Zeppetella, G., & Ribeiro. M.D. (2006). Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004311.

To explore and assess evidence regarding the use of opioids in the management of breakthrough pain in patients with cancer

Databases searched were Cochrane Pain, Palliative & Supportive Care Register, Cochrane Controlled Trials Register, MEDLINE, EMBASE, CANCERLIT, Science Citation Index, CINAHL, System for Information on Grey Literature in Europe (SIGLE), LILACS, and databases related to these journals: European Journal of Palliative Care, International Journal of Palliative Nursing, Progress in Palliative Care, The Hospice Journal, Journal of Palliative Medicine, and American Journal of Hospice and Palliative Care.

Authors analyzed four randomized controlled trials that involved opioids used as rescue medication. Each trial compared the action of an opiod to an active or placebo comparator in patients with cancer pain. All studies were conducted in an outpatient setting in the United States. In each study, oral transmucosal fentanyl citrate (OTFC) was the subject of the investigation.Two studies examined dose titration of OTFC, one study compared OTFC to placebo, and one study compared OTFC to normal-release morphine. All studies were divided into two phases.

In the two studies assessing the effectiveness of OTFC, investigators evaluated the performance of the rescue drug in phase 1. In phase 2, participants were randomized to two groups: one started drug therapy at 200 mcg OFTC; the other, at 400 mcg OTFC. Clinicians titrated to the effective dose and then evaluated the performance of the drug. 

In the study assessing OTFC to placebo, in phase 1 drug therapy started at 200 mcg OTFC and the dose was titrated for effective relief. After adequate pain control, patients entered phase 2 and received OTFC equal to the amount effective in phase 1 plus placebo.

In fourth study, which compared OTFC with normal-release morphine, participants started drug therapy at 200 mcg OTFC and titrated up for effective pain relief. Once obtaining effective pain relief, participants entered phase 2, where they received equal amounts of OTFC versus their pretrial dose of normal-release morphine.

All studies recruited adults who experienced at least one episode but no more than four episodes of breakthrough pain daily. Each participant was taking a stable dose of opioid that consisted of either an oral opioid (at least the equivalent of 60 mg oral morphine per day) or transdermal opioid (at least 50 mcg/hour transdermal fentanyl). Two studies recruited 129 patients and identified the dose of OTFC adequate to treat one episode of breakthrough pain. One study of 130 participants compared OTFC to placebo. Another study, with 134 participants, compared OTFC and normal-release morphine. Across all four studies the sample consisted of 393 participants.

The studies identified in this review were specific to the use of OTFC for breakthrough pain in patients with cancer. All studies included similar outcome measures and were of high quality. This review shows that, compared to usual rescue medication or placebo, OTFC is an effective treatment for breakthrough cancer pain and is associated with a greater analgesic effect, better satisfaction, and a more rapid onset.

The evidence base relates to OTFC only. An increasing number of opioids are in use; these opioids (morphine, oxycodone, hydromorphone, and oxycodone) should be studied and compared in regard to effectiveness in the treatment of breakthrough pain. Such studies should be performed using the OTFC template.