Women suffer from chronic pain conditions in far greater numbers than do men, and recent research suggests that the basic biology of men’s and women’s experiences of pain might differ. Yet the overwhelming majority of basic pain studies are performed on male animals and male-derived cells. That is set to change, at least for researchers funded by the US National Institutes of Health (NIH), with new NIH guidelines mandating equal representation of both sexes in preclinical research. NIH director Francis Collins and Janine Clayton, director of the NIH’s Office of Research on Women’s Health, Bethesda, US, outlined the new policy in a commentary published May 14 in Nature.
According to the commentary, “The NIH is now developing policies that require [grant] applicants to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted,” such as in research of diseases affecting only males or only females.
The move will surely benefit women in the long run, said Rebecca Craft, who studies sex differences in pain at Washington State University Pullman, US. “This [policy] is finally going to hold people’s feet to the fire to test female [animals],” Craft told PRF.
Jeffrey Mogil at McGill University, Montreal, Canada, also praised the new policy, which he described as particularly relevant to pain research. “There are huge, striking sex differences in pain—big stuff, not just a little more or a little less of something,” he said. “Robust evidence of sex differences is as good or better in pain than in any other field,” Mogil told PRF.
Clinical study design has undergone a revolution over the past 20 years, since the NIH began requiring equal numbers of women and men in nationally funded clinical trials. For decades, women took prescription drugs that were tested solely in men. In some cases, that practice led to unforeseen side effects and risks for women from medications. Although the transformation to gender-balanced trials took years to implement, researchers today hail it as a great achievement in medicine.
Now the NIH has taken the next step toward gender equality in science by requiring equal sex representation in animal experiments, and in work done with cells. The change is particularly important to pain researchers, said Craft, considering that “a number of pain syndromes are much more common in women.” Without testing female animals, she added, “you are really not modeling the phenomenon very well.”
Mogil echoed that sentiment. Whether or not there are sex differences that affect pain on a cellular level, “there are sex differences in the circuitry, and that is all you need to have the biology be robustly and fundamentally different between males and females,” Mogil said.
The news has some researchers worried that the change might come with high costs, but Mogil said that fear is unfounded. “There is no downside and no tradeoff. We have everything to gain and very little to lose at all,” he told PRF.
For example, if twice the animals will be required, that could double the price of breeding, housing, and tracking the animals. But Mogil doubts the new decree will drastically change research costs. “If you’re using 12 animals, for example, you just use six male and six female,” Mogil said, and track the data separately, “and combine again if there are no sex differences.”
“I don’t think six animals per sex is enough,” to reveal subtle sex differences, Craft said, but then, that is not the purpose of the policy. “This is definitely a start. What we need to know most is when there are big differences … which would leap out at you, even with that small sample size.”
The new rule could affect the progress of target validation and drug development. “For agents based on mechanisms determined from experiments performed on males, there is the possibility the biology is less relevant to females,” said Mogil.
Researchers have stayed stuck in the rut of studying predominantly male animals and cells mostly out of convention. A single sex animal pool, researchers reasoned, would yield more reproducible results. And until recently, clinical trials overwhelmingly tested drugs on men, so it made sense to stick with male animals at the preclinical stage. “Until funders or journals start requiring it, no one is going to change,” Craft said. The new guidelines will provide that push, she added.
A popular misconception also contributed to the historical male dominance, Mogil said. “People resisted before because they thought that data would be more variable in females.” But as he demonstrated years ago (Mogil and Chanda, 2005), “that idea is empirically false. If anything, there is more variability in males. So what people were worried about all this time turns out to be wrong.”
For researchers daunted by the thought of embarking on a new experimental paradigm built around equal representation of male and female animals, Craft suggests two papers for guidance (Greenspan et al., 2007; Becker et al., 2005), and the NIH will reportedly provide training materials as part of the rollout of the new policy. The change will mean more work for researchers unfamiliar with female biology, Craft said, but that will be a worthy investment indeed.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California, US.
Image: © Mihaly Pal Fazakas | Dreamstime.com
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David Yeomans, Stanford University School of Medicine
Some researchers have
Some researchers have expressed concern that a new NIH mandate calling for equal gender representation in preclinical experiments could hinder their animal research or drive up costs—particularly in the pain field. How smoothly academic researchers will make the transition to gender-equal research might depend on their university’s Institutional Animal Care and Use Committee (IACUC).
Just as an Institutional Review Board must approve human clinical research, the IACUC approves animal studies. Their function is twofold: to minimize pain and discomfort in animals and to reduce the number of animals used, as long as that does not interfere with scientific validity. The committees are made up of faculty, veterinarians, undergraduate students, and people from the local community.
Here’s a possible scenario: You amend your approved protocol, and say you have to increase the number of rats you use because the NIH wants you to determine whether effects on males are also true in females. My guess is that most IACUCs are going to say “fine,” but those of us doing pain research have another layer of scrutiny we have to go through. We have to educate IACUCs who don’t have experience with pain research about what we are doing.
I have a suggestion for all pain researchers: Join your institution’s IACUC. The committees are always looking for members, and you can provide a real service by helping to educate them. And hey—it also looks good on your application for tenure or promotion. Even if you do not join the committee, they will very likely be happy to have you talk to them at their monthly meeting. Sometimes presenting your case in person is much more effective than a written proposal alone.
When I arrived at my present job at Stanford University, the first thing I did was get on the IACUC. They had never seen animal pain protocols before, and the members had a lot of misconceptions and an obvious lack of understanding about pain research. Because I joined the committee and talked responsibly about the discomfort potential of various experiments, not just my own, they saw that I was not a monster and that I understood the value of minimizing the discomfort of the animals for both humane and scientific reasons. I have been here for 14 years now, and I believe that getting on the committee was one of the smartest things I’ve done during that time.
Although the new NIH policy requirements are not specific to pain research, we in the pain field face particular challenges from IACUCs. The committee’s primary function is to minimize pain and discomfort in animals, so proposals for pain research protocols present an inherent conflict, and it takes thoughtful effort to design protocols that minimize pain and yet provide valid information for our field. I have found it helpful to explain the nature of my experiments and the fact that we use standard techniques that impart minimal noxious energy to an animal.
I emphasize that, for the most part, I am measuring changes in a threshold—not pain. What I know is that something I do has changed the minimal amount of energy—be it thermal, mechanical, or chemical—that needs to be imparted to elicit a behavioral response. I have a pretty good idea that I have engaged the nociceptive system, but I do not pretend to know if the animals (particularly rodents) have a percept that is equivalent to human pain. Thus, I rarely use the word “pain” in my protocols, but rather describe changes in sensitivity to stimulation, which is more accurate.
Researchers face great financial pressures today; the NIH continues to cut back more and more on funding. An IACUC could potentially increase the cost of research under the new NIH rules by, for example, requiring separate housing for male and female animals. And if this new policy ends up meaning that we need more animals for each experiment, that will cost more. My advice for researchers when it comes to the IACUC is: Don’t wait to see what happens—you have to proactively lobby for what makes the most sense.