Treating breakthrough pain (BTP) with opioids is well established in chronic cancer pain; extension of this approach to noncancer pain is increasing. However, the time to peak intensity of BTP precedes the onset of analgesia with short-acting opioids. FBT is designed to provide rapid-onset analgesia and may address this problem. The efficacy and safety of FBT in the management of BTP were examined in opioid-tolerant, noncancer patients with chronic, persistent neuropathic pain (Study 1) or chronic, persistent low back pain (Study 2). Patients identifying an effective FBT dose (100-800 µg) during a titration phase (Study 1, 80/102; Study 2, 84/104) entered a double-blind phase to treat 9 BTP episodes (6 with FBT, 3 with placebo). Pain intensity (PI; 11-point scale) was measured through 2 hours. The primary efficacy measure was the time-weighted sum of pain intensity differences (PIDs) for the first 60 minutes (SPID₆₀). In both studies, SPID₆₀ was significantly better with FBT than placebo (Study 1, mean±SE: 9.6±0.75 vs 5.7±0.72, P<0.0001; Study 2, 8.3±0.66 vs 3.6±0.57, P<0.0001). PIDs were significantly greater after FBT vs placebo at 10 minutes (Study 1, P=0.0463; Study 2, P=0.0184) and each subsequent time point (P<0.01). The proportion of BTP episodes with ≥33% improvement in PI significantly favored FBT beginning at 10 (Study 1) and 15 minutes (Study 2, P<0.01 for both). In the pooled safety analysis (N=206), AEs were typical of opioids (e.g., nausea, dizziness, and somnolence); more were reported during the dose titration (55%) than double-blind phase (31%). Thirteen patients (6%) experienced application-site AEs, the majority of which were mild; all resolved without residual effect. A total of 24 patients (12%) discontinued due to AEs. In conclusion, results of two studies of noncancer pain were consistent in showing that FBT was effective and well tolerated in the management of opioid-tolerant patients with BTP.