Background

Nonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated transient receptor potential vanilloid subfamily member 1 agonists for analgesia after surgery. This study examines intraoperative vocacapsaicin, a novel prodrug of the transient receptor potential vanilloid subfamily member 1 agonist capsaicin, in a validated model of postsurgical pain.

Methods

This was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. Patients were randomized 1:1:1:1 to surgical site administration of 14 ml of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/ml. The prespecified primary endpoint was the area-under-the-curve of the numerical rating scale pain score at rest through 96 h for the 0.30 mg/ml group. Prespecified ordered, secondary endpoints for the 0.30 mg/ml group included the percentage of patients who did not require opioids from 0 to 96 h, total opioid consumption through 96 h, and the area-under-the-curve of the numerical rating scale pain score for the first week.

Results

The 147 patients were randomized. During the first 96 h, vocacapsaicin (0.30 mg/ml) reduced pain at rest by 33% versus placebo (primary endpoint, 95% CI [10%, 52%], effect size [Cohen’s d] = 0.61, P = 0.005). Of patients receiving vocacapsaicin (0.30 mg/ml), 26% did not require postoperative opioids for analgesia (P = 0.025) versus 5% of patients receiving placebo. Vocacapsaicin (0.30 mg/ml) reduced opioid consumption over the first 96 h by 50% versus placebo (95% CI [26%, 67%], effect size = 0.76, P = 0.002). Vocacapsaicin (0.30 mg/ml) reduced pain over the first week by 37% versus placebo (95% CI [12%, 57%], effect size = 0.62, P = 0.004). The treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration-versus-response relationship. Vocacapsaicin was well tolerated with no differences between groups in any safety parameter.

Conclusions

A single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 h after surgery compared to control.

Editor’s Perspective
What We Already Know about This Topic
  • No locally administered analgesic provides relief for more than 48 h after surgery
  • Capsaicin produces sustained analgesia without loss of sensation, proprioception, or muscle strength by activating transient receptor potential vanilloid subfamily member 1 receptors on C-fiber nociceptors, the nerves that mediate dull, aching pain after surgery
  • Vocacapsaicin, a novel water-soluble prodrug, rapidly releases capsaicin at the surgical site after local administration during surgery
What This Article Tells Us That Is New
  • A triple-blinded, randomized, placebo-controlled trial compared three doses of intraoperative locally administered vocacapsaicin to placebo in 147 patients undergoing bunionectomy, a standard model of postsurgical pain
  • In patients receiving 14 ml of vocacapsaicin (0.30 mg/ml), the median (95% CI) decrease in pain at rest over the first 96 h was 33% (10 to 52%) despite a 50% (26 to 67%) decrease in opioid consumption compared to patients receiving placebo and otherwise identical perioperative anesthesia and postoperative analgesia
  • There was no difference in the rate, type, or severity of adverse events among the four study groups