Researchers studying the effects of general anesthesia recently made a startling discovery: the drugs used to knock out patients during surgery may lead to increased pain when they wake up.

Doctors have known for decades that most general anesthetics may cause a temporary burning sensation when administered or swelling around the injection site. Similarly, inhaled agents can cause momentary coughing bouts, according to Gerard Ahern, a pharmacologist at Georgetown University Hospital in Washington, D.C.

Now Ahern has discovered that some drugs used to put patients to sleep may also increase postoperative pain from the procedure itself by boosting the activity of a protein called TRPA1 on the surface of pain-sensing nerve cells.

Ahern and his colleagues write in the journal Proceedings of the National Academy of Sciences USA that anesthesiologists may be able to limit post-op pain by sticking to meds that do not have this effect. "By understanding the mechanisms for these noxious effects," says Hugh Hemmings, a professor of anesthesiology at Weill Cornell Medical College in New York City, "it gives you a way to screen for new drugs that don't have these effects, but do produce anesthesia."

Ahern says the study may shed light on why some patients complain of more pain than others who have the same surgical procedure, although the researchers did not identify a particular ingredient in anesthesia that may cause the effect.

In attempting to pinpoint pain sources, Ahern and his team examined the effect of various anesthetics on TRPA1 and TRPV1, two proteins known to sense pain and respond to chemical irritants. Cells containing TRPA1 were activated by the drugs, but TRPV1 cells appeared to be unaffected. Research confirmed their findings on lab mice engineered not to produce TRPA1. When anesthesia was administered to them, they did not twitch their legs or frantically rub their noses against the walls and floors of their cages as they normally do.

That meant the researchers knew that the anesthetic was causing irritation while it was being administered. "We've shown that a direct irritation [from the anesthetic] is caused by TRPA1," says Ahern. "This is a provocative finding in terms of the clinical setting, because it was not really recognized that use of these drugs result in [the] release of lots of chemicals that recruit immune cells to the nerves, which causes more pain and inflammation."

The next step was to determine if more noxious drugs were likely to increase the pain following surgery. To do that, the team anesthetized one group of mice with an agent called isoflurane (the most widely used gaseous general anesthetic), and another group of animals with a drug called sevoflurane (which generally elicits a much milder reaction when it is administered). The researchers then swabbed the ears of the mice with another known irritant—to simulate tissue damage from surgery. They found that the ears on the mice injected with isoflurane swelled more dramatically, and the swelling persisted for much longer.

"During surgery a surgeon is cutting in with a scalpel and it's causing a lot of tissue damage," says Ahern. "[This result] suggests that during surgery you might get more activation of the TRPA1 if you use a pungent anesthetic" such as isoflurane, which will cause increased and longer-lasting pain at the surgery site. Avoiding such drugs or developing ones that ignore this protein, he notes, should lead to greater patient comfort.