By L. Joseph Parker, MD

In an article I recently wrote about a new calcium channel-blocking medication that could be effective in treating central chronic pain, I mentioned that medications like lidocaine block sodium channels to prevent the transmission of pain through the peripheral nervous system. I also said that these medications have limited use, usually just in the ER, because they are short-acting and injected, though there is a lidocaine patch that some people find soothing.

This might soon change. Doctors might be able to prescribe an oral sodium channel-blocking medication, giving us a non-opiate central pain-treating Cav2.2 calcium channel blocker and a Nav1.8 sodium channel blocker for peripheral pain. Let’s look at why this matters.

Nociceptors in the peripheral tissues detect chemicals released by cell injury and generate an initial signal. These immediate signals are related to the activation of Nav1.7 sodium channels and are important for the fast generation of pain signals by nociceptors. Once generated, these signals are transmitted through the dorsal root ganglion, where the cell body is, and sent on to the spinal cord. There are primary or first-order afferent synapses with a second-order neuron, which transmits the signal up to the brain.

In the ER or medical office, we can inject lidocaine or bupivacaine into the tissues around an injury and block pain from that entire area by blocking the Nav1.7 sodium channel. This creates that numb feeling you get as your finger laceration is stitched or the dentist works on your teeth, though lidocaine does affect other channels, including some in the heart called Nav1.5. Blocking Nav1.5 channels reduces cardiac activity, and lidocaine was, in fact, in the ACLS protocols for arrhythmia, at least until amiodarone came around. Nav1.7 channels are also blocked by tetrodotoxin, for fans of pufferfish or fugu, as is Nav1.8.

Mutations in the SCN9A gene cause overactive pain signaling by Nav1.7 channels, creating conditions like erythromelalgia, where patients have redness, warmness, and severe burning pain in the extremities that can be triggered by almost any mild activity or stimulus. An inherited hyperalgesia/allodynia, if you will. Or paroxysmal extreme pain disorder (PEPD). Which causes severe recurrent stabbing pain throughout the body. Hard to imagine a worse condition to inherit. Please don’t tell me if you know one. Other mutations in SCN9A cause the opposite condition. Underactive Nav1.7 channels, which is called congenital insensitivity to pain (CIP) or channelopathy-associated insensitivity to pain (CIP-C). These people truly “feel no pain” and are subject to injury and accidents, usually dying young as they never learn the hot stove lesson.

While Nav1.7 is responsible for immediate pain signal generation, Nav1.8 channels are more important for sustained pain signaling, and they are more related to chronic neuropathic pain conditions. This could be critical to the treatment of chronic pain, as right now, the only effective pain medication for severe chronic pain is opioid-based. All opioids bind the mu opiate receptors in the peripheral tissues, spinal cord, and brain. It is in the brain that these opioids bind receptors in the ventral tegmental area and trigger a release of dopamine in the nucleus accumbens, the reward center of the brain.

The brain uses endogenous endorphins to mark something for targeting or reward when we do something good for our survival, like catching a deer when we are hunting, or smiling at an attractive mate. This marking gives us a feeling of bliss or euphoria. It is mainly an opioid’s ability to trigger this dopamine release that can cause upregulation of the gene deltaFosB in the nucleus accumbens, leading to addiction. They can also suppress the respiratory drive, leading to death. Finding a way to treat pain without opioids is critical to reducing the risk of addiction and overdose.

I wrote in a previous article about a new medication that blocks the Cav2.2 channels in the central nervous system like gabapentin and pregabalin. Gabapentinoids like these can be effective for many kinds of pain, but in some people, they can generate a euphoric response. Something the new medication does not appear to do. I say appear because, like all the other “non-addictive” painkillers of the past, someone somewhere will probably feel good taking it and want more, just like tramadol. And don’t forget that Bayer invented heroin as a “non-addictive” substitute for morphine. Skepticism is allowed here.

VX-548, however, should truly be non-addicting, though, of course, those in severe chronic pain will beg for it, as anyone with their leg on fire would beg for a bucket of water, leading to the DEA branding them as “drug-seeking” no doubt. VX-548 blocks the Nav1.8 channels, which, as noted previously, are important for a sustained nociceptive signal from the peripheral nervous system. Sustained nociceptive signals can lead to “sensitization” of the second and third-order pain neurons in the CNS, leading to chronic pain syndromes. If we can treat someone quickly after an injury, such as a lumbar compression fracture or shingles, so that there are no sustained signals, we could prevent the creation of many chronic pain problems.

VX-548 can be taken by mouth and appears to have fewer side effects than other broad-spectrum pain medications and with a reduced or absent risk of overdose or addiction. Clinical trials have shown it to be effective in treating both acute postoperative pain, a good test of “standardized” pain as everyone got the same operation, and for treating chronic neuropathic pain, though how it does this has me confused. If it mainly works in the peripheral nervous system, that will mean there is still a considerable peripheral component to some chronic neuropathic pain. I’m wondering if it worked in some conditions, say reflex sympathetic dystrophy, or post-herpetic neuralgia, and not others, or if it seemed to work in all of them.

If this treatment proves effective, we may soon have a good way to treat acute and subacute pain, VX-458 blocking Nav1.8 sodium channels, and one to treat subacute and chronic pain, CBD3063, which blocks the Cav2.2 calcium channels. This would be fantastic for patients suffering from severe pain and the doctors who treat them. But maybe not for the DEA. They would then need to go after actual drug dealers, who make fentanyl and ship it over the border, instead of kicking in the doors of medical clinics and pointing machine guns at people in wheelchairs.