The analgesic efficacy of opioids in different application modalities for the treatment of breakthrough cancer pain-a systematic review with network meta-analysis.

Breakthrough cancer pain episodes often require oral immediate release opioids or parenteral opioid treatment. Different formulations and application modalities have been approved for this condition. This study aimed to identify the most effective of the available substances and applications to treat breakthrough cancer pain. We conducted a comprehensive systematic review with network meta-analysis. The database search included MEDLINE, CENTRAL, Embase, and Web of Science. Eligible were randomized controlled trials comparing opioids and application modalities for the treatment of breakthrough cancer pain episodes. Primary end points were the pain intensity difference (PID) at 15 and 30 minutes. Secondary end points were side effects and adverse events, as well as dichotomous outcomes of treatment success. Frequentist network meta-analysis was conducted using the package netmeta in R. From 5133 records initially identified by the literature review, 23 studies were eligible for quantitative analysis. Compared with placebo, the most effective interventions at 15 minutes (PID) were intravenous or subcutaneous applications of morphine, and intranasal fentanyl or sublingual fentanyl tablets. After 30 minutes (PID), the most effective interventions were still subcutaneous and intravenous morphine, but also sublingual fentanyl tablets. Intranasal fentanyl spray was equally effective as buccal and other transmucosal applications by 30 minutes. The quality of evidence on the topic is poor as most studies are phase III trials for drug approval. The risk of publication bias is therefore high. Sublingual fentanyl tablets were as effective as intravenous or subcutaneous morphine and are a practical modality for self-administration.