High-Dose VX-548 Reduces Acute Pain Post-Surgery

The highest dose of VX-548, a novel highly selective inhibitor of Na_V1.8, better reduced acute pain over a 48-hour period after abdominoplasty or bunionectomy when compared with placebo, according to a study published in The New England Journal of Medicine.¹ However, results were not replicated with lower doses of the drug.

James Jones, MD, PharmD

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Patients with acute pain are often prescribed opioids targeting the central mechanisms concerning the perception of pain. However, these medications are limited due to the potential for misuse and addiction, as well as other safety concerns. Other common treatment options include nonselective sodium-channel inhibitors, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs).² The Na_v1.8 voltage-gated sodium channel has been shown to play a part in transmitting nociceptive signals.

“Our understanding of the role of Na_V1.8 in pain transmission is supported by its function in normal sensory physiologic response, pathologic states arising from mutations in SCN10A, animal models, and pharmacologic effects of Na_V1.8-modulating agents,” wrote James Jones, MD, PharmD, vice president of Vertex Pharmaceuticals, and colleagues. “We hypothesized that selective inhibition of Na_V1.8 would provide effective pain relief without the risks associated with opioid treatments.”

Investigators first confirmed the selectivity of VX-548 for Na_v1.8 inhibition in vitro before they conducted 2 double-blind, placebo-controlled, phase 2 trials of patients experiencing acute pain after bunionectomy or abdominoplasty. Eligible patients were adults (aged 18 to 75 years), self-reported their post-operative pain as moderate or severe according to the Verbal Categorical Rating Scale (VRS), and rated pain as a score of ≥4 on the Numeric Pain Rating Scale (NPRS).

Patients in the abdominoplasty trial were randomly assigned to receive either a 100 mg oral dose of VX-548, followed by a 50 mg maintenance dose every 12 hours (high-dose group); a 60mg dose of VX-548, followed by a 30 mg maintenance dose every 12 hours (middle-dose group); 5 mg hydrocodone bitartrate and 325 mg acetaminophen every 6 hours; or oral placebo every 6 hours. In the bunionectomy trial, patients were randomized to receive 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); 5 mg hydrocodone bitartrate and 325 mg acetaminophen every 6 hours; or oral placebo every 6 hours.

The primary endpoint of interest was the time-weighted sum of the pain-intensity difference (SPID) over a 48-hour span. This was determined from the NPRS score, in which higher scores represent greater pain, at 19 points after the first dose of VX-548 or placebo. Each dosing regimen of VX-548 was also separately compared with placebo.

In total, 303 patients were recruited into the abdominoplasty trial and 274 were included in the bunionectomy trial. Clinical characteristics and baseline demographics were comparable across trial groups, including baseline NPRS scores (6.6 to 6.9 in the bunionectomy trial and 7.2 to 7.4 in the abdominoplasty trial). In the first 24 hours, the difference between VX-548 and placebo was 19.6 (95% CI, 6.5 to 32.7) in the abdominoplasty trial and 13.7 (95% CI, −1.8 to 29.1) in the bunionectomy trial.

At the 48-hour mark, the least-squares mean difference between high-dose VX-548 and placebo was 37.8 (96% 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.

In both phase 2 trials, patients who received the lower doses of VX-548 had results comparable to the placebo group. Common adverse events were headache (14% in the high-dose cohort and 6% in the placebo cohort) and constipation (9% in the high-dose cohort and 5% in the placebo cohort). Most adverse events were mild or moderate in severity.

As these procedures are typically performed in an outpatient setting where pain is treated with multiple therapies, evaluating VX-548 as monotherapy may have limited results, according to investigators. However, this choice minimized potential confounding factors. Additionally, most participants included were women, which may have reduced generalizability. Future research will focus on the treatment effect of VX-548 when compared with the hydrocodone bitartrate-acetaminophen regimen.

“VX-548 is a potent and selective inhibitor of Na_V1.8 currents relative to other Na_V channels in human dorsal-root ganglion neurons in vitro,” investigators concluded.

References

1. ^{Jones, J., Correll, D., Lechner, S., & Jazic, I. (2023). Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2209870}
2. ^{Chou R, Gordon DB, de Leon-Casaso- la OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Ad- ministrative Council. J Pain 2016;17:131-57.}