Prophylactic Fentanyl Sublingual Spray for Episodic Exertional Dyspnea in Cancer Patients: A Pilot Double-Blind Randomized Controlled Trial

Abstract

Context: The optimal dose of fentanyl sublingual spray (FSS) for exertional dyspnea has not been determined.

Objectives: We examined the effect of two doses of prophylactic FSS on exertional dyspnea.

Methods: In this parallel, dose-finding, double-blind randomized clinical trial, opioid-tolerant cancer patients completed a shuttle walk test at baseline. Patients completed a second shuttle walk test 10 minutes after a single dose of FSS equivalent to either 35%-45% (high dose) or 15%-25% (low dose) of the total daily opioid dose. The primary outcome was change in modified dyspnea Borg scale (0-10) between the first and second shuttle walk tests. Secondary outcomes included adverse events as well as changes in walk distance, vital signs, and neurocognitive function.

Results: Thirty of the 50 enrolled patients completed the study. High-dose FSS (n = 13) resulted in significantly lower dyspnea (mean change -1.42; 95% CI -2.37, -0.48; P = 0.007) and greater walk distance (mean change 44 m; P = 0.001) compared to baseline. Low-dose FSS (n = 17) resulted in a nonsignificant reduction in dyspnea (mean change -0.47; 95% CI -1.26, 0.32; P = 0.24) and significant increase in walk distance (mean change 24 m; P = 0.01) compared to baseline. Global evaluation showed high-dose group was more likely to report at least somewhat better improvement (64% vs. 24%; P = 0.06). No significant adverse events or detriment to vital signs or neurocognitive function was detected.

Conclusion: Prophylactic FSS was well tolerated and demonstrated a dose-response relationship in improving both dyspnea and walk distance. High-dose FSS should be tested in confirmatory trials.

Keywords: Dyspnea; fentanyl; neoplasms; opioid analgesics; physical exertion; randomized controlled trial.

Figure 1.. Consolidated Standards of Reporting Trials (CONSORT) Flowchart.

Abbreviations: KPS, Karnofsky performance scale; MEDD, morphine equivalent daily dose

Figure 2.. Change in Dyspnea Intensity and Walk Distance With and Without Study Medications.

(A) In the high dose fentanyl sublingual spray (FSS) group, significantly lower modified dyspnea Borg scale (mean change −1.4; 95% CI −2.4, −0.5; P=0.007) was observed between the first (no medication) and second (10 minutes after FSS administration) walk. (B) In the low dose FSS group, there was also a non-significant reduction in modified dyspnea Borg scale (mean change −0.5; 95% CI −1.3, 0.3; P=0.24). Walk distance was increased after both high ([C]; mean change 44 m; P=0.001) and low ([D]; mean change 24 m; P=0.01) dose FSS administration as compared to baseline.