Men and Women Experience Pain Differently. Learning Why Could Lead to Better Drugs.
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."
Few things are more painful than a urinary tract infection (UTI). Common in men and women, these infections account for more than 8 million trips to the doctor each year and can cause an array of uncomfortable symptoms, from a burning feeling during urination to fever, vomiting, and chills. For an unlucky few, UTIs can be chronic—meaning that, despite treatment, they just keep coming back.
But new research, presented at the European Association of Urology (EAU) Congress in Paris this week, brings some hope to people who suffer from UTIs.
Clinicians from the Royal Berkshire Hospital presented the results of a long-term, nine-year clinical trial where 89 men and women who suffered from recurrent UTIs were given an oral vaccine called MV140, designed to prevent the infections. Every day for three months, the participants were given two sprays of the vaccine (flavored to taste like pineapple) and then followed over the course of nine years. Clinicians analyzed medical records and asked the study participants about symptoms to check whether any experienced UTIs or had any adverse reactions from taking the vaccine.
The results showed that across nine years, 48 of the participants (about 54%) remained completely infection-free. On average, the study participants remained infection free for 54.7 months—four and a half years.
“While we need to be pragmatic, this vaccine is a potential breakthrough in preventing UTIs and could offer a safe and effective alternative to conventional treatments,” said Gernot Bonita, Professor of Urology at the Alta Bro Medical Centre for Urology in Switzerland, who is also the EAU Chairman of Guidelines on Urological Infections.
The news comes as a relief not only for people who suffer chronic UTIs, but also to doctors who have seen an uptick in antibiotic-resistant UTIs in the past several years. Because UTIs usually require antibiotics, patients run the risk of developing a resistance to the antibiotics, making infections more difficult to treat. A preventative vaccine could mean less infections, less antibiotics, and less drug resistance overall.
“Many of our participants told us that having the vaccine restored their quality of life,” said Dr. Bob Yang, Consultant Urologist at the Royal Berkshire NHS Foundation Trust, who helped lead the research. “While we’re yet to look at the effect of this vaccine in different patient groups, this follow-up data suggests it could be a game-changer for UTI prevention if it’s offered widely, reducing the need for antibiotic treatments.”
MILESTONE: Doctors have transplanted a pig organ into a human for the first time in history
Surgeons at Massachusetts General Hospital made history last week when they successfully transplanted a pig kidney into a human patient for the first time ever.
The recipient was a 62-year-old man named Richard Slayman who had been living with end-stage kidney disease caused by diabetes. While Slayman had received a kidney transplant in 2018 from a human donor, his diabetes ultimately caused the kidney to fail less than five years after the transplant. Slayman had undergone dialysis ever since—a procedure that uses an artificial kidney to remove waste products from a person’s blood when the kidneys are unable to—but the dialysis frequently caused blood clots and other complications that landed him in the hospital multiple times.
As a last resort, Slayman’s kidney specialist suggested a transplant using a pig kidney provided by eGenesis, a pharmaceutical company based in Cambridge, Mass. The highly experimental surgery was made possible with the Food and Drug Administration’s “compassionate use” initiative, which allows patients with life-threatening medical conditions access to experimental treatments.
The new frontier of organ donation
Like Slayman, more than 100,000 people are currently on the national organ transplant waiting list, and roughly 17 people die every day waiting for an available organ. To make up for the shortage of human organs, scientists have been experimenting for the past several decades with using organs from animals such as pigs—a new field of medicine known as xenotransplantation. But putting an animal organ into a human body is much more complicated than it might appear, experts say.
“The human immune system reacts incredibly violently to a pig organ, much more so than a human organ,” said Dr. Joren Madsen, director of the Mass General Transplant Center. Even with immunosuppressant drugs that suppress the body’s ability to reject the transplant organ, Madsen said, a human body would reject an animal organ “within minutes.”
So scientists have had to use gene-editing technology to change the animal organs so that they would work inside a human body. The pig kidney in Slayman’s surgery, for instance, had been genetically altered using CRISPR-Cas9 technology to remove harmful pig genes and add human ones. The kidney was also edited to remove pig viruses that could potentially infect a human after transplant.
With CRISPR technology, scientists have been able to prove that interspecies organ transplants are not only possible, but may be able to successfully work long term, too. In the past several years, scientists were able to transplant a pig kidney into a monkey and have the monkey survive for more than two years. More recently, doctors have transplanted pig hearts into human beings—though each recipient of a pig heart only managed to live a couple of months after the transplant. In one of the patients, researchers noted evidence of a pig virus in the man’s heart that had not been identified before the surgery and could be a possible explanation for his heart failure.
So far, so good
Slayman and his medical team ultimately decided to pursue the surgery—and the risk paid off. When the pig organ started producing urine at the end of the four-hour surgery, the entire operating room erupted in applause.
Slayman is currently receiving an infusion of immunosuppressant drugs to prevent the kidney from being rejected, while his doctors monitor the kidney’s function with frequent ultrasounds. Slayman is reported to be “recovering well” at Massachusetts General Hospital and is expected to be discharged within the next several days.