Although acute pain in patients with herpes zoster can be severe and has a substantial impact on health-related quality of life, there have been no randomized clinical trials of oral medications specifically for its ongoing treatment. A randomized clinical trial was conducted in which 87 subjects >or=50 years of age with herpes zoster within 6 calendar days of rash onset and with worst pain in the past 24h >or=3 on a 0-10 rating scale initiated 7 days of treatment with famciclovir in combination with 28 days of treatment with either controlled-release (CR) oxycodone, gabapentin, or placebo. Subjects were evaluated for adverse effects of treatment, acute pain, and health-related quality of life. The results showed that CR-oxycodone and gabapentin were generally safe and were associated with adverse events that reflect well-known effects of these medications. Discontinuing participation in the trial, primarily associated with constipation, occurred more frequently in subjects randomized to CR-oxycodone (27.6%) compared with placebo (6.9%). Treatment with CR-oxycodone reduced the mean worst pain over days 1-8 (p=0.01) and days 1-14 (p=0.02) relative to placebo but not throughout the entire 28-day treatment period as pain resolved in most subjects. Gabapentin did not provide significantly greater pain relief than placebo, although the data for the first week were consistent with a modest benefit. By demonstrating that CR-oxycodone is safe, generally adequately tolerated, and appears to have efficacy for relieving acute pain, the results of this clinical trial provide a foundation for evidence-based treatment for acute pain in herpes zoster.