Spicy Combo Blocks Pain Without Numbness

BOSTON, Oct. 3 -- Adding capsaicin to an unusual anesthetic resulted in a combination that blocked pain but didn't cause numbness or paralysis, researchers here said.
The anesthetic in question is a lidocaine derivative called QX-314, which isn't used clinically because it doesn't ordinarily affect nerve cells in the same way other pain-blocking drugs do, according to Bruce Bean, Ph.D., of Harvard Medical School, and colleagues.
When the drug was combined with capsaicin, the potent ingredient in chili peppers, it gained the ability to enter nerve cells -- but only the pain-sensing nociceptors, the researchers reported in the Oct. 2 issue of Nature.
The finding -- in experimental rats -- could lead to new painkillers that specifically target pain-sensing neurons, eliminating the numbness, paralysis, and blockage of autonomic nerves associated with current anesthetics, the researchers said.
"Eventually this method could completely transform surgical and post-surgical analgesia, allowing patients to remain fully alert without experiencing pain or paralysis," Clifford Woolf, M.D., of Massachusetts General Hospital, the study's senior author.
Most anesthetics are neutral compounds that diffuse though the cell walls of neurons and, once inside, block sodium ion channel activity, thereby halting electrical signaling in the cell, the researchers said.
But QX-314 is electrically charged and is usually unable to get through the cell walls of nerve cells, although if placed in a cell it also blocks sodium channels.
That's where capsaicin comes in. Dr. Bean and colleagues took advantage of the fact that only pain-sensing neurons have the so-called TRPV1 receptor -- which opens when stimulated either by excessive heat or by the spicy compound.
In vitro experiments showed that the combination of capsaicin and QX-314 was able to block electrical activity in pain-sensing neurons, but had no effect on other nerve cells, the researchers reported.
In rats, injecting QX-314 alone into the animals' hindpaws had little or no effect on their sensitivity to being pricked with stiff fibers, while injecting capsaicin alone made the animals significantly more sensitive to the painful stimulus.
But a combination of the two immediately eliminated the increased sensitivity caused by the capsaicin and, within two hours, the rats were half as sensitive as they had been at the start -- a difference that was significant at P<0.05.
The effect persisted for about three hours, the researchers said.
They found a similar response when the rats were exposed to a heat source. With either compound alone, the animals were able to withstand the heat for between eight and 20 seconds.
But two hours after injection with the combination, none of the animals reacted for at least 25 seconds -- a difference that was significant at P<0.05.
Finally, Dr. Bean and colleagues tested the ability of the combination to produce a nerve block when injected near the sciatic nerve of the animals. As expected, a standard 2% lidocaine solution caused complete paralysis of the lower limb by 15 minutes and complete or partial paralysis was still evident 15 minutes later.
In contrast, injecting QX-314 had no effect, while capsaicin alone caused flexion of the limb (although motion of the hip and knee were unimpaired), which the researchers interpreted as a response to the irritant effects of the compound.
When QX-314 was injected, followed by capsaicin, "an effective anesthesia to noxious stimuli developed" -- the animals didn't respond to being pricked with even very stiff fibers and had a significantly higher tolerance for heat.
At the same time, five of six animals had no motor deficit, the researchers said, while the sixth had transient flexion similar to that seen when the capsaicin was given alone.
"We're optimistic that this method will eventually be applied to humans and change our experience during procedures ranging from knee surgery to tooth extractions," said Dr. Woolf.
"In fact, the possibilities seem endless," Dr. Woolf said. "I could even imagine using this method to treat itch, as itch-sensitive neurons fall into the same group as pain-sensing ones."
But that may be going a bit fast, said Edwin W. McCleskey, Ph.D., of the Howard Hughes Medical Institute, in Chevy Chase, Md.
"Before we get carried away, the TRPV1 trick must first be shown to work in humans," Dr. McCleskey argued in an accompanying News&Views article.
In addition, the "ideal cocktail" of anesthetic and capsaicin will have to be developed to avoid the painful effects of the capsaicin, he said.
That said, Dr. McCleskey noted, the discovery may have additional significance. For one thing, he said, it might open the way to deliver other sorts of drugs to specific cell populations. And it may shed new light on how current anesthetics operate, particularly when used to treat persistent pain.
The researchers were supported by the National Institute of Neurological Disorders and Stroke, the National Institute of Dental and Craniofacial Research, and the National Institute of General Medical Sciences. The researchers did not report any potential conflicts. Dr. McCleskey also did not report any conflicts. Primary source: NatureSource reference: Binshtok AM et al. "Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers." Nature 2007; 449: 607-11. Additional source: NatureSource reference: McCleskey EW. "A local route to pain relief." Nature 2007; 449: 545-46.