BACKGROUND: Pain following total knee arthroplasty (TKA) interferes with rehabilitation. Capsaicin applied in high concentration to nociceptors can cause relatively selective C-fibre desensitization for a period of weeks to months. Resultant long-lasting analgesia might facilitate rehabilitation. OBJECTIVE: The objective of this study was to determine if direct instillation of a high-concentration capsaicin preparation into the wound following TKA would provide pain relief, improve physical functioning and rehabilitation, and reduce opioid requirements. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase II trial carried out in a teaching hospital system. Non-opioid-tolerant males or females aged 18-85 years with a body mass index (BMI) ≤45 kg/m2, American Society of Anesthesiologists (ASA) physical status 1-3 and end-stage osteoarthritis who were scheduled for primary unilateral TKA were included. Patients received placebo vehicle or capsaicin 15 mg (Anesiva 4975) by instillation immediately prior to wound closure. Surgery was conducted under spinal anaesthesia and femoral nerve block. Postoperative rescue analgesia consisted of intravenous patient-controlled analgesia with morphine for 24 hours; oral oxycodone was provided thereafter as needed. It was hypothesized prior to data collection that capsaicin instillation would reduce postoperative pain scores and result in improved patient satisfaction and ambulation. The primary outcome was the area under the numerical rating scale (NRS) for pain score-time curve from 4 to 24 hours (AUC(4-24)). NRS for pain scores were obtained every 4 hours for 24 hours then daily with ambulation and physical therapy for 3 days. Function and patient satisfaction were assessed at 14, 28 and 42 days. RESULTS: Data from 14 patients (seven per group) from a single centre (data were not available from other sites because of sponsor bankruptcy) were available for this preliminary report. AUC(4-24) was not significantly different clinically (placebo 70.3; capsaicin 65.7) in this sample; however, a significant opioid-sparing effect was seen in the capsaicin group despite the fact that patients in this group had higher BMIs. Pain scores tended to be lower in the capsaicin group, despite the fact that patients in this group received significantly less rescue opioid medication. Morphine use from 12-24 hours was lower (capsaicin group mean 13.4 mg; 95% confidence interval [CI] 7.4, 19.5; range 10-21 mg vs placebo group mean 25.9 mg; 95% CI 19.8, 32.0; range 15-36 mg; p = 0.009). Total intravenous and oral opioid in morphine equivalents over 72 hours was also lower with capsaicin compared with placebo (p = 0.03). Active range of motion (ROM) was also significantly improved at day 14 in the capsaicin group compared with the placebo group (p = 0.0014). A higher percentage of patients in the capsaicin group reported being extremely satisfied with their treatment. The only statistically significant difference in treatment-emergent adverse events was for pruritus, which was more frequent in the placebo group (p = 0.03). CONCLUSION: Despite having higher BMIs, patients in the capsaicin group achieved comparable or better pain scores with significantly less opioid use in the first 3 postoperative days. They also had less pruritus, which may have been a consequence of the opioid-sparing effect. The effects of capsaicin with respect to function, however, appeared to be longer lasting, with improved active ROM reported at 14 days.