Lennernas, B., Frank-Lissbrant, I., Lennernas, H., Kalkner, K.M., Derrick, R., & Howell, J. (2010). Sublingual administration of fentanyl to cancer patients is an effective treatment for breakthrough pain: Results from a randomized phase II study. Palliative Medicine, 24(3), 286–293.

To evaluate the efficacy and tolerability of sublingual fentanyl for the treatment of breakthrough pain in opioid-tolerant cancer patients

This study was conducted from July 2002 to January 2004 at five university clinics in Sweden. Patients had locally advanced or metastatic cancer and were currently

• Receiving scheduled opioids equivalent to 30–1000 mg/day of oral morphine or 25–300 mcg of transdermal fentanyl
• Experiencing at least four episodes of acute breakthrough pain over a 14-day period

Each patient received, at four pain episodes occurring between 0700 and 1600 (defined as the treatment period), a placebo dose and 100, 200, and 400 mcg doses of sublingual fentanyl. The doses were provided in a random order, according to a computer-generated randomization list. At least one day fell between each treatment period, to avoid carry-over effects. Patients were asked to rate their pain at the onset of an episode of breakthrough pain and then at 5, 10, 15, 20, and 30 minutes postingestion of the study drug. At 60 minutes, the patients were asked to make a global assessment of the treatment by using a four-point scale.

• Twenty-three patients completed the study.
• The sample was composed of male and female patients 18–90 years old.
• Ten of the 23 patients were female. Mean patient age of females was 63 years, and the age range of females was 46–80 years. Thirteen patients were male. Mean patient age of males was 65 years, and the age range of males was 40–74 years.
• Patients had locally advanced or metastatic cancer, and all 23 patients were opioid tolerant and Caucasian.

• Multisite
• Outpatient
• Five university clinics in Sweden

Randomized, multicenter double-blind, four-period crossover study

• Ungraded 100 mm visual analog scale (VAS), with 0 = no pain, 100 = worst conceivable pain
• Four-point scale (none, mild, moderate, excellent)

Twenty-three patients completed all four treatment doses. Twenty-two of the 23 patients (95%) reported that at least one dose of the sublingual fentanyl produced a clinically important decrease in pain intensity, as measured by a decrease in pain intensity of more than 20 mm on the VAS. In regard to adverse events, 13 patients reported 15 adverse events considered to be related to the study drug. The most common treatment-related adverse effects were nausea and dizziness. Increasing the doses of sublingual fenanyl did not appear to increase the number or severity of adverse events, when evaluated related to increasing doses of sublingual fentanyl.

Within 15 minutes of administration, 400 micrograms of sublingual fentanyl proved more effective than placebo at significantly improving overall pain intensity difference. This was true over the entire treatment period. In regard to reducing pain intensity, results showed that the 100 and 200 mcg doses of sublingual fentanyl were more effective than placebo.

• The study had a small sample size, with fewer than 30 patients.
• Authors did not specify whether the patients were concurrently receiving treatment for cancer.
• Authors did not provide an analysis of a dose-response relationship.
• The study did not evaluate statistical differences between the dose strengths used.

Further study is needed to determine, in regard to decreasing breakthrough pain, the efficacy of each of the doses of sublingual fentanyl.