HIS PAIN, HER PAIN

When It Comes To Hurting Men Are From Mars And Women Are From Venus After
All, Says Lisa Melton

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 Center. "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 fetus, 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
progress-but 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 (see Diagram, p 34). 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 yoyos 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 Gainsville.

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", p 35). 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 women-the 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 mates. 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 flipside 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 Rutgers 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 painblocking 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.

Further reading: Sex, Gender, and Pain edited by Roger Fillingim,
International Association for the Study of Pain (IASP) Press (2000) "The
evaluation of pharmacologic therapy in humans: a brief summary of the drug
evaluation process and guidelines for clinical trials as they relate to
women" by Janice Schwartz, The Journal of Gender-Specific Medicine, vol 4,
p 13 (2001)

SIDEBAR

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 babies-is 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 neurosteroids, from
cholesterol or progesterone. In mounting doses, they may act as analgesics,
anticonvulsants and even anaesthetics.

Researchers are now intent on harnessing these effects. The trick is to
untangle one neurosteroid 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 -a lphadolone 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 antiepileptic with few, if
any, side effects. "I think neurosteroids are going to be the
pharmaceuticals of the future," says Goodchild.