Efficacy and safety of fentanyl for episodic breathlessness in patients with advanced life-limiting illnesses: a systematic review and meta-analysis of randomized controlled trials

Episodic breathlessness is a sudden, severe, and distressing symptom affecting patients with advanced life-limiting illnesses. The delayed onset of conventional oral opioids renders them suboptimal for this acute symptom. Rapid-onset fentanyl formulations offer a pharmacologically rational treatment; however, their evidence base for breathlessness remains fragmented and inconclusive, with no prior meta-analysis. Therefore, this systematic review and meta-analysis was conducted to evaluate the efficacy and safety of rapid-onset fentanyl formulations for episodic breathlessness in this population. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed. RCTs were identified through searches of PubMed, Embase, CENTRAL, and Google Scholar from inception to December 25, 2025. The review included RCTs comparing a rapid-onset fentanyl formulation (intranasal, buccal, sublingual) with a control (placebo, usual care, or another opioid) in adults with episodic breathlessness. The primary outcome was the change in dyspnea intensity. Secondary outcomes included walk distance and adverse events (e.g., dizziness). Risk of bias was assessed using the Cochrane RoB 1.0 tool. Data were pooled using random-effects models, with mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes. This systematic review was conducted according to a pre-defined protocol, which was registered on PROSPERO (Registration number: CRD420251273024). Six RCTs ( n = 119 participants) were included. Five trials contributed to the meta-analyses of outcomes. For the primary outcome meta-analysis, data from four trials ( n = 87) were available. The pooled MD for change in dyspnea intensity (0–10 scale) was − 0.83 (95% CI: -1.66 to -0.01, P = 0.05), favoring fentanyl, with negligible heterogeneity (I²=0%). This observed reduction falls below the established minimal clinically important difference (MCID) of 1 point. Sensitivity analysis excluding the active-comparator trial showed loss of significance (MD -0.72, 95% CI: -1.89 to 0.46, P = 0.23). There was no significant improvement in walk distance (MD 6.28 m, 95% CI: -10.84 to 23.39, P = 0.47). The risk of dizziness was not significantly increased (RR 1.15, 95% CI: 0.06 to 20.72, P = 0.92), but heterogeneity was substantial (I²=76%). No studies reported serious adverse events related to fentanyl. Rapid-onset fentanyl may reduce the intensity of breathlessness during episodes. However, the evidence is very uncertain according to GRADE, and the effect did not surpass the minimum clinically important difference (MCID). No major safety issues were found, but the analysis lacked power to identify rare side effects. Due to the very low certainty of the evidence, these results should be viewed with great caution and are only for generating hypotheses. Larger, definitive randomized controlled trials are needed to establish efficacy and safety before rapid-onset fentanyl can be considered a standard intervention.