Oral Transmucosal Fentanyl Citrate: Randomized, Double-Blinded, Placebo-Controlled Trial for Treatment of Breakthrough Pain in Cancer Patients

Author: Reviewer: Ryan P. Smith, MD
Content Contributor: Abramson Cancer Center of the University of Pennsylvania
Last Reviewed: December 05, 2003

Authors: Farrar JT, Cleary J, Rauck R, Busch M, Nordbrock E
Source:JNCI, Vol 90(8), 1998, 611-616


  • The majority of cancer patients will experience pain as a symptom of their disease
  • In addition to persistent pain, many patients experience "breakthrough pain", which are episodes of acute pain that are superimposed on the chronic pain syndrome
  • Normal treatment for cancer pain includes long-acting opioids for control of chronic pain and shorter-acting narcotics for breakthrough pain
  • Breakthrough pain episodes are thought to often have an onset of 15-20 minutes and a peak effect of 30-45 minutes, with variable duration
  • Because of this rapid onset and often shorter duration, those medications with rapid action are beneficial
  • Oral transmucosal fentanyl citrate (OFTC) has been developed as a short-acting opioid in the form of a sweetened lozenge designed to be delivered transmucosally through the buccal mucosa
  • This is a report of a randomized, double blind, placebo controlled study of the use of OFTC in the treatment of breakthrough pain in cancer patients

Materials and Methods

  • 130 cancer patients who were on long-acting opioid medication for management of chronic pain with at least one episode of breakthrough pain per day were enrolled on the study
  • All were started on 200 mcg of OFTC for breakthrough pain and were titrated up over a 2 week period until an adequate response was attained
  • In 93 patients who completed this phase and went on to participate in the randomized trial, 89 were evaluated as intent-to-treat
  • In the randomized, double blind, placebo controlled portion, patients were given a box of 10 units, of which 3 were placebos. This insured the use of both the OFTC and placebo during the trial.
  • If pain relief was not adequate within 30 minutes, patients were encouraged to take their previous non-study breakthrough pain medication
  • By patient personal medication diary, pain intensity, total pain relief, and toxicity data was obtained
  • All patients who consumed at least one active unit and one placebo were included in the study


  • Of the 37 patients who did not go on to the randomized portion, 10 did not go on due to side effects and four felt the OFTC was ineffective
  • 730 episodes of pain were studied during the randomized portion of the study, of which roughly 30% were treated with placebo
  • Difference in pain intensity (from prior to medication/placebo until after) was significantly greater in the OFTC group
  • Pain relief was significantly greater in the OFTC group
  • More additional rescue medication was used for breakthrough episodes in the placebo group (34% vs. 15%)
  • Of the original cohort of patients enrolled in the randomized study, 74 chose to continue to treat their breakthrough pain with OFTC
  • Toxicity was mild and most commonly included dizziness, nausea, somnolence, and constipation; similar to any opioid medication

Author's Conclusions

  • OFTC was significantly better than placebo in every analysis completed
  • OFTC has relatively few side effects
  • The advantages of rapid onset, ease of delivery, and acceptance by patients make OFTC ideally suited for the treatment of breakthrough pain in cancer patients

Scientific Implications

This is an important report of a newer type of short-acting narcotic designed to treat episodes of breakthrough pain. The main advantage, as pointed out by the authors, is that OFTC has a rapid onset, hence relieving cancer patients' breakthrough pain quicker. This study indicates that OFTC is useful in this regard, as compared to placebo controls. This advantage started at the 15 minute self-report by the patients, which would indicate a more rapid, efficacious onset. This relief also lasted the entire 60 minutes that the patients were required to self-report. There was also little toxicity involved in the use of OFTC. Although the OFTCs were more efficacious, there was an obvious placebo effect, as noted by the fact that patients used rescue medication in only 34% of the episodes.

What is perhaps most impressive about the study is the amount of breakthrough pain episodes that the patients reported. There were hundreds of episodes in these 93 patients, indicating that pain management is of utmost importance in cancer patients. Hopefully OFTC can play a role in the treatment of breakthrough pain. Although it was efficacious when compared to placebo in this study, the true test of its usefulness would lie in a randomized study comparing it to other medications designed to treat breakthrough pain. This is exemplified by the fact that, out of the original 130 patients that started in the open label portion of the study, only 74 patients chose to continue OFTC as their primary treatment of breakthrough pain. Obviously, pain management must be individualized, but OFTC's rapid onset and safe toxicity profile should at least be considered in patients for the treatment of breakthrough pain

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