Researchers explore how design of chronic and acute pain trials might be improved

Up to $4.5 million supports studies to boost development of new, much needed therapies

For chronic pain sufferers, a day can feel like a year and a year can feel like an eternity. With very few truly new therapies approved by the U.S. Food and Drug Administration for this condition since 2005, the outlook is far from bright.

Fortunately, the FDA has taken note. With up to $4.5 million in funding from the agency over the next five years, researchers at the University of Rochester Medical Center will study different approaches to improve the methods used to evaluate and approve new, safe, and effective treatments for the more than 76 million Americans with acute and chronic pain.

"Pain can cause considerable suffering and it represents an enormous financial burden to society," said Robert H. Dworkin, Ph.D., professor in the Department of Anesthesiology and the Center for Human Experimental Therapeutics at the Medical Center, who will spearhead the research. "Despite substantial attention in the pharmaceutical industry to developing novel pain therapies, the fact that so few improved treatments have become available is really surprising and is why the FDA is funding this initiative."

According to Dworkin, one possible reason pain clinical trials are often unsuccessful is that patients in the placebo group, who get a dummy pill instead of the real treatment, frequently show greater-than-expected improvements. Consequently, it becomes difficult for researchers to show meaningful differences between the pain-lessening effects of the real drug and the dummy drug.

The FDA agrees that the problem may lie in the way new pain therapies are identified and studied.

"We've seen over the years that analgesic [pain] clinical trials frequently fail, and often with drugs that we know work. When opioids that have been known to be effective for hundreds of years are put in clinical trials, we can't get a positive result," said Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Addiction Drug Products at the FDA's Center for Drug Evaluation and Research. "It has become clear to the entire pain community that there are design problems with the trials, making it difficult to accurately evaluate whether drugs work or not."

With the grant from the FDA, Dworkin, working closely with Dennis Turk, Ph.D., from the University of Washington in Seattle, will lead a team exploring how the design of chronic and acute pain trials might be improved. A multitude of factors may play a role, including: patient features, such as the patient's pain intensity and duration; the way studies are planned, like the length of a trial and frequency of patient visits; and study site characteristics, for example, the experience and training of the lead investigator and staff.

"We may see increasing improvement in the placebo group because the patients have a good relationship with the study nurse they see for each visit; she makes them feel supported and reassured, so they feel better and think their pain is getting better, even though they aren't getting the real treatment," said Dworkin. "It could just be positive, ongoing interactions with a really nice nurse that is leading to this effect - we don't know."

Research shows that in psychiatry clinical trials, the more visits the greater the improvement in patients in the placebo group. "Among other research questions, we plan to study the number of visits built into pain clinical trials, testing weekly versus monthly patient visits. Perhaps we'll see a greater difference in pain reduction between patients taking the active drug and those getting placebo if there are fewer visits," he noted.

Other studies the team may pursue involve developing and testing the usefulness of methods to improve how accurately patients report their pain. If patients aren't good at describing their symptoms, this could influence the results of a trial. For example, it's possible that patients don't understand how important it is to very carefully rate their pain on the standard 0-10 scale that is used in most studies - another factor that may lead to the failure of a trial to distinguish between placebo and active therapy patients.

To examine these and many other questions, the team will scour FDA databases housing information from hundreds of pain clinical trials - an invaluable resource not typically available to researchers. They will also analyze previously published pain clinical trials and data from studies sponsored by various pharmaceutical companies.

Beyond Dworkin and Turk, the initiative, known as ACTTION (Analgesic Clinical Trial Translations, Innovations, Opportunities, and Networks), involves the collaboration of public and private organizations, including professional societies, patient advocacy groups, industry, and government. It stems from a one-year, $1 million contract awarded to the group in 2010.

According to a report by the FDA, "Advancing Regulatory Science for the Public Health", the time for the research is right. "We are facing a global epidemic of prescription pain medicine abuse and misuse. At the same time, patients in agonizing pain are often left untreated. New pain pathways have been discovered and new medicines are being developed that can help. But to accelerate the delivery of new treatments to patients, we need to find better pain models, measurement tools (including patient-reported assessments) and clinical trial designs to enable development of effective medications with less potential for abuse."