One day last fall, Kiran’s period cramps became so painful they woke her up from a nap. The 19-year-old took some ibuprofen, but found little relief.
“The pain was so bad, it felt like someone was punching me,” said Kiran, who asked to be referred to by only her first name for privacy. It felt “like I was giving birth.”
The standard treatment for menstrual cramps — non-steroidal anti-inflammatory drugs (NSAIDs) like Midol, Motrin, and Aleve — provide Kiran with a few hours of relief at most, if they even work at all. She’s tried the other common treatment for cramps, hormonal birth control, but it gave her nausea and fatigue so severe she couldn’t stay on it.
That intractable pain is a monthly reality for many others who menstruate. It’s estimated that nearly 1 in 5 people with dysmenorrhea — or painful periods with or without an underlying medical issue like endometriosis or uterine fibroids — don’t get relief from existing treatments.
And yet, period pain has long been seen as a solved problem. There’s little funding for research into dysmenorrhea. Studies of treatments that looked promising — including research on Viagra to treat menstrual pain — have all but stalled for lack of investment or participation from patients.
The problem starts, experts said, with how unclear the science still is on the various causes of cramps. The prevailing theory behind cramps is a group of compounds called prostaglandins. At the beginning of menstruation, levels of the hormones progesterone and estradiol drop, leading to an increased production of prostaglandins. The compounds cause the uterus to contract to help it expel tissue, but may also cause painful cramps.
NSAIDs stop the production of prostaglandins. This should provide pain relief, especially if the drugs are taken before pain begins. The fact that they don’t work for everyone could be due to absorption issues, but it also hints that a different mechanism might be at play.
“In short, there are probably many mechanisms responsible for menstrual pain,” said Kevin Hellman, a menstrual pain researcher at the University of Chicago. Uterine contractions are a likely cause, and abdominal muscle soreness, inflamed tissue, pelvic floor muscle fatigue, and a number of other factors could also be at play, he said.
Having a better understanding of what’s causing the pain could help researchers develop more effective treatments. It could also help doctors know how to better treat those who don’t find relief from NSAIDs.
“There’s a whole raft of these newer treatments that we can test out if we just know who to use them on,” said Frank Tu, an OB-GYN and menstrual pain researcher at NorthShore University HealthSystem.
Those include electrical stimulation, sensory integration therapy, and even cognitive behavioral therapy, but clinicians have no way to assess which patients might benefit from which treatments.
“I envision a future where, if a woman is not responding to a medication, we might be able to do a series of tests and provide some guidance on what treatment might help her,” Hellman said.
One of those possible treatments is the erectile dysfunction drug Viagra. Sildenafil citrate (the generic version of Viagra) increases blood flow by dilating blood vessels. Prostaglandins, the compounds blocked by NSAIDs, may build up inside the blood vessels in the uterus, which could contribute to pain.
Theoretically, dilating blood vessels in the uterus could “lead to kind of a flushing away of those painful stimulants,” said Richard Legro, an OB-GYN and reproductive endocrinology researcher at Penn State who launched a clinical trial in 2007 to study the treatment. He also hypothesized the drug could bring more oxygen to the uterus — low oxygen levels can change the local pH and stimulate nerve endings, leading to pain. That’s why tourniquets and blood pressure cuffs can be painful. Dilating blood vessels would make room for more fresh, oxygenated blood.
Participants received sildenafil citrate or a placebo drug — administered vaginally in the hopes of getting a stronger effect and bypassing any absorption issues — while menstruating.
The small study of 25 people produced promising results. At the beginning of the treatment, the participants rated their pain with an average of 93 on a 100-point scale. The average pain rating for the women who received sildenafil citrate decreased to 23 within two hours, and 9 after four hours. There was a placebo effect, however — pain for the women who received the placebo decreased to 73 within two hours and 51 by four hours.
But the study ran out of funding before Legro’s team could recruit enough participants, and Legro’s application for an additional grant from the National Institutes of Health has been rejected twice. Legro said the reviewers didn’t think dysmenorrhea was worth studying. “I just feel they’re out of touch with women’s health,” he said.
They also had issues with the study’s design, in which each participant would receive both the placebo drug and sildenafil citrate at different points. Yet the FDA has backed that study design, and outside experts who spoke to STAT said they did not have concerns about it. Legro said reviewers were unfamiliar with why it was a suitable design for a dysmenorrhea trial.
“Those were the two issues that still burn almost a decade later,” Legro said. Legro published his results in 2013 and the study hasn’t progressed since.
Chen X. Chen, a menstrual pain researcher at the Indiana University School of Nursing, has similarly struggled to get funding to expand on a promising line of research into how the vaginal microbiome might relate to dysmenorrhea symptoms. In 2019, Chen ran a small study of 20 women that found that those with more severe period pain had less “good” bacteria, and more bacteria linked to inflammation.
Chen’s applications for further grant funding have been rejected twice, and two other applications are still under review. “The other day I was joking with a colleague and said, ‘It’s a practice of resilience and perseverance to get a grant funded,’” Chen said.
Chen’s experience points to one of the primary challenges of menstrual pain research: securing funding. Much of the funding comes from the federal government, specifically the National Institute of Child Health and Human Development (NICHD) within the NIH.
“There’s no foundation to pay for menstrual pain research,” Hellman said. “There is for endometriosis, there is for fibromyalgia, there is for Crohn’s disease, but there’s no philanthropic organization to pay for menstrual pain research.”
The institution does support research into dysmenorrhea, and has even put out calls for more grant applications on the condition.
But “there is always a portion of people who review grants who don’t really see [dysmenorrhea] as necessarily that important, in part because NSAIDs work really well for a portion of the population,” said Laura Payne, a clinical psychologist at McLean Hospital who has received NICHD funding to study menstrual pain as a risk factor associated with developing chronic pain.
Even if they get funding, many menstrual pain studies struggle to recruit enough participants. The Viagra study recruited women for over three years, but only ever enrolled 25 of its targeted 62 participants.
The study participants must be willing to come into the lab when they are menstruating and in pain. “That is an incredible challenge,” Hellman said. “We’re willing to do that — we have a high cancellation rate — but it’s very hard. You have to be in contact with a large number of women and keep track of their cycles.”
Researchers are getting creative about how to carry on their work despite those challenges. Hellman developed an MRI technique to visualize what’s going on in the uterus during menstrual cramps. He is currently using the technique in a clinical trial to test whether NSAIDs stop contractions. If NSAIDs don’t work for someone, this method should reveal why. It could be a drug absorption issue, but if the person never had contractions to begin with, there may be a different cause for the pain.
Payne is studying how emotions and pain perception interact with dysmenorrhea. “There’s that emotional component to the pain experience that we know can make the pain experience worse,” she said. Some people with dysmenorrhea have a higher risk of developing chronic pain, and she is studying if pain perception plays a role. If it does, she said, cognitive behavioral therapy may stop chronic pain from emerging, although no research has demonstrated this yet.
And the Viagra study may get a second chance. Tu said he and Hellman, who frequently collaborate, still hope to pick the sildenafil citrate project back up. It’s all a matter of playing the funding game. Tu hopes to include a small sildenafil citrate study as part of a larger, multi-arm trial testing different treatments with a strong chance of approval, like sneaking vegetables into a picky eater’s favorite meal. He already does this with bladder pain and dysmenorrhea studies.
“We think it could be done,” Tu said. “We just have to be patient.” While he strategizes and waits for the right opportunity, people like Kiran will continue dealing with their pain, month after month. They’ll wait for new treatments too — just not as patiently.
This story is part of ongoing coverage of reproductive health care supported by a grant from the Commonwealth Fund.