High doses of VX-548 reduced acute pain over a period of 48 hours after major surgery: NEJM

A recent study has found effective acute pain management with VX-548, an oral, highly selective inhibitor targeting the NaV1.8 voltage-gated sodium channel expressed in peripheral nociceptive neurons. The findings were published in the The New England Journal of Medicine.

The NaV1.8 voltage-gated sodium channel has long been recognized as a key player in transmitting nociceptive signals, making it a promising target for acute pain relief. Jim Jones and team established VX-548's selectivity for NaV1.8 inhibition through rigorous in vitro studies.

Two separate phase 2 trials were conducted to evaluate VX-548's efficacy in acute pain management after abdominoplasty and bunionectomy surgeries. The trials involved a total of 303 participants for abdominoplasty and 274 participants for bunionectomy, respectively.

During the abdominoplasty trial, participants were randomly assigned to one of four groups: a high-dose group receiving a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours; a middle-dose group receiving a 60-mg loading dose, followed by a 30-mg maintenance dose every 12 hours; a hydrocodone bitartrate–acetaminophen group receiving 5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours; or an oral placebo every 6 hours. Similarly, the bunionectomy trial had five groups with various VX-548 dosages and a placebo.

The primary endpoint of the trials was the time-weighted sum of the pain-intensity difference (SPID48) over a 48-hour period, measured using the Numeric Pain Rating Scale. The results were then compared with placebo groups.

Excitingly, the findings revealed that participants who received the highest dose of VX-548 experienced a significant reduction in acute pain after both abdominoplasty and bunionectomy surgeries. The difference in SPID48 between the high-dose VX-548 and placebo groups was 37.8 after abdominoplasty and 36.8 after bunionectomy. However, lower doses of VX-548 did not show a similar pain-relieving effect and were comparable to placebo.

Adverse events associated with VX-548 were generally mild to moderate and included headaches and constipation. Despite these side effects, the potential pain relief benefits far outweighed the risks in the high-dose group.

Reference:

Jones, J., Correll, D. J., Lechner, S. M., Jazic, I., Miao, X., Shaw, D., Simard, C., Osteen, J. D., Hare, B., Beaton, A., Bertoch, T., Buvanendran, A., Habib, A. S., Bozic, C., Negulescu, P., & White, P. F. (2023). Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. In New England Journal of Medicine (Vol. 389, Issue 5, pp. 393–405). Massachusetts Medical Society. https://doi.org/10.1056/nejmoa2209870