NaV1.8 inhibitor VX-548 reduces acute post-operative pain

1. In this randomized controlled trial, the elective NaV1.8 inhibitor VX-548 reduced acute pain over 48 hours following abdominoplasty and bunionectomy.

2. The main adverse events associated with VX-548 use were headaches and constipation.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Acute pain, especially following traumas and surgical procedures, remains an area of unmet medical need. Multimodal analgesic regimens, consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, nonselective sodium-channel, and opioids can be effective approaches, but drug-related adverse events and variability in patient response translate to a high incidence of inadequately treated pain burdens. VX-548 is an investigational drug that selectively inhibits NaV1.8 channels involved in peripheral pain signaling. This article reported results from two clinical trials investigating VX-548 in patients with acute pain after abdominoplasty and bunionectomy. Over a 48-hour treatment period, the high-dose VX-548 regimen resulted in lower pain scores compared to placebo and hydrocodone bitartrate-acetaminophen. Although, these trials were not designed to directly compare VX-548 against hydrocodone bitartrate-acetaminophen. The safety profile of VX-548 was acceptable, with headache and constipation being more prevalent than placebo. The study was limited by its monotherapy design, short follow-up, and lack of independent adjudication. Overall, it provided early evidence of the efficacy and safety of VX-548 as a novel addition to pain management.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: The present article reported results from two randomized placebo-controlled trials investigating the efficacy and safety of oral VX-548 in treating acute postoperative following abdominoplasty or bunionectomy. Patients between 18 and 75 years of age reporting a pain score of four or greater on the Numeric Pain Rating Scale (NPRS) and who rated their pain as moderate or severe on the Verbal Categorical Rating Scale (VRS) on postoperative day one were included. Patients were excluded if they had a history of sensory abnormality, pre-existing painful physical condition, or long-term use of opioids or NSAIDs. In the abdominoplasty trial, 303 patients were randomized 1:1:1:1 to a 48-hour period of high-dose VX-548 (100mg loading dose followed by 50mg maintenance dose every 12 hours), middle-dose VX-548 (60mg loading dose followed by 30mg maintenance dose every 12 hours), hydrocodone bitartrate-acetaminophen combination (in 5mg and 325mg doses, respectively, every 6 hours), or placebo every 6 hours. In the bunionectomy trial, 274 patients were randomized 2:2:1:2:2 to a 48-hour period of high-dose, middle-dose, or low-dose (20mg loading dose followed by 10mg maintenance dose every 12 hours) VX-548, hydrocodone bitartrate-acetaminophen every 6 hours, or placebo every 6 hours. The primary outcome was the time-weighted sum of the pain-intensity difference over 48 hours (SPID48). The least-squares mean difference between the high-dose VX548 and placebo group in SPID 48 was 37.8 (95% Confidence Interval [CI], 9.2 to 66.4) in the abdominoplasty trial and 36.8 (95% CI, 4.6 to 69.0) in the bunionectomy trial. The middle- and low-dose VX-548 groups, however, reported similar pain outcomes to hydrocodone bitartrate-acetaminophen and placebo. In summary, the efficacy and safety of VX-548 was demonstrated as a potential new drug class to treat acute pain.

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