New drug reduces acute pain after common surgeries

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

The primary endpoint was the weighted sum of pain intensity difference (SPID) over 48 hours (SPID48), calculated from Numerical Pain Rating Scale (NPRS) scores (ranging 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 abdominoplasty 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 the authors.

In the bunionectomy 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 New England Journal of Medicine.

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

“Attempts to use systemic nonselective sodium channel blockers have not failed because of dose-limiting side effects,” Wallace pointed out. “Now, years of research into sodium channel blockers that are specific for the subtypes found in structures of the peripheral nervous system have come to fruition.”

“It is perhaps disappointing that the effect size of this highly novel selective peripheral sodium channel blocker was small and limited conclusions can be drawn about its efficacy compared with other agents because it was not directly compared with hydrocodone-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 challenging field.”

Opioids are used to treat acute pain, but come with safety concerns about the potential for misuse and addiction. Non-opioid pain treatments include non-selective sodium channel blockers such as lidocaine, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen. Most approved pain medications either act on the opioid receptor system or are NSAIDs, Jones and his co-authors noted.

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

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

“Abdominoplasty, which is considered a model of soft tissue pain, and vaginectomy, which is considered a model of bony pain, are common surgical procedures that result in moderate to severe postoperative acute pain that is generally managed with analgesic medications, including opioids, NSAIDs and acetaminophen,” the researchers noted.

Baseline demographic and clinical characteristics were similar between groups in each trial. Most participants were female and white.

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

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

The primary analysis compared each dose of VX-548 with placebo. Participants who received lower doses of VX-548 had placebo-like results.

Most side effects were mild or moderate, and headache and constipation were common. In the abdominoplasty trial, three participants had serious adverse events, including one in the medium-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-acetaminophen tartrate. Both studies appeared to show a therapeutic effect with VX-548 compared with hydrocodone-acetaminophen, Jones and his co-authors said.

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

“Modulation of the sodium channel is one of many mechanisms involved in pain transmission, and it is perhaps unlikely that modulation of just one mechanism would lead to large effects on pain,” Wallace observed. “At present, postoperative pain is still best managed with multimodal therapies, such as those that combine drugs with different mechanisms.”