The Mouse Trap
How and what we measure in animal studies of pain has huge implications for clinical translation. We speak with Jeffrey Mogil, E. P. Taylor Professor of Pain Studies and Canada Research Chair in the Genetics of Pain at McGill University, Quebec, Canada, to find out more.
What is the focus of your work?
Pain is the most prevalent – and arguably the most important – human health problem in the world. It’s also a huge scientific challenge; studying it has a range of unique problems.
Up until a few years ago, my research focused almost exclusively on the genetics of pain, but in recent years it has become more diverse. We have major focuses on sex differences in pain, developing new models and measures of pain, in addition to social modulation of pain, in both mice and humans. Our results so far tell us that the way we conduct both animal and human studies in pain has a lot of room for improvement.
Can you provide an example?
It is now known that there are huge and surprising sex differences in pain. In a study published last year, we found that male and female mice process certain types of pain using different immune cells altogether (1). And yet a lot of animal studies use only male rodents, on the incorrect assumption that data from females will be more variable. In many cases then, we have been studying only one of two parallel pathways – completely ignoring the pathway that applies to women, who make up the vast majority of pain patients. I firmly believe that all researchers should be using animals of both sexes all the time.
It’s not just the sex of the animal that is important – the sex of the experimenter matters as well. Why? Stress can significantly change sensitivity to pain; we already knew that noise, injections, and so on, could cause stress in laboratory experiments. But one stressor that people didn’t anticipate was the presence of male experimenters – or more precisely, their smell. Rodents of both sexes tend to be stressed by the presence of males of the same species and, as it turns out, human men invoke a similar stress response – to a mouse, all males smell dangerous (2). Preliminary results suggest that the same may apply in human trial subjects. This is a major potential confounder – if a female post doc leaves halfway through a study and is replaced by a man, the results could be skewed significantly. So what is the solution? Clearly, we cannot ban all men from the lab. Even the less extreme solutions of having the male experimenter enter the room half an hour before the experiment (the effect is strong but short-lived) or gown up are likely to prove impractical. However, what is both practical and reasonable is for the sex of the experimenter to be disclosed in the “Methods” section of all published studies.
Will understanding the implications drive the field forward?
Paying more attention to sex-based factors in pain research should help us to make better progress in preclinical trials. However, I believe the biggest reason for the poor translation of preclinical into clinical trials in pain is that we have been studying the wrong symptom. When we study chronic pain in animals, we measure reflex withdrawals – mechanical allodynia or thermal hyperalgesia. These are not the major symptoms of clinical pain. Most patients suffer from spontaneous pain, which is something we don’t measure in animals because there is no consensus on how to do so. When it comes to clinical trials, these drugs may well be blocking mechanical allodynia reflexes, but that’s not always clinically relevant.
Is there still hope for discovering new pain therapies?
Things are changing. People are coming up with new ways to measure spontaneous pain and some of the biggest labs in pain research are publishing new methods. One of the tools we have developed to help measure pain more accurately is the Mouse Grimace Scale (3). We published the Mouse Grimace Scale in 2010 and there are now grimace scales for rats and other species, and photos of grimacing rodents on display in labs and vivaria all over the world, providing more accurate assessment of pain for animal welfare and experimental purposes. It is rare and rewarding thing in science to come up with something that is immediately useful in the real word.
It may be some time before improvements in the lab pay off in the clinic. The new techniques are more labor intensive, so things may even go slower for a while, but it’s a case of taking one step back in order to take two steps forward.
The Politics of pain
From the opioid wars to disability benefits, societal attitudes to pain are often more influenced by politicians than doctors. We spoke with Keith Wailoo, Professor of History and Public Affairs at Princeton University and author of “Pain: A Political History” to discover how politics shapes pain medicine.
What inspired the book?
Unlike many areas in biomedicine, such as cancer, genetics and immunology, pain exists in a subjective realm — we don’t have a clear consensus on what it is, how to measure it, and how much pain relief is reasonable. As a result, there has been much political debate over the years on how to translate research into medical care or public policy.
How have politics changed over time?
In the post WWII era, there was a lot of skepticism. Physicians knew that chronic pain existed, but were often unwilling to deal with it. Some skeptics even viewed those with chronic pain as maladjusted.
By the early 1960s, we began to see a more liberal, open-minded, therapeutically compassionate view on pain. A federal judge at this time ruled that chronic pain should be considered a disability and – crucially – that if the pain is real to a patient it should be treated as real by the government. The early 1970s saw further liberalization, with the introduction of patient-controlled analgesia – instead of relying on a doctor’s opinion, trusting the patient to decide on the level of relief required.
In the late 70s and early 80s, a conservative backlash emerged, fueled by the growing cost of disability benefits. In the US, the change in attitude became obvious in 1981 when President Ronald Reagan began the process of removing half a million people from the social security disability rolls, many of whom were people with so-called subjective ailments, such as pain. The 1990s saw another swing, with a focus on end of life care and undertreatment of pain.
Where are we today?
In the US, we have been through a period of intense criminalization of drug abuse and that has made doctors more cautious about prescribing pain medicine, as they fear prosecution or removal of their license. In the last year or so we have just begun to have a new conversation about legislation to destigmatize and even decriminalize addiction. In US politics, we tend to pivot wildly, from so-called liberal approaches to pain to more conservative ones, and from pressure for better end of life pain relief in the 1990s to today’s focus on addiction. Policymakers often struggle to recognize that there could be two different problems that coexist – both overtreatment and undertreatment of pain. What gets missed in this highly political environment is the everyday struggles of the person in chronic pain.
"Crossing the Threshold Basic and clinical researchers must join forces to fight pain" Michael Gold
"The Pain Puzzle" Roger Fillingim
"Growing Pains" Suellen Walker
- RE Sorge et al., “Different immune cells mediate mechanical pain hypersensitivity in male and female mice”, Nature Neuroscience 18, 1081–1083 (2015).
- RE Sorge et al., “Olfactory exposure to males, including men, causes stress and related analgesia in rodents”, Nature Methods 11, 629–632 (2014).
- D Langford et al., “Coding of facial expressions of pain in the laboratory mouse”, Nature Methods 7, 447–449 (2010).
Jeffrey Mogil, E. P. Taylor Professor of Pain Studies and Canada Research Chair in the Genetics of Pain at McGill University, Quebec, Canada.