It's one of the more puzzling observations in medicine: The vast majority of chronic pain patients are women. Women suffer disproportionately from irritable bowel syndrome, fibromyalgia, headaches (especially migraines), pain caused by damage to the nervous system, osteoarthritis and much more. Women also report more acute pain than men after the same common surgeries.
In the lab, when researchers ask male and female volunteers to subject themselves to experimental pain —increasingly hot stimulation on the inner arm, immersion of the hand in very cold water, electrical jolts to the skin — women show lower pain thresholds (that is, they report pain at lower levels of stimulus intensity) and lower tolerance (they can't bear intense pain as long).
Women are also better able to detect small gradations in pain stimuli. And they respond differently to certain opioid painkilling drugs. (It's not clear whether men and women differ in sensitivity to cancer pain.)
Only recently have researchers begun to study the genetic, physiological, hormonal and psychosocial factors that may underlie these sex differences. In part, that's because pain researchers have been hampered by one rather shocking fact: Most basic pain research is still done in male mice and rats.
This has been "a catastrophe," says McGill University pain geneticist Jeffrey Mogil. Men and women can be so different in the way their nervous systems process pain that someday there may be "pink pills for women and blue pills for men," he says. The lopsided research exists solely because of "inertia," he adds, saying that the old rationale that menstrual cycles make females too difficult to study is bogus.
Others agree, among them Dr. Roger B. Fillingim, lead author of an exhaustive review of sex and pain research published by the American Pain Society in 2009. Fillingim, a pain researcher at the University of Florida, notes in that paper that, while the National Institutes of Health require routine inclusion of both sexes in human studies, much animal research "continues to eschew females."
Given that pain is mainly a female problem, he adds, this means research that excludes females "is incomplete at best and invalid at worst."
Luckily, this shutout is not total. And some human research does specifically address sex differences —with complex and fascinating results.
Take hormones. Growing up, boys and girls show comparable patterns of pain until puberty, notes Dr. Navil Sethna, a pediatric anesthesiologist at Children's Hospital Boston. "After puberty, certain types of pain are more common in girls, and even if the incidence is the same, reported pain severity is more intense in girls than boys, especially for headaches and abdominal pain," Sethna says. This pattern persists through adulthood. For example, the lifetime prevalence for migraines is 18% for women and 6% for men.
The same pattern holds for temporomandibular joint disease ( TMD). There are no sex differences before puberty, but there are significant differences afterward.
Not all studies agree, but many do show that after puberty women experience striking fluctuations in their response to pain at different points in the menstrual cycle. This has been noted for irritable bowel syndrome, TMD, headache and fibromyalgia. One explanation, some researchers say, is that estrogen protects against pain at high levels and enhances it at low levels. (The male hormone testosterone seems to protect against pain.)
This theory fits with the observation that during pregnancy, when estrogen levels are high, women often get fewer migraines and less TMD pain. And it fits with the observation that, after childbirth, when estrogen falls abruptly, the number of migraine attacks increase.
The absolute level of estrogen may not be what's key, says Dr. Fernando Cervero, a pain researcher at McGill, in Montreal. Instead, what may matter are the fluctuations in hormone levels during the menstrual cycle. (Estrogen levels climb in the first half of the cycle, then decline in the second half.) "It's the change that produces the change" in perceptions of pain, he says.
You'd think this would mean that women should experience more pain after menopause, a time when estrogen falls abruptly.
In fact, research results are all over the place.
Several studies have shown that women who combat low levels of estrogen by taking hormone replacement therapy have more back pain and more pain from TMD. Other studies detect no link between hormone replacement therapy and pain in older women. Still others show that when women stop taking hormone replacement therapy, their pain appears to go up, and they may get more migraines.