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Pain perception
Sex and drugs
Jul 21st 2005
From The Economist print edition
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.
The evolutionary reason why men resist pain better than women is, however, a mystery.
After all, pain is there to stop you doing bad things to yourself. Perhaps it is because
males and females are exposed to different sorts of pain. Males, for instance, get into
fights much more often than females do, and thus get wounded more often. On the other
hand, they do not have to undergo the visceral pain of childbirth. And perhaps a
willingness to tolerate less pain than men do helps to explain why women live longer
than their menfolk.