The peak intensity of breakthrough pain (BTP) in patients with chronic, controlled persistent pain typically occurs before the onset of analgesia with short-acting opioids; thus opioids that provide rapid-onset analgesia are needed. Fentanyl buccal tablet (FBT) provides rapid-onset analgesia by enhancing the transbuccal absorption of fentanyl. In an ongoing, 18-month open-label study, opioid-tolerant patients with controlled, persistent pain unrelated to cancer completed the Profile of Mood States (POMS) and 36-item Short-Form Health Survey (SF-36). Enrolling patients were either FBT-naive or previously treated with FBT in one of two randomized, double-blind studies. Treatment-naive patients identified an effective dose of FBT (100-800 µg) during a titration period; rollover patients continued on their previous effective dose. Data for 272 patients who had received ≥6 months of therapy and completed the POMS and SF-36 were available for this interim analysis. On the POMS, total mood disturbance score (mean±SE) changed from 33.2±1.5 at baseline to 25.3±1.9 at 6 months (23% improvement from baseline). Notable improvements in POMS subscales were seen in tension-anxiety (24% improvement in mean score from baseline), confusion-bewilderment (21%), fatigue-inertia (16%), depression-dejection (15%), and anger-hostility (12%). Vigor-activity did not improve. Improvements in SF-36 scores were most apparent in the domains of vitality (7% improvement from baseline), bodily pain (6%), and social functioning (5%). General health, mental health, physical functioning, physical composite, role physical, and mental composite also improved (≤3%), but not role-emotional. Greater improvements in the majority of scores on both POMS and the SF-36 were seen in patients with moderate or severe pain at baseline vs mild pain. These interim results suggest that treatment with FBT may be associated with improvements in mood and QOL in patients with BTP associated with chronic noncancer pain, especially those with moderate or severe pain at baseline.