Testimony of Diana Zuckerman at the FDA Advisory Committee Meeting on Extended-Release/Long-Acting Opioid Analgesics Post-marketing Requirements

April 19, 2023

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. My comment today will rely on my research experience at Yale and Harvard and in my current position, and my expertise on FDA policies.

Our nonprofit think tank focuses on the safety and effectiveness of medical products and we do not accept funding from companies that make those products.  So we have no conflicts of interest.

What do we know about opioids for chronic pain?

• AHRQ analyzed hundreds of studies and concluded that opioids are associated with “small improvements versus placebo in pain and function, and increased risk of harms at short-term (1 to > 6 months) followup; evidence on long-term effectiveness is very limited, and there is evidence of increased risk of serious harms that appear to be dose dependent.”
• CDC developed guidance that stated “Nonopioid therapies are preferred for chronic pain. Clinicians should maximize the use of nonpharmacologic and nonopioid pharmacologic therapies as appropriate for the patient and specific condition.”

We agree with Commissioner Califf that CDC’s 2022 revised guidance concluded that after all these years there is still a “paucity of evidence on the potential benefits of long-term opioid use.”

Study Design Issues

The consortium has provided impressive experts today.  I agree with many of their statements; however, my perspective and expertise results in different conclusions.

• Enriched Enrollment Data will only be relevant to patients who tolerated and responded well to opioids. That’s the intent of the design.  But that’s why the results will not inform clinical practice in a way that can improve care for chronic pain.  And the results will not inform opioid labeling, which is the major goal.
• We’ve heard this morning how difficult it is to enroll pain patients in a randomized study. Any randomized study is going to delay labeling changes for years. Doesn’t it make more sense to change the labels now based on what we already know?
• The study purports to be a 1 year randomized trial but most of the study consists of an open label study, which we all know has major limitations. The taper (maximum 8 weeks) is too short to prevent terrible withdrawal symptoms for some patients, and the plan to give patients up to 240 mg of morphine is too dangerous. Those design issues can be modified, but they add to questions about the quality of the research design, which is fundamentally flawed.

More Study Design Flaws

• The study is not really blinded because most patients on placebo will know that, as will the clinicians conducting the study.
• What will the study tell us? How generalizable will the results be? Unfortunately, they would not be really generalizable.
• Is it ethical to require patients who were dependent on opioids to be given high doses of morphine, followed by a rapid taper, followed by placebo? In addition to withdrawal, won’t that make them even more desperately reliant on opioids?

Patients deserve better

• The study designs being considered have fundamental flaws and will not be generalizable to most chronic pain patients.
• Will patients be fully informed of the risks of these studies? Will family members be fully informed? Who would be willing to participate if they were fully informed?
• Who will benefit from the results of the study?
  • I don’t think the study could ever be completed, because the design is likely to result in too many placebo patients dropping out.
  • If the study is completed, the results will tell us nothing about the risks and benefits of extended release/long-acting opioids for all patients with chronic pain.
  • The designs being considered seem to favor the status quo, since the patients being randomized for the double blind phase will have responded well to opioids and the general population of patients with chronic pain will not be studied
  • And so, the people who manufacture, sell, or prescribe extended release/long-acting opioids are most likely to benefit, not the patients.

Thank you for serving on this important Advisory Committee and please consider the fundamental changes that would be needed to design a randomized clinical trial that answers the essential questions about which patients will be most likely and least likely to have benefits that outweigh the risks of extended release/long acting opioids.

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