快猫短视频

JON LEVINE was just testing painkillers on people who鈥檇 had a wisdom tooth
extracted, when he uncovered rather more than he鈥檇 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鈥檛
work for the men at all. 鈥淚n fact, the doses used in the clinical trial made
pain worse for men,鈥� says Levine, a clinical neuroscientist from the University
of California in San Francisco.

He was shocked. 鈥淭he idea that a therapy that had been around for decades
could affect women and men in such dramatically different ways was anathema,鈥� he
says. 鈥淚t was such an incredible mindset in the field of pain, missing what had
clearly gone on in front of their eyes for years.鈥�

It鈥檚 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鈥檚 been five years now since Levine first spotted a sex difference, yet we
still don鈥檛 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. 鈥淚
myself have never been able to get relief from ibuprofen and now I understand
why,鈥� says Marietta Anthony, a pharmacologist at Georgetown General Clinical
Research Center. 鈥淭his is very dramatic, and has a direct impact for the
肠濒颈苍颈肠.鈥�

There have always been playful stereotypes of how men and women suffer pain
differently. Women are more delicate鈥攂ut endure childbirth. Men are
stoical鈥攗ntil they see a dentist鈥檚 chair. But these few studies show
there鈥檚 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鈥檚 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鈥檚 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鈥攂ut
it鈥檚 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鈥檚 and men鈥檚 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鈥檚
guess.

To Marietta Anthony, who was previously acting deputy director of the Office
of Women鈥檚 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.
鈥淪ide effects and efficacy really are different in men and women,鈥� says Anthony,
鈥淸and] there may be a very fundamental biological reason.鈥�

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).
So differences in how women
and men report feeling pain have often been dismissed as being solely down to
the pain鈥檚 different origins. But origins aside, there鈥檚 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.FIG-23264801.jpg

Sex hormones are one reason for the differences in pain perception. Women
always cry 鈥渙uch鈥� first. Whether it鈥檚 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鈥檚 pain sensitivity also yo-yos
throughout the menstrual cycle, and just before a period, pain thresholds take a
dive. 鈥淭here is a view that oestrogen is excitatory and could enhance pain
transmission in the peripheral nervous system, the spinal cord and in the
brain,鈥� explains Roger Fillingim from the University of Florida at
Gainsville.

Progesterone has quite the opposite effect: it dampens the nervous system鈥檚
response to any nasty stimulus. And it鈥檚 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 鈥淢ake your own Valium鈥�). The
rest of the time鈥攚hen not pregnant鈥攚omen鈥檚 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鈥檚 and women鈥檚 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鈥攁
potent inflammatory mediator that protects injured tissues. He believes these
differences might account for the different responses to opioids seen in his
trial. 鈥淎s difficult as it is for many of us to acknowledge differences other
than in reproductive function, there really are differences between men and
women,鈥� says Levine.

Another curious difference caused by our distinct physiology is
that鈥攅specially in women鈥攖he visceral organs 鈥渢alk鈥� 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鈥攁 condition called dysmenorrhoea鈥攖he typical
searing back pain from the urinary tract caused by the stones is much more
vicious.

Giamberardino鈥檚 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鈥檚 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. 鈥淚 told my students that these women were just more comfortable
expressing their pain.鈥� Then she became aware of studies in which neonatal rats
injected with capsaicin鈥攖he chemical that gives chilli its hot
bite鈥攄id 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鈥檚 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. 鈥淲e found that the women
who ate a diet high in hot chilli peppers do not get the pain-blocking effect,鈥�
she says.

The physiological differences don鈥檛 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. 鈥淲omen tend to process pain more in one part of the brain concerned
with attention and emotion,鈥� he says. He suggests that the experience of pain is
bound to differ between men and women. 鈥淲omen tend to process things in a more
affective way,鈥� 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鈥檚 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. 鈥淲hat 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.鈥� 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鈥檚 too late.
Women鈥檚 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.

快猫短视频s have known since the 1940s that progesterone鈥攖he female
hormone we usually associate with the Pill and making babies鈥攊s 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. 鈥淒uring pregnancy, for example, as a woman comes close to term, the
levels of these breakdown products of progesterone are extremely high,鈥� says
Jeremy Lambert, a neuropharmacologist at the University of Dundee in Scotland.
Only the natural hormone will do鈥攖he 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鈥攁lphadolone鈥攖hat can do exactly that. 鈥淚t can work
as a pain-relieving drug without causing sedation,鈥� 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 鈥渁ll-natural鈥� sleeping pill and antiepileptic with few, if any, side
effects. 鈥淚 think neurosteroids are going to be the pharmaceuticals of the
future,鈥� says Goodchild.