Slatkin, N.E., Xie, F., Messina, J., & Segal, T.J. (2007) Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. Journal of Supportive Oncology, 5, 327–334.

The study involved three phases: the screening visit, an open-label dose-titration phase, and a double-blind treatment phase. Titration was based on each patient's previous opioid dose. The dose of fentanyl buccal tablet (FBT) was increased stepwise from 100 mcg to 200, 400, 600, or 800 mcg until investigators identified an effective dose. If investigators could determine an effective dose for a patient, the patient entered the next phase of the study. In the double-blind treatment phase, patients were randomly assigned to 1 of 18 double- blind dose sequences (seven FBTs of the dose identified as effective and three placebos) to treat 10 episodes of breakthrough pain (BTP). Ten tablets were labeled 1–10, and patients were to take them consecutively. The treatment sequence was randomly assigned by a statistician who had used a computer to generate it. Patients continued to use their ATC regimen. If no relief occurred within 30 minutes, they continued pretrial supplemental medication.

• Study enrollment consisted of 129 patients; 87 patients entered the double-blind phase. Of these, 86% completed the study and 90% of those were evaluable for efficacy.
• Of all patients, 41% had nociceptive pain, 17% had neuropathic pain, and 42% had mixed pain.

• Multisite
• Outpatient
• Thirty treatment centers in the United States, January 2005–September 2006

Randomized double-blind, placebo-controlled design

• An 11-point (0–10) scale, to measure pain intensity (PI)
• Sum of pain intensity differences (PID) for the first 60 minutes (SPID60)
• PIDs and measure of pain relief (PR), using a five-point Likert scale (0 = none, 4 = complete), assessed from five minutes through two hours
• Patient's assessment of total pain relief
• A five-point scale (0 = poor, 4 = excellent), to measure patient's rating of global medication performance
• Proportion of breakthrough pain episodes requiring supplemental medication
• Adverse events

Investigators were able to identify an effective dose of FBT for 70% of patients. The list that follows cites the single-tablet dose of FBT that the cited percentage of patients found adequate for the treatment of two consecutive breakthrough pain episodes: 100 mcg, 8%; 200 mcg, 12%; 400 mcg, 18%; 600 mcg, 28%; 800 mcg, 34%. SPID60 favored FBT versus placebo (p < 0.0001). PIDs and PR showed significant differences versus placebo at 10 minutes (p < 0.0001). Adverse events were typical (nausea, dizziness, fatigue) and were reported in 66% of participants during the study. Ten percent had adverse events related to FBT application site. Most adverse events occurred during dose titration and were mild and transitory. Difference in SPID60 of 3 was considered clinically relevant. Sample size of 70 was associated with a power of 90%.

For opioid-tolerant patients with chronic cancer pain and breakthrough pain, FBT was efficacious and well tolerated. FBT demonstrated rapid onset (with effect within 10 minutes), and the effect of FBT was sustained.

• Most common reasons for withdrawal were adverse effects, lack of efficacy, and withdrawal of consent; 11% of patients withdrew because of adverse effects; 6%, for lack of efficacy; and 6%, for withdrawal of consent.
• The use of an open-label dose-titration phase may have increased the chance of unblinding by sensitizing patients to the effects of FBT.
• The subgroup that entered the double-blind phase had already demonstrated a favorable response to FBT. Therefore, generalizing the results to the general population is difficult. However, this process is consistent with clinical practice. This study assessed effectiveness of FBT versus placebo, not versus supplemental medications.