Shimoyama, N., Gomyo, I., Katakami, N., Okada, M., Yukitoshi, N., Ohta, E., & Shimoyama, M. (2015). Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined by titration for the treatment of breakthrough pain in Japanese cancer patients: A multicenter, randomized, placebo-controlled, double-blind phase III trial. International Journal of Clinical Oncology, 20, 198–206.

To evaluate the safety and efficacy of sublingual fentanyl orally disintegrating tablets for breakthrough cancer-related pain

The trial had several phases. In the initial observation phase over four consecutive days, pain intensity and pain relief were evaluated. Patients who showed an analgesic effect for opioid for breakthrough episodes were entered into the titration phase. In the titration phase (no more than 21 days long), patients received 100 mcg of sublingual fentanyl for the first breakthrough episode. The dose was increased by 100 mcg until the optimal dose was determined. Effectiveness was defined as no needed additional dose, and pain scores at 30 and 60 minutes were reduced by at least 18 mm or a third of pain levels prior to administration. Patients for whom optimal dose was determined were entered into the 21-day, double-blinded treatment phase in which three random breakthrough episodes were treated with a placebo for comparison. This was followed by a 12-week extended treatment phase. All pain scores were recorded by subjects in a diary.

• N = 37 (double-blinded phase), 13 (completed extended treatment )
• MEAN AGE = 66 years (SD = 9.2 years)
• MALES: 59.5%, FEMALES: 40.5%
• KEY DISEASE CHARACTERISTICS: Multiple tumor types; lung and colon most prevalent
• OTHER KEY SAMPLE CHARACTERISTICS: The median Visual Analog Scale pain score at baseline was 72.9.

• SITE: Multi-site  
• SETTING TYPE: Multiple settings  
• LOCATION: Japan

• PHASE OF CARE: Late effects and survivorship
• APPLICATIONS: Palliative care 

Open-label titration, double-blinded, placebo-controlled, comparative phase trial with a 12-week extended treatment phase

• 100 mm Visual Analog Scale (VAS) for pain severity (pain measured at 15, 30, and 60 minutes during breakthrough episodes)
• Patient global evaluation of relief and satisfaction on five-point scale

Overall, 90.5% of participants were titrated to an effective dose. Pain at 30 and 60 minutes during breakthrough episodes was significantly better with the sublingual fentanyl oral dissolving tablets compared to a placebo (p < 0.0001). No subjects discontinued the trial because of adverse drug effects. In the extended treatment phase, 50% of participants had dose reductions because of somnolence. Opioid analgesics were changed in 68.8% of patients because of uncontrolled pain or adverse events. The most common titrated dose was 300 mcg. The number of days needed to obtain an effective titrated dose ranged from 1–21 days with a median of three days.

Sublingual oral fentanyl dissolving tablets were effective in reducing breakthrough pain compared to a placebo.

• Small sample (< 100)
• Unintended interventions or applicable interventions not described that would influence results
• Measurement/methods not well described
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: Neither the timing of pain measures nor how multiple measurements were handled for the analysis were described. There was no clear description of changes in baseline analgesia or how this was handled in the analysis.

Transmucosal opioids such as sublingual fentanyl oral dissolving tablets were effective in treating episodes of breakthrough pain. In this study, patients received this medication for extended periods, demonstrating few side effects over time.