Opioids for the management of breakthrough pain in cancer patients

Giovambattista Zeppetella, Andrew N Davies

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 1, 2006). Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger despite relative stable and adequately controlled background pain. Breakthrough pain usually related to background pain and is typically of rapid onset, severe in intensity and generally self limiting with a mean duration of 30 minutes. Breakthrough pain has traditionally been managed by the administration of supplemental oral analgesia (rescue medication) at a dose proportional to the total around-the-clock (ATC) opioid dose. To determine the efficacy of opioid analgesics given by any route, used for the management of breakthrough pain in patients with cancer, and to identify and quantify, if data permitted, any adverse effects of this treatment. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and trial registries in January 2005 for the original review, and again on 6 February 2013 for this update. We included randomised controlled trials (RCTs) of opioids used as rescue medication against active or placebo comparator in patients with cancer pain. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction and quality of life. We applied no language restrictions. Two review authors independently selected and examined eligible studies. We retrieved full text if any uncertainty about eligibility remained. We screened non-English texts. We conducted quality assessment and data extraction using standardised data forms. We compared drug and placebo dose, titration, route and formulation and recorded details of all outcome measures (if available). The original review included four studies (393 participants), all concerned with the use of oral transmucosal fentanyl citrate (OTFC) in the management of breakthrough pain. Two studies examined the titration of OTFC, one study compared OTFC versus normal-release morphine and one study compared OTFC versus placebo.Fifteen studies (1699 participants) met the inclusion criteria for this update. All studies reported on the utility of seven different transmucosal fentanyl formulations, five of which were administered orally and two nasally. Eight studies compared the transmucosal fentanyl formulations versus placebo, four studies compared them with another opioid, one study was a comparison of different doses of the same formulation and two were randomised titration studies. Oral and nasal transmucosal fentanyl formulations were an effective treatment for breakthrough pain. When compared with placebo or oral morphine, participants gave lower pain intensity and higher pain relief scores for transmucosal fentanyl formulations at all time points. Global assessment scores also favoured transmucosal fentanyl preparations. One study compared intravenous with the transmucosal route and both were effective. Oral and nasal transmucosal fentanyl is an effective treatment in the management of breakthrough pain. The RCT literature for the management of breakthrough pain is relatively small. Given the importance of this subject, more trials, including head-to-head comparisons of the available transmucosal fentanyl formulations are required.