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A novel, investigational NaV1.8 sodium channel blocker known as VX-548 reduced acute pain after abdominoplasty or bunionectomy at the highest dose, but not at lower doses, two phase II trials showed.

The primary endpoint was the time-weighted sum of the pain-intensity difference (SPID) over 48 hours (SPID48), calculated from Numeric Pain Rating Scale (NPRS) scores (which range from 0 to 10, with higher scores indicating greater pain) at 19 time points after the first dose of VX-548 or placebo.

In the trial, the mean difference in time-weighted SPID48 between high-dose VX-548 and placebo was 37.8 (95% CI 9.2-66.4), said Jim Jones, MD, PharmD, of Vertex Pharmaceuticals in Boston, and co-authors.

In the study, the mean SPID48 difference between high-dose VX-548 and placebo was 36.8 (95% CI 4.6-69.0), the researchers wrote in the .

Sodium channels are a logical target for pain reduction, noted Mark Wallace, MD, of the University of California San Diego, in an .

"Attempts to use systemic nonselective sodium channel blockers have not succeeded because of dose-limiting side effects," Wallace pointed out. "Now, years of research on sodium channel blockers that are specific to the subtypes located on structures of the peripheral nervous system have come to fruition."

"It is perhaps disappointing that the effect size of this very original selective peripheral sodium channel blocker was small, and limited conclusions can be made about its effectiveness as compared with other agents because it was not directly compared with hydrocodone bitartrate-acetaminophen, which is a standard drug for the treatment of acute pain," he added. "However, these trials represent an early foray into an exciting new class of drugs in a difficult field."

Opioids are used to treat acute pain, but come with safety concerns about the possibility of misuse and addiction. Non-opioid pain treatments include nonselective sodium-channel inhibitors like lidocaine, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen. Most approved analgesic drugs either act on the opioid-receptor system or are NSAIDs, Jones and co-authors noted.

"The voltage-gated sodium channel NaV1.8 is a therapeutic target for pain because of its role in transmitting nociceptive signals and its selective expression in peripheral nociceptive neurons of the dorsal-root ganglia," they wrote.

Jones and colleagues randomized 303 participants in the abdominoplasty study and 274 in the bunionectomy trial. Baseline mean NPRS scores were 7.2 to 7.4 in the abdominoplasty trial and 6.6 to 6.9 in the bunionectomy trial.

"Abdominoplasty, which is considered to be a model of soft-tissue pain, and bunionectomy, which is considered to be a model of bone pain, are common surgical procedures resulting in moderate-to-severe postoperative acute pain that is generally treated with analgesic medicines, including opioids, NSAIDs, and acetaminophen," the researchers noted.

Baseline demographic and clinical characteristics were similar across groups in each trial. Most participants were women and white.

In the abdominoplasty trial, participants were randomly assigned 1:1:1:1 to receive one of the following over 48 hours: a high-dose of VX-548 (100-mg oral loading dose followed by a 50-mg maintenance dose every 12 hours), a middle dose of VX-548 (60-mg loading dose followed by a 30-mg maintenance dose every 12 hours), hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours), or placebo every 6 hours.

In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive either high-dose VX-548, middle-dose VX-548, low-dose VX-548 (20-mg loading dose followed by a 10-mg maintenance dose every 12 hours), hydrocodone bitartrate-acetaminophen every 6 hours, or placebo every 6 hours.

The main analysis compared each dose of VX-548 with placebo. Participants who received lower doses of VX-548 had results similar to placebo.

Most adverse events were mild or moderate, and headache and constipation were common. In the abdominoplasty trial, three participants had serious adverse events, including one in the middle-dose VX-548 group; none were considered treatment-related. No serious adverse events occurred in the bunionectomy trial.

In both trials, fewer participants discontinued high-dose VX-548 than placebo or hydrocodone bitartrate-acetaminophen. Both studies appeared to show a treatment effect with VX-548 compared with hydrocodone bitartrate-acetaminophen, Jones and co-authors said.

Most participants were women, which was a limitation, the researchers acknowledged. No accepted effect size based on SPID is considered minimally clinically meaningful, they added.

"Sodium channel modulation is one of many mechanisms involved in pain transmission, and it is perhaps unlikely that modulating just one mechanism will lead to large effects on pain," observed Wallace. "At the moment, postoperative pain is still best managed by multimodal therapies, such as those that combine drugs with different mechanisms."

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