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Acute Pain Relief Through Selective Inhibition of Voltage-Gated Sodium Channels With VX-548

An oral, highly selective inhibitor of the NaV1.8 voltage-gated sodium channel, VX-548 was more effective than placebo when used at its highest doses for 48 hours in phase 2 trials of patients with acute pain after abdominoplasty or bunionectomy. Adverse events with VX-548 were mild to moderate in severity.

Doses used in the abdominoplasty trial were a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. Used in the bunionectomy trial were high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours.

Based on a primary endpoint of the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), the study showed the following: “A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548.”

Editorial 1: “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,” an editorialist writes. “However, these trials represent an early foray into an exciting new class of drugs in a difficult field. Many early-phase trials of drugs for patients with acute pain are failing to achieve significant results with respect to primary end points despite showing promising positive trends in both primary and secondary end points, including very minimal safety concerns. 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. At the moment, postoperative pain is still best managed by multimodal therapies, such as those that combine drugs with different mechanisms. Perhaps our expectations are too high in trials of new agents for acute pain.”

Editorial 2: “Clinical trials of potential therapies for pain can be challenging, because of the subjective nature of numerical rating scales and their failure to capture the complexity of pain and because of large placebo responses and the current lack of validated biomarkers,” writes an editorialist. “Nonetheless, phase 3 trials of VX-548 are under way…. Positive results would spur the development of other NaV1.8 blockers and knockdown strategies. These could include small interfering RNAs, epigenetic repression through CRISPR (clustered regularly interspaced short palindromic repeats), messenger RNA editing, and targeted protein degradation. Additional research may also shed further light on the potential of targeting of NaV1.7, which functions in tandem with NaV1.8, and the less-well-studied NaV1.9, which regulates the excitability of peripheral sensory neurons. A combined block of two or all three channels might also be studied. In addition, the exploration of other clinical indications is warranted: peripheral sodium channels have roles in neuropathic pain (e.g., diabetic neuropathy, chemotherapy-induced neuropathy, and pain after nerve injury) and in inflammatory pain.”

Source: New England Journal of Medicine