Painkillers Designed Especially for You?

May 11, 2005 -- -- As part of his research, Dr. Jeff Mogil scoops up lab mice, one at a time, into specially designed cardboard and cloth pockets and holds each of them over a vat of hot water.

The mice don't seem to have a problem getting in the pockets, Mogil said. "It's dark and smelly in there."

But the pockets aren't quite big enough to hold the entire mouse. The tail hangs outside -- allowing Mogil to dip the tail into the 120-degree Fahrenheit water. Then he measures how long it takes for the mouse to flick its tail out.

Each mouse takes a different amount of time to react. And Mogil, a professor of pain studies at McGill University in Montreal, is trying to find out why.

Scientists have long recognized that all living things, from lab mice to human beings, have a range of pain sensitivity, and they're starting to discover the genetic basis of these differences. Doctors are on the cusp of a revolution in pain relief, they say.

Today, patients undergoing surgery get painkillers in a standard dosage mainly determined by body weight. But "there may be a point in time when we may be able to tell which patient responds to which type of pain medicine," said Dr. Sunny Anand, director of the Pain Neurobiology Laboratory at Arkansas Children's Hospital in Little Rock.

A patient could get a regimen of painkillers that will take into account his or her age, sex and pain threshold, and compensate for any side effects or possible predisposition to addiction.

"I don't think it's science fiction," Anand said. "Within the next five years we will be there."

Brain and Sex Differences

There has already been some progress in understanding the genetic basis of pain. One of the primary areas of discovery has been the most fundamental: the difference between men and women.

Many scientists believe that male and female brains differ in architecture, and consequently, "some of the genetic differences that create sex brain differences may make pain vulnerability different," said Dr. Lonnie Zeltzer, director of the pediatric pain program at UCLA Mattel Children's Hospital.

For example, she says she found that mothers who are highly sensitive to pain tended to have daughters who are highly sensitive to pain, but the mother's level of sensitivity seemed to have no effect in sons. She said she also found that while pain tolerance generally increases with age, boys' pain tolerance rises in late puberty while girls' pain tolerance drops.

Different areas of men's and women's brains light up during "arousal" events, she said. Using an earthquake as an example, she said women tend to remember more of the details, such as what day it was or what somebody was wearing, whereas men would remember more of the overall event.

Zeltzer said such disparities might be due to hormones such as testosterone. But the results of a seven-year study involving eight laboratories released earlier this year suggest another genetic basis for these differences -- not only between sexes but individuals.

A Key in COMT?

Dr. William Maixner, one of the scientists involved in the study, said they found that individuals who had a variation in a gene responsible for creating an enzyme called COMT were likely to be more sensitive to pain.

COMT breaks down the stress hormone ephinephrine, and if the gene doesn't produce enough COMT, ephinephrine continues to circulate throughout the body. When that happens, the body is more sensitive and more likely to develop chronic pain.

Maixner, director of the Neurosensory Disorders Unit at the University of North Carolina at Chapel Hill's School of Dentistry, said women in general have lower levels of COMT because the enzyme is regulated by estrogen.

The study also suggested the genetic variation that produced less COMT could be one of the causes of chronic pain.

The More Sensitive Sex

The COMT discovery echoes the general notion that women are more sensitive in general -- not only to pain, but other sensations.

Men have "morphine-like proteins that deal with this flight-or-fight response that makes them more pain-tolerant," Maixner said. "Women don't have the same capacity to engage this system." Their bodies produce a different type of protein to deal with pain, he said

Maixer suggests females might have this heightened sensitivity to better raise and protect their children.

This difference in pain regulation has implications in the operating room. Not only do men's bodies create morphine-like proteins to deal with pain, but their bodies are more able to process these agents, called opioids.

"If you give [opioid-based painkillers like] morphine or Dilotid in fact you have to give more to women than men because they have a lower density of opioid receptors," said Zeltzer. "Women tend to require more than men to achieve the same type of relief."

Other Genetic Differences

This sort of genetic predisposition isn't limited to gender though. Scientists have long known that people with fair skin and red hair are generally more sensitive to pain and also more resistant to opioid-based painkillers.

In the early 1980s, scientists discovered as many as 10 percent of Caucasians have a variation in a gene that makes them unable to make the enzyme that would allow them to metabolize codeine, another painkiller.

"Giving them codeine is useless, maybe worse than that because they might get side effects," Mogil said.

And Anand says there is some recognition that genetics can also determine the effectiveness of certain types of antidepressants called SSRIs.

Nature and Nurture

But genetics is far from the only thing to determine a person's susceptibility to pain.

In his tests, Mogil says even more important than genetics in determining how long the mouse would leave its tail in the 120-degree water was the experimenter -- although he doesn't know why.

"When I do the testing, the latencies are short," he said. "When my grad students do it, they're longer."

The order of testing also matters, he said. The first mouse out of a cage of four takes longer to remove its tail than the fourth. He thinks there is some sort of communication that takes place.

Zeltzer, who studies pain in children, said pain vulnerability is a complex interaction between genes and environment. "It's very much an interplay of nature and nurture," she said.

But for all doctors, this research is a sign that the old prescriptions may soon become obsolete. It's getting to the point where they won't be able to say "just take two and call me in the morning" anymore.