JON LEVINE was just testing painkillers on people who’d had a wisdom tooth extracted, when he uncovered rather more than he’d bargained for. The women in his study group found that strong painkillers related to morphine, called kappa-opioids, were most effective at numbing pain. But the same drugs didn’t work for the men at all. “In fact, the doses used in the clinical trial made pain worse for men,” says Levine, a clinical neuroscientist from the University of California in San Francisco.
He was shocked. “The idea that a therapy that had been around for decades could affect women and men in such dramatically different ways was anathema,” he says. “It was such an incredible mindset in the field of pain, missing what had clearly gone on in front of their eyes for years.”
It’s not an effect specific to opioids, either. Another recent study showed that ibuprofen, a widely used anti-inflammatory drug, can be much less effective for women than for men. Researchers at the University of New South Wales found that when they used mild electric shocks to induce pain in healthy young people, only the men got any relief with ibuprofen. It was only a small study, but still worrying, as the drug is often marketed with women in mind.
It’s been five years now since Levine first spotted a sex difference, yet we still don’t really understand why it exists. And when it comes to testing or prescribing painkillers, or studying pain, nothing much has changed. Remarkably, even many of those involved in pain research are unaware of these findings. “I myself have never been able to get relief from ibuprofen and now I understand why,” says Marietta Anthony, a pharmacologist at Georgetown General Clinical Research Centre. “This is very dramatic, and has a direct impact for the clinic.”
There have always been playful stereotypes of how men and women suffer pain differently. Women are more delicate but endure childbirth. Men are stoical until they see a dentist’s chair. But these few studies show there’s more to the caricatures than meets the eye. Real differences in the underlying biochemistry of male and female pain are revealing themselves. The differences are also starting to suggest some surprising strategies for sex-specific painkillers.
It’s perhaps no surprise that the differences have eluded scientists for so long. Pain is multidimensional and highly subjective, and therefore very difficult to study. It varies with the time of day, age, diet, stress, genetic background, location, past and present injuries, and in women, reproductive status and the menstrual cycle.
But not only that. Only 10 years ago, pharmaceutical compounds were tested almost exclusively on men. Women were left out of tests in case their inconveniently fluctuating hormones messed up the analysis. The testers also feared harming a pregnant woman’s foetus, while ignoring the obvious safeguard of a pregnancy test and contraceptives.
Only in 1993 did the US make it a legal requirement for women to be included in clinical trials. According to a recent report, on average, 52 per cent of subjects in large-scale trials are women. This looks like progressbut it’s not. This figure includes women-only studies such as those investigating hormone therapies or drugs to treat breast cancer. And when testing medications for diseases common to both sexes, women’s and men’s results are often still lumped together, burying any differences in a statistical quagmire.
In Britain, things are not much better. The Department of Health advises that gender should be taken into account when determining whether a medicinal product is safe and effective. But how strictly this advice is heeded is anyone’s guess.
To Marietta Anthony, who was previously acting deputy director of the Office of Women’s Health at the FDA, change is imperative. If a drug works differently in men and women, this information should be displayed clearly on the label. “Side effects and efficacy really are different in men and women,” says Anthony, “[and] there may be a very fundamental biological reason.”
One of the more obvious biological reasons is that men and women tend to suffer from different disorders, mostly the result of a complex bag of hormones, reproductive status and anatomy. So differences in how women and men report feeling pain have often been dismissed as being solely down to the pain’s different origins. But origins aside, there’s growing evidence that even when the source is the same, the biochemical signals, nerve connections and the way the brain handles pain are all quite different in the two sexes.
Sex hormones are one reason for the differences in pain perception. Women always cry “ouch” first. Whether it’s in the clinic or the lab, using the heat of a small laser, the pressure of a tourniquet or electrodes placed on the skin, women are less tolerant of pain. But women’s pain sensitivity also yo-yos throughout the menstrual cycle, and just before a period, pain thresholds take a dive. “There is a view that oestrogen is excitatory and could enhance pain transmission in the peripheral nervous system, the spinal cord and in the brain,” explains Roger Fillingim from the University of Florida at Gainesville.
Progesterone has quite the opposite effect: it dampens the nervous system’s response to any nasty stimulus. And it’s most obvious during pregnancy. When progesterone levels rocket in the third trimester, they induce a state of profound analgesia in preparation for labour. Indeed, these hormonal influences are being turned to medical advantage (see “Make your own Valium”). The rest of the time when not pregnant women’s tolerance generally remains below that of men.
Levine was one of the first to get an inkling of how sex hormones might be setting men’s and women’s pain thresholds at different levels. His team found that women consistently reported more severe pain than men after removal of a wisdom tooth. Since inflammation is known to underlie most aches and pains, Levine decided to investigate whether inflammatory signals differed between sexes. He gave oestrogen to castrated male rats, and found their pain tolerance plummeted to female levels. And giving testosterone to sterilised females gives them masculine tolerance. In other words, if you switch the sex hormones around, you switch their pain sensitivity around too.
Looking deeper into the biochemical pathways, he has recently found that sex hormones alter the chemical signals involved in inflammation and tissue repair. The female hormone oestrogen quenches the production of bradykinin, a potent inflammatory mediator that protects injured tissues. He believes these differences might account for the different responses to opioids seen in his trial. “As difficult as it is for many of us to acknowledge differences other than in reproductive function, there really are differences between men and women,” says Levine.
Another curious difference caused by our distinct physiology is that especially in womenthe visceral organs “talk” to each other, so that pain in one internal organ can be triggered or enhanced by pain in another. Maria Adele Giamberardino at the University of Chieti, Italy, first noticed this effect in women with kidney stones. She has found that when women have painful periods, a condition called dysmenorrhoea, the typical searing back pain from the urinary tract caused by the stones is much more vicious.
Giamberardino’s findings ring true to pain specialists. In the clinic, both men and women who suffer from chronic conditions such as irritable bowel syndrome often also experience fibromyalgia, headaches and chronic pelvic pain. But this coexistence of painful disorders is greater in females than in males. Giamberardino’s hypothesis is that the female reproductive organs are highly interconnected with the other organs, and that pain in one organ may trigger painful conditions in others that have linked nerve supplies. The flip side is that these links could become new avenues for treating pain. By tapping into the same communication channels, treating period pains, for example, might help to alleviate other aches.
Our different reproductive organs can also lead to differences in how our diet affects pain ratings, says Beverly Whipple, a neurophysiologist and obstetric nurse from Rutger’s University in New Jersey. She noticed that Hispanic women seemed to experience more pain during labour, and at first she attributed this to culture. “I told my students that these women were just more comfortable expressing their pain.” Then she became aware of studies in which neonatal rats injected with capsaicin, the chemical that gives chilli its hot bite, did not experience a certain pain-blocking effect that females normally get when pressure is applied to the cervix. Could a diet rich in hot peppers be interfering with the Hispanic women’s natural analgesia?
To find out, Whipple set up a study with Mexican women whose consumption of chillies ranged from one or two a week to three a day. “We found that the women who ate a diet high in hot chilli peppers do not get the pain-blocking effect,” she says.
The physiological differences don’t stop at our reproductive organs and hormones, however. They run all the way to the brain. In a study soon to be published, Anthony Jones, director of the Human Pain Research Group at the University of Manchester, has scanned the brains of people experiencing pain from a variety of natural causes. Although many parts of the brain are engaged when a person is in pain, Jones pinpointed one main area of disparity between the sexes. “Women tend to process pain more in one part of the brain concerned with attention and emotion,” he says. He suggests that the experience of pain is bound to differ between men and women. “Women tend to process things in a more affective way,” he says. For women, pain depends on how much attention they pay to a tender spot. So when it comes to treatment, for women it may be as important to provide them with distractions, coping mechanisms and psychological care as painkilling drugs.
Distractions may work in a different way for men. It seems to be important for men to act tough in public. In experiments performed at the State University of New York, Fredric Levine and Laura Lee De Simone found that men’s pain thresholds soared if an attractive female technician was conducting the tests. Women, however, seemed immune to the charms of hunky men. And according to Knox Todd, a specialist in the assessment and treatment of pain at Emory University in Atlanta, Georgia, the differences make their way into the clinic. “What we see in the emergency department is that males make a public display of stoicism, ask for no pain medication, and keep up a good public front.” But their stoicism evaporates as soon as men leave the hospital to go home, he says.
But who wins out in the end? Is having a higher pain threshold good or bad? To women, pain is a wake-up call to sort out the problem before it gets too big. Men, who can put up with more, postpone asking for help until it’s too late. Women’s prompt action could be at least part of the key to their longer life expectancy. In the meantime, a message to dithering males: stop procrastinating, make that dental appointment, and your niggling shoulder pain might get sorted into the bargain. And to overdue pregnant women: ignore the advice that a curry will bring on labour. Chillies are the last thing you need when the contractions kick in.
* * *
Make your own Valium
Sex hormones might complicate our understanding of pain, but one day they might help us beat it, too. Locked inside your brain is the most powerful sedative, anti-anxiety drug and painkiller rolled into one. This magical compound derives from the sex hormone progesterone and, if medicinal chemists get it right, it may soon lead to an analgesic to rival morphine.
Scientists have known since the 1940s that progesterone, the female hormone we usually associate with the Pill and making babiesis, also an incredibly potent sedative. Now researchers have found that it is the breakdown products of progesterone that have such a potent anaesthetic and analgesic effect. “During pregnancy, for example, as a woman comes close to term, the levels of these breakdown products of progesterone are extremely high,” says Jeremy Lambert, a neuropharmacologist at the University of Dundee in Scotland. Only the natural hormone will do, the synthetic compounds used in contraceptive pills do not work in the same way.
Fortunately, this natural analgesia and anxiolysis is not exclusive to women. There are enzymes in the brain and spinal cord of both men and women that produce similar breakdown compounds, known as neuro-steroids, from cholesterol or progesterone. In mounting doses, they may act as analgesics, anti-convulsants and even anaesthetics.
Researchers are now intent on harnessing these effects. The trick is to untangle one neuro-steroids action from another: to induce pain relief without knocking you unconscious and without affecting fertility. Colin Goodchild, an anaesthesiologist at Monash University in Victoria, Australia, may have already hit on a compound alphadolone that can do exactly that. “It can work as a pain-relieving drug without causing sedation,” says Goodchild.
Goodchild hopes that alphadolone may eventually replace opioids such as morphine, or at least reduce their usage. Progesterone metabolites might also lead to an “all-natural” sleeping pill and anti-epileptic with few, if any, side effects. “I think neuro-steroids are going to be the pharmaceuticals of the future,” says Goodchild.