Effects of Prophylactic Subcutaneous Fentanyl on Exercise-Induced Breakthrough Dyspnea in Cancer Patients: A Preliminary Double-Blind, Randomized, Controlled Trial

Abstract

Context Dyspnea is one of the most distressing symptoms in cancer patients, and often worsens with breakthrough episodes on exertion. We hypothesized that fentanyl given prophylactically may alleviate breakthrough dyspnea. Objectives To determine the feasibility of conducting a randomized trial of subcutaneous fentanyl in cancer patients, and examine the effects of fentanyl on dyspnea, walk distance, vital signs and adverse events. Methods In this double-blind, randomized, controlled trial, we asked ambulatory patients with breakthrough dyspnea to perform a baseline six-minute walk test (6MWT), and then assigned them to either subcutaneous fentanyl or placebo 15 minutes before a second 6MWT. We documented the change in dyspnea numeric rating scale (NRS) score, walk distance, vital signs and adverse events between the first and second 6MWT. Results Twenty patients were enrolled (1:1 ratio) without attrition. Comparison between baseline and second walk showed that fentanyl was associated with significant improvements in dyspnea NRS score at the end of the 6MWT (mean [95% CI]: −1.8 [−3.2, −0.4]), dyspnea NRS score at rest 15 minutes after drug administration (−0.9 [−1.8, −0.04]), Borg Scale fatigue score at the end of the 6MWT (−1.3 [−2.4, −0.2]), 6MWT distance (+37.2m [5.8m, 68.6m]) and respiratory rate (−2.4 [−4.5, −0.3]). Non-statistically significant improvements also were observed in the placebo arm, with no difference between the two study arms. No significant adverse effects were observed. Conclusion Prophylactic fentanyl was safe and improved dyspnea, fatigue, walk distance and respiratory rate. We also observed a large placebo effect. Our results justify larger randomized controlled trials with higher fentanyl doses. (clinicaltrials.gov registration: NCT01515566).

Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial

“…(13, 16) In a double-blind, randomized controlled trial, we found that prophylactic subcutaneous fentanyl given at proportional dose of 15-25% of MEDD was safe and significantly improved dyspnea at rest, dyspnea at the end of 6MWT, walk distance, fatigue and respiratory rate in intra-individual comparison. (13) In another double-blind randomized controlled trial, FPNS at proportional dose of 15-25% of MEDD was also found to significantly improve dyspnea at rest, dyspnea at the end of 6MWT, and walk distance. (16) Interestingly, the walk distance and the dyspnea at rest did not improve significantly in the current study, which may be related to the differences of medication, timing of administration and variability among patients.…”

“…6MWT were carried out following guidelines from the American Thoracic Society and have been described in detail. (13, 28) We also assessed both dyspnea and fatigue using the 0-10 modified Borg scale before and after each 6MWT, and measured the distance walked every minute. (28) The minimal clinically significant difference was 1 point for both the NRS and modified Borg scale.…”

“…(8, 9) Several case series of oral transmucosal fentanyl citrate and intranasal fentanyl reported some benefits. (10-12) However, subsequent randomized controlled trials of subcutaneous fentanyl,(13) nebulized fentanyl (14, 15) and fentanyl pectin nasal spray (FPNS)(16) yielded mixed results compared to placebo.…”

Epidemiology and Characteristics of Episodic Breathlessness in Advanced Cancer Patients: An Observational Study

“…In another trial, doses of parenteral fentanyl given prophylactically, proportional to opioids given chronically (15e25%), were safe and effective. 20 This study suggests that fentanyl products could be given before an expected trigger, as it is for preventing predictable breakthrough pain, for example, before starting an activity.…”

“…Interestingly, exercise has been used as a model for inducing episodic breathlessness. 20 It could be surprising that episodic breathlessness is more likely in patients with higher Karnofsky Performance Status scores. Paradoxically, patients with a higher Karnofsky score are more physically active and, therefore, more likely to experience episodes of breathlessness on exertion.…”