Is Capsaicin plus QX-314 a Breakthrough for Pain?

Medicine is full of surprises. Here is one of the latest.

Although you may have missed it, Kory McHenry, formerly with the National Institutes of Health NIDCR, a contributor at , has already pointed out that the mechanism of lidocaine is still in debate. The contest centers around whether lidocaine acts at the sodium channel itself, or in the membrane immediately adjacent to the channel. This debate is highly technical and of interest mainly to cellular biochemists. However, recent work at Harvard suggests we may not have to wait for the final answer to develop NEW treatment for pain.

We have already praised Brad Galer for his longstanding contributions to pain science and his deep compassion, as well. One of his main contributions has been the development of and bringing to market a lidocaine patch. We have received a number of favorable comments on this patch from those who contribute to the site, although like other patches, there are so many factors controlling rate of absorption that improvments are always possible.

The main benefit so far has been with respect to the EVOKED or ELICITED forms of touch dysesthesia. Not everyone seems to repond, but enough have written favorably that it is not unreasonable to give consideration to such treatment, under the direction of your personal physician, of course.

The recent “breakthrough” at Harvard has to do with the delivery of sufficient lidocaine into the neuron to stop pain without blocking motor function. This is a long standing challenge and great researchers, such as Marshall Devor (who has also contributed here) have studied various approaches to lidocaine.

In a brilliant venture, Binshtok, Bean, and Woolf (yes, Clifford Woolf whom we have praised so often) the team at Harvard OPENED the TRPV-1 channel with capsaicin, and then, administered lidocaine. Voila! It worked!

In other words, there was TRPV-1 channel mediated entry of sodium channel blockers, to which the neuronal membrane would ordinarily be impermeable. In pain research, this is a very important development.

Note that most local anesthetics don’t like to combine with water (they are hydrophobic). Water tends to be polar, with one end more positive than the other, so charged molecules combine more readily with water.

The authors described their method thus:

“We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability.”

It has always been difficult to achieve sensory block without taking out motor function. The new technique managed to achieve this. The authors relate as follows:

“Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.”

QX-314, which is a modified lidocaine, may therefore prove to be of considerable benefit to the evoked portion of central pain. Perhaps we will soon have a QX-314 patch, as a follow-up to the lidocaine patch.

Central pain subjects have been so patient and longsuffering. What choice did they have? It would certainly be gratifying if capsaicin, by opening the TRPV-1 channel, could finally make blockade possible.