Despite advances in many fields of medicine over the past decades, the development of new pain medications has been sluggish. ACTTION — Analgesic Clinical Trial Translations, Innovations, Opportunities, and Networks — is a new public-private partnership set up to encourage the development of more effective and safer treatments for pain. The group says that widely-used analgesics — acetaminophen, non-steroidal anti-inflammatory drugs and opioids — have “serious, potentially life-threatening toxicities, even when used properly.”
DR. JOHN MARKHAM...Image Tools
The U.S. FDA, which is a founding constituent of the ACTTION partnership, last year awarded a five-year research contract to the University of Rochester to launch the initiative and establish a working agenda. One key goal is to find ways to improve the design and methodology of clinical trials so that promising therapies get an appropriate vetting.
Neurology Today spoke with the Executive Committee Co-chair of ACTTION, John Markman, MD, an associate professor at the University of Rochester who leads the university's Neuromedicine Pain Management Center. He also is chairman of the AAN Pain and Palliative Care Section, which is among the professional organizations that are founding ACTTION members.
WHAT ISSUES SPARKED THE FORMATION OF ACTTION?
There has been an enormous amount of neuroscience research elucidating the underlying biology of pain and the experience of pain in animals. That has led to the identification of therapeutic targets, but that research has not spawned a generation of new drugs for pain. As a result, we're limited to the same treatments we've had for a long time, and many patients have significant difficulty tolerating those drugs. Approximately half of the patients who tolerate these drugs experience partial relief. Even in that group, there are significant toxicity concerns that arise with long-term use.
The failure of novel analgesics in clinical development has prompted a deeper evaluation of clinical trial methods. ACTTION aims to look at the barriers that prevent new drugs from coming to market. Why do so many drugs fail in the phases of clinical development when they looked so promising in the laboratory?
We seem to be at impasse, with more pain drugs failing in development. The likelihood of success for new analgesics is around 15 percent — about 85 percent of them are failing in the testing phase as they go from animals to humans.
WHY A PUBLIC-PRIVATE PARTNERSHIP?
We wanted to bring together all of the key stakeholders — regulators, researchers, patient advocacy groups, industry, and professional societies — to share information so that we can move this field forward.
SO WHAT SPECIFICALLY IS YOUR GROUP FOCUSING ON?
Often we don't know why medications are failing because results are not being published. ACTTION has a database from about 200 clinical trials that we will use to identify the methodological roadblocks that might account for why so many promising candidate drugs end up failing in human subjects. We need to look at the design of trials and the specific methods used in the research to see if they are contributing to disappointing results.
We have to think more about how to build internal checks into the testing of drugs in humans. We know, for instance, that there are drugs that work for a myriad of acute and chronic pain conditions — such as morphine and oxycodone — that fail in clinical trials for index conditions when compared to a placebo. In these instances we assume it is not that the drug lacks efficacy, but that a key factor such as subjects dropping out of the protocol account for the failure to demonstrate superiority of drug over placebo. Often times it is claimed that the nonspecific treatment effects experienced by subjects in the placebo arm overwhelm the specific analgesic actions of the active drug.
Recent research that ACTTION is undertaking has demonstrated that the magnitude of the placebo effect differs in populations of subjects with neuropathic conditions such as diabetic peripheral neuropathy as compared with postherpetic neuralgia. Other research has shown increasing magnitude of the placebo effect with longer duration of clinical trials.
WHAT ARE SOME OF THE OTHER OBSTACLES?
We also need to consider the issue of standardization in clinical trials. What are the outcomes being measured? How do questions get asked within a trial? How do we better use measurement tools, such as patent-reported assessments, to gather information? There is no biomarker for pain, there is no picture you can take to see if a drug is working. Like clinicians in practice, investigators must rely on a patient'sreport. It is well recognized that not every subject reports the experience of pain with the same degree of accuracy and reliability. Equally important, not all investigators and research coordinators ask questions in the same way. Training of subjects and research staff alike may go a long to way to reduce the variability from one clinical site to another that degrades the sensitivity of a trial to detect the difference between the specific effects of an analgesic and placebo.
We also have to find ways to understand if there certain patients who are more or less better subjects for clinical trials.
CAN YOU PROVIDE AN EXAMPLE OF A CONDITION THAT MIGHT BENEFIT FROM THIS EFFORT
Chronic lumbosacral radiculopathy. Neuropathic lower back pain is one of the most common types of pain, but there has never been a drug approved for that indication in the United States. A study published last year that compared pregabalin to a placebo found no difference between that drug and placebo. The study didn't rule out that the drug might be effective in some patients, but it said that further research was needed to understand the potential of pregabalin for treating lumbosacral radiculopathy.
WHY IS THE AAN INVOLVED IN THIS INITIATIVE?
Pain is central to what neurologists do every single day in clinical practice. Pain is the leading reason to see a neurologist for an outpatient visit. Neurologists are the caretakers of the nervous system and the central role of the nervous system in modulating the experience of pain has never been clearer. There is a growing evidence that experience of pain previously thought to be localized to non-neural tissues such as joints has its intensity regulated at spinal cord and cortical synapses, which now are therapeutic targets.
DO MISUNDERSTANDINGS AROUND THE ROLE OF PAIN MANAGEMENT HINDER PATIENT CARE?
There is under-recognition of pain in certain vulnerable groups that can result in inadequate treatment of pain. It's especially a problem in groups of patients who cannot communicate their needs. That includes patients with dementia and nursing home patients. Patients are often given pain drugs but at sub-optimal doses that don't offer relief but produce side effects such as sedation.
THERE HAS BEEN AN ALARMING INCREASE IN OPIOID-RELATED DEATHS. HOW DO YOU SQUARE THE NEED TO PROTECT THE PUBLIC FROM PRESCRIPTION DRUG MISUSE OR ABUSE WITH THE NEED TO DEVELOP NEW AND EFFECTIVE PAINKILLERS?
There is a growing recognition that there is a huge unmet need for safer drugs. We need drugs that have greater efficacy, with reduced side effects and reduced toxicity. The desire to protect society from harm underscores the urgency of establishing collaborative efforts to discover new and safer therapies.