May 5, 2025
I’m Dr. Diana Zuckerman, president of the nonprofit National Center for Health Research. We do not accept funding from pharmaceutical companies or any entities with financial interests in our work, so I have no conflicts of interest.
Thank you for the opportunity to share my views at this very important meeting. I’m speaking as a scientist trained as a post-doc in psychiatric and psychosocial epidemiology at Yale Med School, and as someone who has worked extensively to train patients to understand the risks and benefits of medical products. On a personal note, a few years ago I was prescribed 3 months of opioids after 2 different surgeries, with absolutely no warnings about long-term use. And, 2 days ago I was with a hospitalized relative who was told nothing about the risks when she was prescribed opioids after surgery. When I was prescribed opioids, I knew to switch to acetaminophen very quickly, but I know from these experiences how important FDA labeling and warnings are, and the harm done when labeling changes are delayed.
Today I will focus on the 3 studies discussed at this meeting as well as the impact of the current labeling that continues to mislead patients and physicians about the benefits and risks of opioids for long-term use.
Labeling
If the FDA does not improve the accuracy of its labels on all opioids, patients will continue to spiral into opioid addiction through no fault of their own.
I want to thank the FDA for previously changing the labeling indication from “moderate to severe pain” to only include “severe pain.” However, the current labels are still much too broad because they don’t restrict use for chronic pain, and they imply that these drugs have benefits that have never been proven. Labels should have clear warnings to help ensure that the benefits outweigh the risks for all patients included in the indication.
As you know, almost all medications – whether over the counter or prescription — include a maximum recommended dose, but opioids do not. That must be changed, even if the maximum recommended dose includes exceptions in specified rare cases.
Studies provided by the Consortium
I’ve taught courses and training in study design and data interpretation, and I have two major criticisms of the studies you’re reviewing today.
The first is the definition of opioid use disorder as used in these studies. The DSM-5 has a very good definition of mild, moderate, and severe OUD. The criteria include physiological and psychological symptoms as well as the impact on a person’s social functioning and daily living. These DSM-5 criteria are widely accepted by experts in the field. But they create a problem for those interested in selling or prescribing opioids: As you’ve heard and can see on page 54 of the Consortium document, it states that that the DSM-5 criteria shows a 22.5% incidence of OUD among patients prescribed Extended Release/Long-Acting opioids in Study 3033-1. To reduce these disturbing numbers, the Consortium worked with researchers to modify the definition of OUD, in 2 ways:
- It includes only moderate and severe OUD, eliminating mild OUD.
- It “adjusts” for pain.
This biases the results of the studies in two inappropriate ways:
- Mild OUD is a very negative outcome and may worsen over time, with more severe opioid dependence and dysfunction in daily life. Any clinician will give you many examples of mild OUD becoming moderate or severe over the years. I challenge any unbiased researcher to provide evidence that contradicts that.
- The DSM-5 criteria are already adjusted for pain, so it makes no sense to revise it to add another so-called adjustment for pain. If you adjust for pain again when measuring OUD you are undermining the validity of the OUD outcome measure. The Consortium’s “adjustment for pain” in their data analysis reduces the number of patients categorized as having OUD but it does not reduce the number of patients who actually have opioid use disorder, which, as FDA noted, can be related to the desire to avoid withdrawal pain, as well as the desire to feel euphoric.
There are other problems with the studies as well. For example, the retrospective study had a lot of missing data, making the results difficult to interpret. Medicaid patients often go in and out of Medicaid coverage, and patients with private insurance change policies. That’s why it is so difficult to study U.S. opioid patients over long periods of time. It is much easier to evaluate in countries with national health plans, so let’s take a look again at the study Dr. Kolodny just shared by Koplovitch et al. of more than 32,000 patients in Canada. They found that the number of opioid-related deaths grew over the years, reaching a total of approximately 2.5% deaths for men in the12 years after starting opioid therapy for chronic pain, and plateauing just below 1.5% for women in the 8 years after starting opioid therapy for chronic pain.
That’s a small percentage but it’s a lot of people who died. And we need to consider the percentage of deaths and OUD in the context of the unproven benefits of long-term opioid use. Research indicates that many of these patients would have managed pain without long-term use of opioids if they had been encouraged to use non-opioid medications when the pain first started after their surgery or accident. Given the lack of evidence of the benefits of using opioids for chronic pain, 22.5% of people with OUD and 2.5% of men and 1.5% of women dying from long-term opioid use should be considered unacceptable because FDA law requires that there is evidence for safety and efficacy for the specific indication.
The U.S. Agency for Healthcare Research and Quality (AHRQ) reviewed 115 randomized controlled trials and 40 observational trials on opioid’s benefits. That federal agency’s report concluded that “In observational studies, opioids were associated with increased risk of an opioid abuse or dependence diagnosis, overdose, all-cause mortality, fractures, falls, and myocardial infarction [compared to] no opioid use” and that the risk was dose-dependent for almost all those outcomes. The report also concluded that “No RCT evaluated intermediate- or long-term benefits of opioids versus placebo” and that “Limited evidence indicated no differences between long- and short-acting opioids in effectiveness, but long-acting opioids were associated with increased risk of overdose.”
In conclusion, we should more seriously consider conclusions from the AHRQ review as we weigh the implications of the Consortium data. Many years ago the FDA promised to revisit the evidence to regarding the risks and benefits of extended release and other long-term opioid use. Despite black box warnings, the FDA is not providing physicians or patients with all the information that they need to make well-informed decisions. On Saturday, I heard medical staff tell my hospitalized relative upon discharge after surgery, “Don’t worry about pain, we can give you medication to control the pain.” I then picked up her prescriptions, which included opioids. At the hospital pharmacy, I was not told about the risks or benefits of opioids for long-term use and there were NO written warnings on the bottle of pills. I respectfully ask this Committee to urge the FDA to rectify that situation.