By Pat Anson, PNN Editor

Seven years ago, Sens. Ed Markey (D-MA) and Joe Manchin (D-WV) wrote a letter to the acting administrator of the Drug Enforcement Administration, asking for stricter limits on the production of opioid pain medication. They joined with over a dozen of their colleagues with another letter in 2017, asking for the same thing.

The letters said too many Americans were becoming addicted to opioids and that there was “insufficient research body about the effectiveness of opioids when used long term.”

The letters and a personal meeting with the DEA administrator had an impact. The agency embarked on a years-long campaign to slash production quotas for opioid manufacturers, which now stand at their lowest levels in two decades. Since their peak, DEA production quotas have fallen by 65% for oxycodone and 73% for hydrocodone. And the U.S. now has chronic shortages of opioid medication.    

Flash forward to 2023, and Sens. Markey and Manchin are at it again, but in a different way.  

In a new letter --- this time to the Food and Drug Administration – the senators called on the agency to scrap plans for a new clinical trial that could help prove whether opioids are effective long term – the very thing the senators said there was “insufficient research” on just a few years ago.

“Other studies have already evaluated prolonged opioid use,” Markey and Manchin wrote in their letter, which was first reported by STAT.

At issue is an FDA plan to use a research design known as enriched enrollment randomized withdrawal (EERW) to study the use of opioids by patients with chronic pain – persistent pain that lasts for over three months.  Such a study would require patients on extended-release morphine to either continue taking the medication or be unwittingly switched to a placebo – which would essentially amount to a rapid taper with no pain relief.  

Markey and Manchin say such a study is biased in favor of opioids and would “needlessly expose” patients on morphine to the risk of addiction. They also make the dubious claim that long-term clinical studies of opioids are no longer needed, citing a controversial Australian study – known as the OPAL study -- that found low dose opioids gave little relief to patients with back and neck pain.

“A recent randomized placebo-controlled study found that prolonged opioid use was ineffective for acute back and neck pain. The study found that after six weeks, there was no significant difference in pain scores for the patients taking opioids compared to those who took a placebo,” the senators wrote.

Critics were quick to note the OPAL study has a number of flaws, the most obvious one being that the treatment period only lasted six weeks. OPAL was a short-term study of opioids for acute pain – not “prolonged opioid use” as Manchin and Markey claimed.   

“The letter by Markey and Manchin is a phenomenon of misinformation and lack of understanding of the opioid crises,” said Stephen Nadeau, MD, a Professor of Neurology at the University of Florida College of Medicine.

“The OPAL study indisputably examined only ACUTE neck and back pain; it is completely inappropriate to apply its results to chronic pain,” said Chad Kollas, MD, a palliative care physician and pain policy expert.

Kollas posted a long thread on Twitter (now known as X) debunking other aspects of the OPAL study, saying its findings were “overstated & oversimplified to support the policy agenda of opioid reductionists.”

“I believe Manchin and Markey are being influenced to shut down any public funding of research that would demonstrate positive benefits for the long-term use of opioids -- of which, enriched enrollment trials are a prime example. By whom, I do not know,” says patient advocate Richard “Red” Lawhern.   

The “whom” in this case appears to be Dr. Andrew Kolodny, the president and founder of Physicians for Responsible Opioid Prescribing (PROP), an anti-opioid activist group that is funded by dark money. Several PROP members, including Kolodny, have repeatedly failed to disclose their conflicts of interest and enriched themselves by testifying as paid expert witnesses in opioid litigation cases.  

Kolodny has worked previously with Manchin on anti-opioid legislation and is apparently doing so again. Manchin is co-sponsoring a bill that would require the FDA to review the use of EERW studies on opioids. Kolodny is quoted in a recent Manchin press release promoting the senator’s bill. 

“The FDA has been putting new painkillers on the market based on improper studies that skew results in favor of approval. The methodology they're using was cooked up in private meetings with drug makers. The time for outside experts to examine the use of enriched enrollment randomized withdrawal is long overdue,” said Kolodny, who is Medical Director of Opioid Policy Research at Brandeis University.  

Coincidentally, when the OPAL study was published in The Lancet medical journal, it was accompanied by an invited commentary from two other PROP members, Drs. Jane Ballantyne and Mark Sullivan, who said the study “raises serious questions about the use of opioid therapy for acute low back and neck pain.”

More Opioid Studies Needed

Although opioids have been used for thousands of years for pain relief, there are surprisingly few placebo-controlled clinical studies of their long-term effectiveness. That is mainly due to the ethical issues involved in giving a placebo to someone in pain. Few pain patients would want to participate in a long-term study in which there’s a good chance they don’t get any pain relief. And few studies duplicate the real world experiences of pain sufferers.

“Depriving patients of benefits they might gain from receiving LTOT (long term opioid therapy) ethically precludes using randomized controlled studies (RCTs) as a research method in studying LTOT. This necessitates using other types of research, including the type of research that the senators seek to eliminate,” Kollas told PNN.

“The reason that RCTs of opioids for chronic pain have failed is very simple:  the trial design is fundamentally flawed. It is simply not adequate to address the scientific question at hand,” says Nadeau. “EERW trials have shown promise, and certainly more evidence of efficacy then the conventionally designed trials, but they have their problems.” 

Nadeau and other have proposed that EERW studies be modified so that patients on opioids are gradually tapered, not just suddenly switched to a placebo. 

“What is glaringly evident is that the gold standard of randomized double-blind trials cannot be applied with opioids because of very high failure rates in the placebo arm, due to breakthrough pain,” said Lawhern. “Moreover, even short-term trials are invalidated by protocols that do not remotely resemble actual clinical use of these medications.”  

As flawed as they might be, EERW studies may be a way to fill in some of the missing gaps in opioid research. Do opioids work long-term? Do they inevitably lead to addiction?  Are chronic pain patients helped or harmed by using opioids? Those are simple questions we still don’t have definitive answers to – and may never know if politicians dictate health policy and try to block much needed pain research. 

“We ask the FDA not to permit the use of EERW to determine the long-term efficacy and tolerability of opioids in chronic pain patients. We also urge you to reject EERW study designs for any future new drug applications for opioids and reconsider past opioid approval decisions using EERW,” Manchin and Markey wrote.