Background & Aims
Pain management after surgery remains an unmet need.(1-5) Oral opioids remain a key part of management (1,2), despite side effects, safety concerns, and the risk of persistent opioid use.(6-8) Treating pain at its source, the nociceptor, is considered an ideal approach.(9-12) Targeting TRPV1 in the periphery is an attractive, untapped strategy.
Brief exposure to a therapeutic dose of capsaicin, a well-studied TRPV1 agonist, causes sustained analgesia without loss of sensation, proprioception, or muscle strength (13,14), by activating TRPV1 receptors on C-fiber nociceptors (15), the nerves that mediate dull, aching pain.(16) Vocacapsaicin is a novel prodrug of capsaicin. Designed specifically for tissue infiltration, vocacapsaicin is more soluble and rapidly releases capsaicin following local administration.(17)
We conducted studies in two surgical models, bunionectomy and total knee arthroplasty (TKA), to test the effect of vocacapsaicin on postsurgical pain and opioid use.
Methods
We completed two multicenter, randomized, double-blind, placebo-controlled, dose-optimization studies of vocacapsaicin during orthopedic surgery in bunionectomy and TKA. Vocacapsaicin doses were 0.05-0.5 mg/mL.
During surgery, patients received full standard-of-care anesthesia and analgesia and blinded local delivery of either placebo or vocacapsaicin. Patients were monitored for 96 hours after surgery at the study site and discharged on day 4. Serial safety and efficacy evaluations were performed at pre-specified times until day 29. Following surgery, NRS pain scores at rest and with ambulation were recorded serially and all rescue opioid use was documented.
The primary efficacy endpoint in both studies was analgesia calculated as the comparative area under the NRS pain at rest curves. Secondary endpoints included pain with ambulation, time to opioid cessation, and cumulative opioid use. Safety endpoints included local and systemic side effects.
Results
The bunionectomy and TKA studies randomized 147 and 187 patients, respectively.
During 14d after bunionectomy, vocacapsaicin 0.3 mg/mL reduced pain at rest 37% (p=0.01), ambulatory pain 30% (p=0.03), and opioid use 55% (p=0.001) vs placebo. By day 5, all vocacapsaicin 0.3 mg/mL patients ceased opioids while at day 14, 8% of placebo patients remained on opioids (p=0.04). The opioid use hazard ratio (HR) for placebo vs vocacapsaicin 0.3 mg/mL was 1.8 (p=0.009).
During 14d after TKA, vocacapsaicin 0.3 mg/mL reduced pain at rest 15% (p=0.03), ambulatory pain 14% (p=0.04), and opioid use 35% (p<0.0001). At day 15, 58% vs 38% of patients ceased opioids in the vocacapsaicin 0.3 mg/mL vs placebo groups, respectively (p=0.02). The opioid use HR was 1.8 (p=0.02). At 72h, 90% of vocacapsaicin 0.3 mg/mL patients vs 63% of placebo patients could ambulate 30m (p<0.01).
Efficacy lasted 2 weeks after surgery, without local or systemic toxicity. A reduced GI side effects trend was seen.
Conclusions
Two randomized, controlled trials in TKA and bunionectomy demonstrated that a single administration of vocacapsaicin 0.3 mg/mL during surgery improved analgesia for 2 weeks, decreased opioid use, improved functional recovery, and allowed patients to stop taking opioids sooner compared to placebo. Further studies are warranted.
References
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Presenting Author
Ben Vaughn
Poster Authors
Topics
- Specific Pain Conditions/Pain in Specific Populations: Acute Pain and Nociceptive Pain