Men and Women Experience Pain Differently. Learning Why Could Lead to Better Drugs.

According to the CDC, one fifth of American adults live with chronic pain, and women are affected more than men.

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It's been more than a decade since Jeannette Rotondi has been pain-free. A licensed social worker, she lives with five chronic pain diagnoses, including migraines. After years of exploring treatment options, doctors found one that lessened the pain enough to allow her to "at least get up."

"With all that we know now about genetics and the immune system, I think the future of pain medicine is more precision-based."

Before she says, "It was completely debilitating. I was spending time in dark rooms. I got laid off from my job." Doctors advised against pregnancy; she and her husband put off starting a family for almost a decade.

"Chronic pain is very unpredictable," she says. "You cannot schedule when you'll be in debilitative pain or cannot function. You don't know when you'll be hit with a flare. It's constantly in your mind. You have to plan for every possibly scenario. You need to carry water, medications. But you can't plan for everything." Even odors can serve as a trigger.

According to the CDC, one fifth of American adults live with chronic pain, and women are affected more than men. Do men and women simply vary in how much pain they can handle? Or is there some deeper biological explanation? The short answer is it's a little of both. But understanding the biological differences can enable researchers to develop more effective treatments.

While studies in animals are straightforward (they either respond to pain or they don't), humans are more complex. Social and psychological factors can affect the outcome. For example, one Florida study found that gender role expectations influenced pain sensitivity.

"If you are a young male and you believe very strongly that men are tougher than women, you will have a much higher threshold and will be less sensitive to pain," says Robert Sorge, an associate professor at the University of Alabama at Birmingham whose lab researches the immune system's involvement in pain and addiction.

He also notes, "We looked at transgender women and their pain sensitivity in comparison to cis men and women. They show very similar pain sensitivity to cis women, so that may reduce the impact of genetic sex in terms of what underlies that sensitivity."

But the difference goes deeper than gender expectations. There are biological differences as well. In 2015, Sorge and his team discovered that pain stimuli activated different immune cells in male and female rodents and that the presence of testosterone seemed to be a factor in the response.

More recently, Ted Price, professor of neuroscience at University of Texas, Dallas, examined pain at a genetic level, specifically looking at the patterns of RNA, which are single-stranded molecules that act as a messenger for DNA. Price noted that there were differences in these patterns that coincided with whether an individual experienced pain.

Price explains, "Every cell in your body has DNA, but the RNA that is in the cells is different for every cell type. The RNA in any particular cell type, like a neuron, can change as a result of some environmental influence like an injury. We found a number of genes that are potentially causative factors for neuropathic pain. Those, interestingly, seemed to be different between men and women."

Differences in treatment also affect pain response. Sorge says, "Women are experiencing more pain dismissal and more hostility when they report chronic pain. Women are more likely to have their pain associated with psychological issues." He adds that this dismissal may require women to exaggerate symptoms in order to be believed.

This can impact pain management. "Women are more likely to be prescribed and to use opioids," says Dr. Roger B. Fillingim, Director of Pain Research and Intervention Center of Excellence at the University of Florida. Yet, when self-administering pain meds, "women used significantly less opioids after surgery than did men." He also points out that "men are at greater risk for dose escalation and for opioid-related death than are women. So even though more women are using opioids, men are more likely to die from opioid-related causes."

Price acknowledges that other drugs treat pain, but "unfortunately, for chronic pain, none of these drugs work very well. We haven't yet made classes of drugs that really target the underlying mechanism that causes people to have chronic pain."

New drugs are now being developed that "might be particularly efficacious in women's chronic pain."

Sorge points out that there are many variables in pain conditions, so drugs that work for one may be ineffective for another. "With all that we know now about genetics and the immune system, I think the future of pain medicine is more precision-based, where based on your genetics, your immune status, your history, we may eventually get to the point where we can say [certain] drugs have a much bigger chance of working for you."

It will take some time for these new discoveries to translate into effective treatments, but Price says, "I'm excited about the opportunities. DNA and RNA sequencing totally changes our ability to make these therapeutics. I'm very hopeful." New drugs are now being developed that "might be particularly efficacious in women's chronic pain," he says, because they target specific receptors that seem to be involved when only women experience pain.

Earlier this year, three such drugs were approved to treat migraines; Rotondi recently began taking one. For Rotondi, improved treatments would allow her to "show up for life. For me," she says, "it would mean freedom."

Kimberly Yavorski
Kimberly Yavorski is a freelance writer with a passion for learning and sharing her new knowledge with anyone interested in listening. She has always been a reader and believes that there is always something new to discover and learn, if we only take the time to look. In addition to science and nature, she also writes about parenting, education, social issues and travel.
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David Kurtz making DNA sequencing libraries in his lab.

Photo credit: Florian Scherer

When David M. Kurtz was doing his clinical fellowship at Stanford University Medical Center in 2009, specializing in lymphoma treatments, he found himself grappling with a question no one could answer. A typical regimen for these blood cancers prescribed six cycles of chemotherapy, but no one knew why. "The number seemed to be drawn out of a hat," Kurtz says. Some patients felt much better after just two doses, but had to endure the toxic effects of the entire course. For some elderly patients, the side effects of chemo are so harsh, they alone can kill. Others appeared to be cancer-free on the CT scans after the requisite six but then succumbed to it months later.

"Anecdotally, one patient decided to stop therapy after one dose because he felt it was so toxic that he opted for hospice instead," says Kurtz, now an oncologist at the center. "Five years down the road, he was alive and well. For him, just one dose was enough." Others would return for their one-year check up and find that their tumors grew back. Kurtz felt that while CT scans and MRIs were powerful tools, they weren't perfect ones. They couldn't tell him if there were any cancer cells left, stealthily waiting to germinate again. The scans only showed the tumor once it was back.

Blood cancers claim about 68,000 people a year, with a new diagnosis made about every three minutes, according to the Leukemia Research Foundation. For patients with B-cell lymphoma, which Kurtz focuses on, the survival chances are better than for some others. About 60 percent are cured, but the remaining 40 percent will relapse—possibly because they will have a negative CT scan, but still harbor malignant cells. "You can't see this on imaging," says Michael Green, who also treats blood cancers at University of Texas MD Anderson Medical Center.

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Lina Zeldovich
Lina Zeldovich has written about science, medicine and technology for Scientific American, Reader’s Digest, Mosaic Science and other publications. She’s an alumna of Columbia University School of Journalism and the author of the upcoming book, The Other Dark Matter: The Science and Business of Turning Waste into Wealth, from Chicago University Press. You can find her on http://linazeldovich.com/ and @linazeldovich.


Reporter Michaela Haas takes Aptera's Sol car out for a test drive in San Diego, Calif.

Courtesy Haas

The white two-seater car that rolls down the street in the Sorrento Valley of San Diego looks like a futuristic batmobile, with its long aerodynamic tail and curved underbelly. Called 'Sol' (Spanish for "sun"), it runs solely on solar and could be the future of green cars. Its maker, the California startup Aptera, has announced the production of Sol, the world's first mass-produced solar vehicle, by the end of this year. Aptera co-founder Chris Anthony points to the sky as he says, "On this sunny California day, there is ample fuel. You never need to charge the car."

If you live in a sunny state like California or Florida, you might never need to plug in the streamlined Sol because the solar panels recharge while driving and parked. Its 60-mile range is more than the average commuter needs. For cloudy weather, battery packs can be recharged electronically for a range of up to 1,000 miles. The ultra-aerodynamic shape made of lightweight materials such as carbon, Kevlar, and hemp makes the Sol four times more energy-efficient than a Tesla, according to Aptera. "The material is seven times stronger than steel and even survives hail or an angry ex-girlfriend," Anthony promises.

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Michaela Haas
Michaela Haas, PhD, is an award-winning reporter and author, most recently of Bouncing Forward: The Art and Science of Cultivating Resilience (Atria). Her work has been published in the New York Times, Mother Jones, the Huffington Post, and numerous other media. Find her at www.MichaelaHaas.com and Twitter @MichaelaHaas!