Inhaled fentanyl aerosol through a drug-device combination for breakthrough cancer pain: A multicenter, randomized, double-blind, placebo-controlled trial.
Authors: Lin Rongbo , Song Binbin , Li Na , Rong Biaoxue , BAI Jinghui , Liu Yong , Wang Wei , LIU Anwen , Luo Suxia , Liu Bo , Cheng Peng , Wu Yani , Li Yu Jie , Yu Xiaohui , Liu Xueying , Dai Xiang Rong , Li Benjamin Xiaoyi , Liu Dongying , Huang Yan 
Published: June 2024

e24058 Background: Breakthrough cancer pain (BTcP) can significantly impact the life quality of the cancer patient. Wide-used rapid-onset opioids (ROOs) for BTcP are transmucosal fentanyl-based preparations. Inhaled fentanyl demonstrated similar pharmacokinetic properties as intravenous administration in healthy volunteers. Fentanyl aerosol can be generated via hand-held drug-device delivery system, providing rapid, consistent multi-dose administration. Fentanyl inhalant was explored as alternative treatment of BTcP in cancer patients in this study to evaluate its efficacy, safety, and tolerability in BTcP patients with well-controlled background cancer pain. Methods: Adults ≥18 years with cancer are eligible if they were experiencing persistent cancer- or treatment-related pain with above mild severity and 1-4 episode occurrences daily. Each patient was treated and observed for 6 BTcP episodes (4 with fentanyl inhalant, 2 with placebo). During each episode, patients were allowed to inhale up to six shots within 1 hour. Pain intensity was recorded using 11-point Numerical Rating Scale (NRS) at predefined time points. The primary endpoint was the time-weighted Sum of Pain Intensity Difference scores at 30 minutes (SPID30) after the first inhalation. Results: 335 BTcP episodes in 59 patients were treated. SPID30 was analyzed using mixed model of repeated measures with treatment (fentanyl inhalant or placebo), BTcP episode, baseline pain intensity score as fixed factors, and subject as random factor. Mean SPID30 ± SD was -97.4 ± 48.43 for fentanyl-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes. Based on treatment adjustment in the mixed covariance model, significant difference (p < 0.001) was reported with mean treatment difference of -27.7 (LS-mean ± SD, -94.2 ± 4.49 for fentanyl and -66.5 ± 4.86 for placebo). It enlarged at 60 minutes (SPID60) with a mean treatment difference of -57.9 (LS-mean ± SD, -231.4 ±105.14 for fentanyl and -162.2 ± 91.21 for placebo, p < 0.001). Significant differences in PID for episodes treated with fentanyl versus placebo were seen 4 minutes after the first dosing and maintained up to 60 minutes. Other endpoints showed statistical significance favoring fentanyl treatment, including the proportion of NRS ≤ 3, NRS pain scores decreased ≥ 33% or ≥ 50% from baseline after completion of BTcP treatment within 30 minutes of first dose, and Pain Relief Score Within 30 Minutes of the First Dose (PR30). Only 4.4% of BTcP episodes required rescue medication in fentanyl group. Major adverse events were mild or moderate in severity and were typical for opioid drugs. Conclusions: Fentanyl inhalant is safe, effective, and well-tolerated for managing BTcP. It provides a non-invasive route for systemic drug delivery and can be self-administered or given by family caregivers as personalized and regular pain management. Clinical trial information: NCT05531422 .