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Headache and nausea are two well-known side effects of many drugs used for general anesthesia. But some general anesthetic drugs also have another surprising side effect: They increase a patient's sensitivity to pain.

Several years ago, Dr. Pamela Flood, assistant professor of anesthesiology, rediscovered the painful effect of the anesthetic gases, including isoflurane, when she was investigating how the gas works as an anesthetic. At the concentrations used during surgery, the anesthetic gases inhibit pain. However, using a mouse model, she found that at the low concentrations that are present for several hours after a patient awakes from surgery, the sensitivity to pain actually increases. The mechanisms responsible for this pain-producing action are the subject of continuing studies in the mouse model. The same effect in humans was observed as early as 1960 but the research results languished.

Now Dr. Flood has discovered that this paradoxical action is greater in females than males and that the difference is hormonally based. In November she started a clinical trial to test ways to reduce the pain sensitivity caused by isoflurane. "We think if we prevent this effect, people will have less pain after surgery and will need less narcotics, which can prolong their recovery," she says.

Anesthesiologists usually use anesthetic gases such as isoflurane to keep a person asleep, immobile, and unaware of pain during surgery. Gas concentration is kept at around 1.2 percent during surgery and then slowly dissipates after surgery. At 0.2 to 0.3 percent concentration the individual normally awakens, but increased sensitivity to pain can be caused by concentrations as low as 0.05 percent isoflurane. Studies show that it can take hours to get rid of this remaining gas, during which time pain sensitivity is enhanced.

From her previous research, Dr. Flood knew that nicotinic receptors in the central nervous system are blocked by the gas molecules at the same low concentration that increases pain. To see if the blockage causes an increase in pain sensitivity, Dr. Flood gave mice nicotine, a substance that activates the nicotinic receptors. Pain sensitivity was measured by applying heat to the mouse's paw and recording the time it took the mouse to lift its paw. Nicotine prevented isoflurane from increasing pain sensitivity, suggesting the involvement of the nicotinic receptors in the pain-enhancing action of volatile anesthetics. The results were published last July in Anesthesiology.

By blocking nicotinic receptors, Dr. Flood says isoflurane is probably preventing the brain from modulating the incoming pain signals. After surgery, signals from the surgical site and the surrounding inflammation are sent from the spinal cord to the brain where the sensations are interpreted as pain. But fibers that descend from the brain into the spinal cord can reduce the amount of pain signals that ultimately reach the brain. Nicotinic receptors are at the end of these descending adrenergic and serotonergic neurons and, when activated, enhance the release of neurotransmitters and reduce pain. By blocking the nicotinic receptors, isoflurane prevents neurotransmitter release and this natural pain relieving-mechanism is made less effective.

In her latest research, Dr. Flood found that females experience a much greater increase in pain sensitivity with isoflurane than males and that the sex difference is related to estrogen levels. Males have a constant level of estrogen from the conversion of testosterone and experience only a modest increase in pain sensitivity with isoflurane. In females, mice that produce no estrogen felt about 25 percent more pain than mice near ovulation that produced the most estrogen. Dr. Flood is now looking to see if the sex difference exists in people and is planning experiments to understand how estrogen acts to modify anesthetic actions.

"Ultimately, the goal of the research," Dr. Flood says, "is to bring the lab results to people and find a practical way to reduce postoperative pain in patients." Her current clinical studies test whether the gender difference occurs in male and female human volunteers and whether nicotine nasal spray given to women after surgery can reduce their pain and narcotic requirements. Results are expected in about one year, but Dr. Flood has already filed a patent for the use of nicotinic agonists on postoperative pain.

"The side effects of anesthesia have been overlooked because everyone expects people to have pain after surgery," Dr. Flood says. "Maybe this is a side effect that can be reversed or prevented."