Source: Economist
Date: 21 July 2005

Sex and drugs

Men and women seem to perceive pain in different ways.
That may mean they sometimes need different pain-relief drugs.

MALES and females respond to pain differently, even as children. In most places, boys are expected to show a stiff upper lip when they get hurt, while in girls wailing is, well, girlie. In part, this difference is learnt—or, at least, reinforced by learning. But partly, it is innate. It is hard, for instance, to blame upbringing for the finding that boy and girl babies show different responses to pain six hours after birth, or that male rats are more long-suffering than females. It is also life-long. Ed Keogh of the University of Bath, in England, and his colleagues have found that women report feeling pain in more bodily areas than men, and also feel it more often over the course of their lives.

Many researchers are therefore concluding that genetics underpins at least some of the difference, and that females really do feel pain more than males. Indeed, some go further. They think that the way men and women experience pain is not only quantitatively different, but qualitatively different, too. In other words, men's and women's brains process pain using different circuits. Some pain scientists therefore think it is only a matter of time before painkillers are formulated differently for men and women in order to account for this difference.

Jeffrey Mogil, director of the pain genetics laboratory at McGill University in Montreal, is one of the leading advocates of such “pink and blue” painkillers. Pick a disease at random, he says, and the chances are that females and males will handle the pain associated with it differently. That seems to be true in mice, at least. When new mouse “models” of human disease are created by genetic engineers, Dr Mogil and his colleagues are often asked to test the engineered mice for their responses to pain. They consistently find differences in the way the mutant, diseased mice and their non-mutation-carrying brethren respond to painful stimuli. But, generally, those differences are seen more strongly in one sex than the other.

A prescribing headache

The latest example of such a difference is in migraine, a condition that is three times more common in women than in men. In 2004, a group of researchers led by Michel Ferrari of Leiden University in the Netherlands reported that they had created what they believed to be the first mouse model of migraine. Since some researchers argue that migraine is associated with heightened sensitivity to pain, they sent their creation to Dr Mogil for testing. He stresses that his data are preliminary. However, he does find a lowered pain threshold in the mouse migraine model compared with healthy mice—but only in females.

Dr Mogil is now convinced that the pain response in men and women is mediated by different brain circuits—and not only because of his own observations. Obstetricians and gynaecologists have long known that certain drugs are particularly effective in women. Mothers in childbirth prefer nalbuphine to morphine, for instance. Men, however, report the opposite preference when they are in pain.

Both nalbuphine and morphine work by stimulating the brain's endogenous-opioid receptors (endogenous opioids are the molecules that opium-derived drugs mimic). But opioid receptors come in several varieties, two of the most important of which are known as mu and kappa. Morphine binds to the mu receptors, while nalbuphine stimulates the less well-studied kappa receptors. Kappa-receptor agonists, as molecules such as nalbuphine are known, appear to have little or no pain-relieving effect in men.

Two years ago, Dr Mogil identified the first gene known to be involved in modulating pain thresholds in women. Variations in this gene have no effect on men's responses to a kappa-receptor agonist called pentazocine, but they do affect the response in women. The protein produced by this gene, melanocortin-1 receptor, also affects hair and skin colour. Working in collaboration with Roger Fillingim of the University of Florida, Gainesville, Dr Mogil found that redheaded women with fair skin—who have a particular version of the receptor—have a heightened response to pentazocine.

Jon Levine and Robert Gear, of the National Institutes of Health Pain Centre at the University of California, San Francisco, also think that there are fundamental differences between the sexes when it comes to pain. They have explored the effects of nalbuphine on post-operative pain in men and women who have had their wisdom teeth removed. The results suggest that kappa-opioid agonists not only fail to alleviate pain in men, they can actually make it worse.

Dr Gear and Dr Levine believe that as well as an analgesia (ie, pain-suppression) circuit, the brain contains what they call an anti-analgesia circuit—one which, when activated, pumps pain up. They have shown that which circuit is activated depends not only on the type of receptor a drug acts on, but also the dose given. Among their dental patients, low doses of nalbuphine had a short-lasting analgesic effect in the women, but profoundly enhanced pain in the men. However, when they added a low dose of naloxone—a drug that blocks all types of opioid receptor—to the nalbuphine, the sex difference disappeared and pain relief was significantly enhanced in everyone. After refining the relative proportions of the two drugs in the mixture, they have succeeded in finding (and patenting) a combination that is effective in both sexes.

Nor is it only the mechanism of pain perception that differs between the sexes. Dr Keogh and his colleagues argue that there are significant differences in the ways men and women cope with pain, as well.

This conclusion is based on studies involving hospital patients, as well as others on volunteers who were exposed to a painful stimulus, such as an ice-water arm-bath. Using this, the researchers were able to measure the point at which people first notice pain, as well as their tolerance—the point at which they can no longer stand it. Men were able to minimise their experience of pain by concentrating on the sensory aspects—their actual physical sensations. But this strategy did not help women, who focused more on the emotional aspects. Since the emotions associated with pain, such as fear and anxiety, tend to be negative, the researchers suggest that the female approach may actually exacerbate pain rather than alleviating it.

Dr Keogh, a psychologist, sees this difference as an effect of social conditioning—and uses it to point up the dangers of under-estimating social influences in favour of those of the genes. But it is not obvious why such male and female “coping strategies” should not be underpinned by genetics, in the same way that perceptions are.

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