A randomised, double-blind, placebo-controlled study to determine the analgesic efficacy, safety and tolerability of VPX638 administered topically to painful wounds

Abstract

New analgesics are needed for painful wounds. Multiple reports suggest that topical sevoflurane may have analgesic effects. This placebo-controlled randomised trial evaluated the analgesic efficacy and safety of VPX638 (topical sevoflurane). Seventy-eight participants with painful wounds, were enrolled at eight Australian centres and randomly allocated to receive 2 × 5 mL of VPX638 (N = 39) or placebo (N = 40) during one wound dressing change. Numerical pain rating scores and use of opioids were recorded for 24 h. The primary endpoint was pain during wound cleaning, secondary endpoints evaluated pain for 24 h after drug application and opioids use. There was no significant difference in mean pain scores during wound cleaning between VPX638 and placebo (0.854; p = 0.23). The mean differences in summed pain intensity difference from baseline suggested VPX638 provided greater analgesia compared to placebo over 8 h (p < 0.02), 12 h (p < 0.01) and 24 h (p < 0.05) and significantly longer duration of analgesia, 24.3 h for VPX638 versus 7.1 h for placebo (p < 0.01). In the 24 h after drug administration, participants receiving VPX638 had a 50% decrease in opioid use over 24 h compared with placebo. VPX638 appeared safe and well-tolerated. In conclusion, this small placebo-controlled randomised trial suggested that VPX638 provides analgesia and is opioid-sparing for up to 24 h after wound cleaning. It supports the need for further evaluation of the benefit of VPX638 as a topical analgesic for painful wounds.

Keywords: analgesia; pain; sevoflurane; topical; wound.

FIGURE 1

Flow diagram of the study. ITT, intent to treat population; mITT, modified intent to treat population (subjects with a baseline NRS [0–10] pain score at rest of five or more).

FIGURE 2

Pain during wound care procedure in the ITT population for VPX638 and placebo groups. Data shown as 25th to 75th percentiles (boxes), min to max (whiskers), and the median (lines in the middle of the boxes). Treatment groups were compared using a two‐sample two‐tailed t‐test.

FIGURE 3

Pain during the first 15 min after study drug application in the mITT population. (A) Comparison of NRS at baseline (0 min) and 15 min after application of VPX638. (B) NRS at baseline (0 min), 5, 10 and 15 min after application of VPX638 or placebo. (C) Post‐hoc analysis: Comparison of SPID over 15 min (without 5‐min time point) of placebo group versus VPX638 group. (A and C) Data shown as 25th to 75th percentiles (boxes), min to max (whiskers), and the median (lines in the middle of the boxes). (B) Data shown as mean ± SEM. Treatment groups were compared using two‐tailed t‐tests.

FIGURE 4

Pain in the mITT (A) and ITT (B) populations for VPX638 and placebo groups over 24 h after study drug application. Data shown as mean NRS ± SEM. BL, baseline.

FIGURE 5

Post‐hoc analysis: PID and SPID in the ITT population for VPX638 (n = 38) and placebo (n = 40) groups. (A) PID over the 24 h after second drug application. Data shown as mean ± SEM. (B) SPIDs over 8, 12 and 24 h. Data shown as 25th to 75th percentiles (boxes), min to max (whiskers), and the median (lines in the middle of the boxes). Treatment groups were compared using a two‐sample two‐tailed t‐test. BD, before drug; WCP, wound care procedure.

FIGURE 6

(A) Post‐hoc analysis: Duration of analgesic effect (PID ≥ 1) using NRS during wound cleaning as baseline represented as a Kaplan–Meier plot I the ITT population. Comparison between treatment group curves for VPX638 and placebo used a Log‐rank (Mantel‐Cox) test (p = 0.0065). Small vertical lines on the curves indicate censored data. (B) Opioid use for VPX638 and placebo groups. Tornado plot showing per participant total opioid use for 24 h after second drug application.