February 15, 2022
I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products. My expertise is based on post-doc training in epidemiology and public health, and as a faculty member and researcher at Yale and Harvard. I’ve also worked at HHS and the White House, and I’m on the Board of the nonprofit Alliance for a Stronger FDA, which educates Congress about the need to support the work of the FDA.
As we all know, the FDA and physicians are under pressure to find ways to reduce the opioid epidemic. That makes today’s meeting especially important. The big question is whether IV tramadol will have benefits that outweigh the risks — not just for individuals but also for public health.
I will focus my remarks on the scientific evidence.
Recent studies have shown that for patients who were not already using opioids, OTC pain relievers can be as effective as an opioid. So why was IV tramadol compared to placebo and compared to morphine, but not compared to effective OTC pain medications? If the risk of addiction can be avoided by giving non-addictive medications, that should always be studied instead of or in addition to a comparison with a placebo. That wasn’t required by FDA but it should have been and that is a fatal flaw in the data provided.
The research indicates that IV tramadol has a delayed onset. Patients given tramadol took a median of 64 more minutes to experience pain relief. They were more likely than those given morphine to use a rescue medication within 2 hours of being given the initial drug.
The sponsor suggested that in clinical practice there is no major delay in pain relief, but that could be due to the placebo effect. That’s why FDA depends on clinical trials for unbiased results when those data are available. The data clearly indicated small differences between placebo and IV tramadol in the first hour after administration, and only moderate differences after 2 hours.
We agree with FDA scientists that the slow action of the drug may lead to a faster acting opioid being given to patients in addition to IV tramadol. Data from Europe has shown that IV tramadol is twice as likely to have “co-use” with other opioids than the oral version of the drug.
The sponsor argued that opioid stacking can be avoided by supplementing with a non-opiate medication, such as ibuprofen. However, as one of the Advisory Committee members pointed out, if patients’ pain can be “adequately managed” with non-opioid OTC medications, then why is an opioid needed? This is a clear acknowledgement of the issue I have raised – if an OTC medication can be as effective as an opioid, there is no documented need to be given IV tramadol!
The sponsor asserted that opioid stacking is standard practice in the hospital setting. I hope you will all agree that that’s not a reasonable justification for approving an opioid that could increase the risks of opioid stacking.
The World Health Organization has noted that the oral version of tramadol has the potential for abuse and/or dependence. Research is needed to determine under what conditions IV tramadol carries those risks. However, the sponsor did not develop any formal evaluation regarding the drug’s abuse potential.
Concerns about post-operative use after leaving the hospital is a legitimate concern despite the unknowns. Although lower than some opioids, what are the safety/efficacy compared to OTC?
Lastly, the proposed indication is broader than what is typical for other immediate-release opioids. According to the FDA, the typical indication for an immediate-release opioid analgesic is “management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.” The Applicant’s proposal to use tramadol IV for moderate to moderately severe pain suggests broader use than the typical immediate-release opioid indication. This is a dangerous broadening of opioid use that absolutely should be avoided.
- opioid analgesics are typically reserved for treatment of opioid-level pain.
- 2) opioid analgesics are typically reserved for treatment of pain when all other treatment options have failed or been excluded.
- These differences between tramadol IV’s proposed indication and the typical immediate-release opioid indication are significant given the known safety concerns of opioids.
Thank you for the opportunity to speak today and please consider these when you vote.
The Committee voted 14 – 8 against approval.