New Avenues for Pain Management

Pain management is a tricky area for physicians: they don’t want patients suffering, but current treatment options are limited, with highly addictive opioids one of the few available resources. There’s a dire need for effective, non-addictive alternatives. New trial results, published in the New England Journal of Medicine, offer hope. Researchers highlight the efficacy of an experimental pill, VX-548, that precisely targets an important pathway involved in pain signaling, reducing acute pain while minimizing adverse effects.

Two Faces of Pain

Although pain comes in many guises, it can generally be broken down into two large umbrella categories: nociceptive and neuropathic pain. Nociceptive pain is pain in response to physical damage to skin, organs, bones, and so on. You touch a hot stove; ouch. That’s nociceptive pain. Neuropathic pain, on the other hand, is pain that arises from lesions or dysfunction at the level of the central nervous system — lingering pain following a bout of shingles, for example. Often, neuropathic pain is a chronic issue.

VX-548 is designed to alleviate acute nociceptive pain.

How Does It Work?

Whenever we feel pain, it is the result of a complex chain reaction; hundreds of nerve cells and signaling molecules come together to relay the message from the source of damage, say the hand, to the brain. Although nerve cells form the bulk of this chain, the initial spark is provided by sodium channels. Writing in the New England Journal of Medicine, Dr. Stephen G. Waxman describes sodium channels as “molecular batteries that provide a route for a small but crucial influx of [sodium] ions”. Without sodium channels, neurons would not be able to communicate with one another — there would be no link in the chain.

For a long time, it was thought that all sodium channels were the same. Same mechanisms and same “scope”. By blocking one sodium channel, you would risk blocking all sodium channels. Take novocaine, for example. This is an injectable anesthetic that numbs a small, localized area to prevent pain. If you’ve ever been to the dentist, then you’ve likely received novocaine. It works by blocking sodium channels. But the reason it’s delivered by injection instead of pill is because it affects all sodium channels equally — if it wasn’t “directed” to a specific area, you would run the risk of also blocking sodium channels in the heart, brain, and other vital organs. Not good.

Now we know that there are multiple subtypes of sodium channels: NaV1.1 to NaV1.9. They largely share the same structure and function, but each is found in a different cell type. The peripheral nervous system —the part of the nervous system in charge of relaying sensory information to the spinal cord— has three dedicated sodium channels: NaV1.7, NaV1.8, and NaV1.9. These channels are necessary for pain-signaling neurons to do their job, but they are fully separate from the sodium channels involved in the heart and brain. You can block the former without having to worry about the latter.

VX-548 targets 1.8 channels. The mechanism itself is quite simple: it locates and binds to the sodium channels, blocking passage like a cork in a bottle. Once the channel has been clogged up, sodium can no longer move from one side to the other. This movement is required for neuronal signaling of pain messages — it’s what “charges up” the molecular signaling battery. With the channel blocked, the battery is as good as dead. And as long as the channel is blocked, so too are feelings of nociceptive pain.

How Well Does It Work?

That’s how the experimental drug should work in theory, but how does it hold up in practice? To test the efficacy, Jones et al. ran two separate trials.

The first trial involved 303 patients, all of whom were recovering from abdominoplasty, or “tummy tuck”. The patients were randomly placed within one of four groups: the first group received a high dose of VX-548, the second received a moderate dose, the third group received a standard opioid painkiller, and the last group received placebo pills.

The other trial involved 274 patients recovering from bunionectomy — corrective surgery to treat bunions. Again, the patients were split into the same four groups.

The highest dose of VX-548 did a noticeably better job at reducing pain than the placebo, based on a pain intensity scale assessed over the span of two days. At lower doses, the gap was negligible. And although the trials weren’t really designed to test the experimental drug against the run-of-the-mill opioid, early results are promising: fewer side effects and improved tolerability.

Jones et al. are currently supervising an ongoing phase 3 trial designed specifically to pit the experimental drug head-to-head with traditional opioids. Results from the trial will provide a better sense of the real-world applicability of VX-548.

Takeaways

These findings act as an important proof of concept that drugs targeting specific sodium-channel subtypes can be used to selectively block pain. Drug design of this type is still in its early stages, but the promise is clear. If all goes well, we can look forward to a new class of powerful painkillers that do not carry the same worrying addiction risks associated with most standard opioids.