FDA’s new plan to study opioids’ effectiveness faces resistance

The Food and Drug Administration’s latest plan to study whether opioids are effective as a chronic pain treatment is facing significant resistance from addiction and pain care experts.

A planned clinical trial, doctors and researchers argued on Wednesday, would not yield significant new information about whether opioids are effective as long-term treatments for chronic pain. The study, some charged, would be biased in favor of opioids’ efficacy — and by extension, biased in favor of painkiller manufacturers.

The pushback came during a Wednesday meeting of a federal scientific advisory committee focused on pain drugs. Throughout the hearing, members of the panel and outside experts lambasted what they viewed as inaction from the FDA, as well as perceived flaws in the clinical trial’s specific design.

“It lacks face validity,” said Maura McAuliffe, a panel member and an emeritus professor of nursing at East Carolina University.

Mary Ellen McCann, another panel member and a Harvard Medical School anesthesiology professor, said the trial represented “an awful lot of work for a very predictable answer.”

The contentious hearing is just the latest chapter in a long-running debate about the appropriate role of opioids in pain treatment, both for current patients and for future patients who wish to use opioids to manage persistent pain.

The FDA’s latest move to reconsider opioids’ effectiveness comes amid the most devastating drug crisis in U.S. history. Over 80,000 Americans die each year from opioid overdoses — though the vast majority are caused by illicit opioids like fentanyl, not common prescription drugs like morphine or hydrocodone.

Because of the crisis, Americans’ attitudes toward prescription opioids have shifted sharply. Many public health and pain treatment experts, in fact, believe that the pendulum has swung too far: Instead of potentially addictive opioids being handed out too easily, they argue, the drugs have become too difficult to access, especially for pain patients who’ve used them for years without issue.

Other doctors, researchers, and lawmakers, however, have questioned whether opioids are still being distributed too broadly, especially to new patients seeking treatment for chronic pain.

Senators from states hit hard by the opioid crisis, in particular, have forcefully urged the FDA to rewrite the drug labels that accompany opioids to remove claims that the drugs are effective treatments for pain in the long term.

“Far too many people develop an opioid addiction that started with a legal prescription, which is why it’s incredibly irresponsible that opioids can be prescribed for long-term use despite the lack of evidence on their effectiveness,” Sen. Maggie Hassan (D-N.H.) said in a statement earlier this year. “I now urge the agency to follow the advice of its external advisers to quickly revise its opioid labeling policies and remove this debunked claim from prescription opioid labels.”

In 2013, in response to the crisis, the FDA pledged to work with pharmaceutical manufacturers to conduct post-approval studies of many prescription opioids currently on the market. Subsequently, pharmaceutical companies formed a joint group called the Opioid PMR Consortium to conduct the research.

Still, in the decade since the FDA first pledged to pursue new research, no such study has been conducted. The agency’s most recent attempt, in 2019, was discontinued after the researchers in charge could not recruit an adequate number of participants.

The new trial relies on a different format known as an enriched enrollment randomized withdrawal study, which the agency hopes will attract enough participants to yield meaningful results. The plan has generated significant criticism, however, including from Sen. Ed Markey (D-Mass.).

“For years, I’ve asked the FDA to consider the impact of its harmful EERW clinical trial methodology on research participants,” he told STAT in a statement. “EERW exposes people to opioids, which could lead to or worsen opioid dependence — fueling our nation’s opioid crisis and downplaying the harmful side effects of medication.”

Under the new study’s design, trial participants would first be switched from their current prescription opioid to extended-release morphine. A randomly selected subgroup would then be switched, without notification, to a placebo group. That group would be tapered off opioids over the course of eight weeks.

That study design, however, has also been criticized on the grounds that it will not yield useful data and that it is biased in favor of preserving access to opioids as a chronic pain treatment.

“These arguments suggest a curious and persistent attachment on the part of the FDA to a statistical design that’s completely at odds with the agency’s professed commitment to a fresh new approach,” Caleb Alexander, a professor of epidemiology at Johns Hopkins University, said during the public comment portion of the hearing.

More specifically, experts criticized the proposed study for its specific focus on hyperalgesia, a paradoxical condition in which some patients become more sensitive to pain after taking opioids, as opposed to other more common potential harms, like addiction.

The eight-week taper period also drew significant condemnation. Removing patients from opioids over such a short span could lead to significant withdrawal symptoms, some doctors argued — making it obvious to both researchers and trial participants which patients have been assigned to the placebo group.

“The design being considered seems to favor the status quo,” said Diana Zuckerman, the president of the nonprofit National Center for Health Research, during the public comment portion. “Is it ethical to require patients who are dependent on opioids to be given a high dose of morphine, followed by a rapid taper, followed by placebo? Won’t that potentially make them even more desperate and more reliant on opioids?”

At one point, Jay Horrow, a Bristol Myers Squibb researcher who was present at the hearing as a drug industry representative, suggested that the research question being discussed was so specific that the FDA should consider dropping it altogether.

“The agency should seriously consider: Is this a [post-marketing requirement] not worth pursuing? In other words, do no study,” he said.

FDA officials conceded that there are few good options.

“Throughout our discussions with OPC, three clinical trial design paradigms were considered,” said Elizabeth Kilgore, a medical officer in FDA’s Division of Anesthetic, Analgesic, and Addiction Products. “Due to the challenges of opioid pharmacology and the patient population, we do not think any of the designs ideally address the research question.”

Ed Silverman contributed reporting.

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.