When it comes to what matters most to patients, the alleviation of pain is often top of the list. But designing clinical trials for new analgesics has proven particularly troublesome
By Pierre Meulien, IMI Director
Pain is one of the most common reasons people see a health care provider, putting a significant strain on public health systems. New pain drugs are urgently needed because current treatments rely on opiates that are linked to addiction and often come with intolerable side effects. In some cases, even opiates do not provide pain relief, leaving no therapeutic option for many people.
Designing clinical trials for analgesics has proven particularly troublesome. Placebo controls are a fundamental part of evaluating the efficacy of medical treatments but the placebo effect can make clinical trial design for new pain drugs extremely challenging. If a significant number of people in the group receiving a sugar pill report that their symptoms have improved, how can drug companies possibly evaluate the true efficacy of the active compound?
To accelerate the development of non-addictive and effective alternatives, we need to solve the product-agnostic problems that plague clinical assessments, and pharma companies have been doing this, once again, under the non-competitive banner of IMI projects.
The EUROPAIN project made progress in understanding the factors that influence the placebo effect. Interestingly, they found that patient expectations have a big part to play in the phenomenon. If a patient knows that the medication being evaluated is a painkiller, they are more likely to report that their pain symptoms have improved, even if they are in the placebo group. The EUROPAIN work influenced the guidelines on the development of analgesics, and led to a better understanding not only of the placebo effect but also the factors can cause pain to become chronic.
Preclinical animal models are useful in advancing our understanding of the physiological basis of pain, but there is an issue – animals can’t tell you if they’re suffering. Different companies had been working with different preclinical models and applying different criteria for measuring pain behaviour in animals, meaning they have generated data that are not comparable.
This lack of standards has made it incredibly difficult to use the knowledge in animal models to make predictions about responses in human subjects. EUROPAIN made a significant effort to develop standards in preclinical animal models and broadly disseminate its results. This helps different companies compare data and facilitates discussions with the regulators. It also helps reduce the number of animals used in research by increasing the replicability of experiments and the relevance to human conditions.
EUROPAIN was also able to establish four different quantitative ways of measuring pain behaviour in animal models, demonstrating that a particular technique that measures pain-related nerve signals can be used both in the animal models and in patients to show very early on whether a potential drug will work. This model is already being used by drug companies.
Other efforts of standard-setting are taking place in IMI-PAINCARE. The project is working on harmonising measures for patient-reported pain-related outcomes to help clinicians and drug developers better evaluate treatments. Individual pain experiences can be described only by the affected person, and the quality of these reports can be improved by using standardised patient reported outcome measures (PROMs) which are indicative of treatment success and predict chronicity or recovery. They are also working on new biomarkers, tools and methods for new treatments for pelvic pain, paying particular attention to the case of endometriosis - an unmet women’s health need. They want to establish perturbations that are specific to pain associated with endometriosis and bladder pain, and to establish whether women with these conditions can be stratified into subgroups and whether the subgroups relate to treatment response. IMI-PAINCARE has a strong patient involvement, with advocates helping to design patient consent forms and clinical trials.
The third IMI project dedicated to pain, NGN-PET, confirmed the role of neuron-glial interactions in the generation of a pain response and identified genes that appear to be involved, creating a new opening for potential new drug targets. The pharma partners in the project are now using this information in their drug development programmes. That project also resulted in a successful new commercial entity.
IMI funds projects that seek to develop medicines to treat the entire spectrum of human diseases, and many if not most of those involve some element of physical suffering for people. Pain relief is a top priority for patients and they are the experts that should be engaged by scientists when research strategies are being drawn up. This is necessary to ensure that research targets what the patient needs. Patients are the ones we ultimately are trying to help and their inclusion and involvement from the outset is critical.