an FDA statement. “The guidance reinforces the agency’s commitment to confront opioid misuse, abuse, and addiction by taking steps to help those with acute pain get access to improved non-opioid treatment alternatives.”

The document spells out features of clinical trials sought by FDA for testing non-opioid pain relief drug candidates. In general, FDA calls for randomized, double-blind, superiority trials, testing repeated doses of a new drug candidates for at least 24 hours. Primary endpoints or main target medical outcomes of the trials, says the document, should be changes in measures of pain intensity, such as sum of pain intensity difference, for the duration of the treatment, tested against a placebo or other pain relief drug.

Measure reductions in opioid use

FDA’s proposed guidance recommends taking frequent pain intensity measures and pre-defined time points, e.g. every hour or four hours over a specified period, beginning as close as possible to the start of a pain episode, such as immediately after surgery. The document also calls for pre-specifying rescue medications designed to quickly relieve pain. Trial protocols, says the agency, need to spell out frequency, quantity, and pain thresholds allowed for rescue pain relievers, since use of rescue drugs in comparison groups could diminish the measured effects of test drugs.

FDA’s discussion of endpoints also covers reduction in opioid use by patients. The document says clinical trial protocols may note quantified reductions in numbers of doses overall or per day, or fewer days using opioids. Endpoint outcomes may include as well reductions in adverse effects from reduced opioid use. Measuring safety of new non-opioid drugs in trials, says the guidance, will depend on novelty of the drug’s mechanism, with new types of pain drugs needing to show more evidence than extensions of existing drugs.

FDA’s guidance spells out different claims drug developers can make about new pain drugs reducing use of opioids: eliminating use of opioids for pain relief, discharge from medical facilities without opioids, and reduction of adverse effects associated with opioids. In addition, the document gives examples of data needed to back up those claims, and encourages follow-up studies that track longer-term effects, including extended benefits of non-opioid pain relief.

The draft guidance spells out FDA programs for expedited review that could apply to non-opioid pain drug candidates. The document notes, however, that pain intensity is a subjective measure provided only by the patient, thus surrogate endpoints often used in expedited reviews might not fit as well for these drugs. But reduced abuse potential of a proposed non-opioid pain drug may be considered if applicable.

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