Editor’s Note: The first-ever North American Pain School (NAPS) took place from June 26-30, 2016 in Montebello, Quebec, Canada. This educational initiative brought together leading experts in pain research and management to provide 30 trainees–part of the up-and-coming generation of pain researchers–with scientific education, professional development and networking experiences. Six of the trainees were also selected to provide first-hand reporting from the event, including summaries of talks presented at the meeting. Here, Kathryn Birnie, a postdoctoral fellow at the University of Toronto and The Hospital for Sick Children, Toronto, Canada, describes a talk delivered by Jeffrey Mogil, a pain researcher at McGill University, Montreal, Canada, who discussed interesting ways in which animal studies are relevant to understanding the pain that people face.
The number one reason new drugs never make it to market is that they fail to help patients in late-stage clinical trials. Strikingly, more than half of newly developed drugs show no benefit for patients in need, despite showing potential in animal studies, and even exhibiting safety in early-stage clinical studies. Pain drugs are a case in point, as the field has seen numerous promising compounds ultimately fail in clinical trials.
“This is obviously very deeply disturbing to all of us in pain research, and in biomedicine in general,” said Jeffrey Mogil, McGill University, Montreal, Canada, in a talk delivered at the North American Pain School. Mogil addressed why the pain field has experienced this difficulty, and what pain researchers can do about it, focusing on the role of animal research. He concluded that there are a number of ways pain scientists can improve animal studies so that they are more relevant to the human experience of pain, and showcased creative new opportunities in this area.
Studying pain in animals
Pain is a complex phenomenon. While the focus of much pain research has been on how biology contributes to pain, researchers now understand that psychological factors, such as a person’s thoughts, feelings and behavior, and social factors too, such as how an individual interacts with others, all contribute to the experience of chronic pain. This view is known as the ‘biopsychosocial model,’ and it emphasizes the importance of considering the whole person to truly understand pain.
On the path to understanding the pain from which people suffer, and to developing new treatments, most pain research begins in animals (see RELIEF related interview with Mogil). However, Mogil said that the way animal studies are traditionally performed (mostly using mice and rats), often limits the relevance of those investigations to humans.
For example, one of the biggest concerns, Mogil explained, is that animal studies of pain investigate the “wrong” symptoms—that is, symptoms that don’t match those commonly experienced by patients. Animal studies usually assess experimental pain caused by heat or touch, by poking the paw of an animal or aiming a light beam at the paw, for example, which is straightforward to measure in the research lab. The problem is that “spontaneous” pain—pain that is just there, in the absence of a stimulus to provoke it—is far more common, and far more problematic, in patients. This makes it hard to know the extent to which animal studies apply to patients’ actual experiences.
Another problem is that the vast majority of studies usually use only specific strains of mice and rats. This can be helpful for research, because when scientists use the same kinds of animals across studies, it makes it easier to determine whether new findings made in one lab can be reproduced in another one; reproducibility is an important part of science, as it gives greater confidence that a study’s results are accurate. But as Mogil explained, pain scientists have learned that different strains of rats and mice respond differently to the same painful stimuli. This complicates efforts to understand how the results may apply to people, since those results may differ from strain to strain.
An additional, increasingly recognized limitation to current animal research is that, historically, it has ignored sex differences in pain. Mogil emphasized this drawback because of research showing substantial differences in how men and women experience pain, at the biological, psychological, and social levels. He said that about 70% of patients with chronic pain are women—and yet, nearly 80% of animal studies use young-adult male rodents. This again begs the question of how relevant animal studies are to understanding the human situation. Perhaps of greatest concern is that, according to Mogil, nothing has changed in over 20 years, as animal research continues to use predominantly males to study pain.
The neglect of sex differences also applies to clinical trials of new pain drugs. For instance, Mogil offered the example of MorphiDex (a combination of morphine and dextromethorphan). Although this drug showed promise in animal studies conducted mostly with male mice and rats, it failed to make it to market because it showed no benefit in clinical trials with people. The clinical trials of MorphiDex included both men and women, but neglected to look for potential sex differences, making it impossible to determine if the drug might actually work depending upon the sex of the patients. “This is a failure at the preclinical level, and also at the clinical level, to take sex differences as seriously as we are beginning to realize they should be.”
Fortunately, efforts are underway to address the limitations of current animal research. For instance, new policies from the US National Institutes of Health (NIH) are requiring scientists to use both male and female animals in lab studies.
Another encouraging sign is an awareness that animal studies can help scientists understand not just the biology of pain, but the psychological and social aspects of pain too; traditionally, pain scientists have assumed that animal studies can only address the “bio” part of the biopsychosocial model, and not the other aspects. The social aspects of pain, in particular, receive the least attention—a mouse or a rat can’t teach us anything about how social factors influence the human experience of pain, the conventional wisdom goes. But recent work from Mogil’s lab challenges the assumption that animals have little or nothing to add to our understanding.
When rodents in pain are studied in a research lab, they are typically observed one at a time. When Mogil’s group decided to observe two mice that were both in pain at the same time, they noticed something interesting: mice that normally lived together (‘cagemates’) showed more pain, compared to mice that lived in different cages (‘strangers’).
The researchers went on to show that a similar process occurs in people. When university students experienced pain by submersing their hand in extremely cold water, they rated their pain as significantly more intense when they did it at the same time as a friend as compared to doing it with a stranger or on their own. Mogil refers to the experience of worse pain while a friend is also in pain as ‘emotional contagion,’ a form of empathy.
These results suggest that empathy is not exclusive to humans, and may stem from the fact that strangers are more stressful than friends, even for mice, and that stress prevents the emotional contagion Mogil has observed in his studies. Indeed, when Mogil and colleagues reduced the stress of mouse or human strangers in their studies by using drugs, or by having humans play a videogame together, they observed the same emotional contagion and increased pain previously seen only with cagemates or friends.
With results like these, Mogil says that pain researchers can and should study social aspects of pain in animals. What was once thought impossible is now achievable, and the understanding of the human experience of pain should ultimately benefit from this research too.
Kathryn Birnie is a postdoctoral fellow at the University of Toronto and The Hospital for Sick Children, Toronto, Canada.