Pinna, M.A., Bruera, E., Moralo, M.J., Correas, M.A., & Vargas, R.M. (2015). A randomized crossover clinical trial to evaluate the efficacy of oral transmucosal fentanyl citrate in the treatment of dyspnea on exertion in patients with advanced cancer. The American Journal of Hospice and Palliative Care, 32, 298–304. 

To evaluate the efficacy of oral transmucosal fentanyl citrate (OTFC) in the treatment of dyspnea on exertion in patients with advanced cancer

Subjects were chosen over the course of one year. The participants were assigned to one of two treatment groups. The study administered a dosage of 200 µg to patients who were not receiving opioid treatment and 400 µg to those using opioids for other cancer-related symptoms. Prior to testing, the patients remained at rest for five minutes. They were then given OTFC, and the 6-Minute Walk Test (6MWT) was carried out. During visit 2, patients who had been receiving the investigational product were given the placebos and vice versa. At least two days passed between visits 1 and 2 to perform the 6MWT. The follow-up of patients covered a maximum period of seven calendar days.

• N = 13
• MEAN AGE = 65.2 years
• MALES: 84.6% (n = 11), FEMALES: 15.4% (n = 2)
• KEY DISEASE CHARACTERISTICS: Average time after diagnosis was 1.88 years; locations of primary tumors were lung (n = 10; 76.9%), kidney (n = 1; 7.7%), breast (n = 1; 7.7%), and stomach (n = 1; 7.7%)
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria included moderate dyspnea defined as dyspnea caused by basic activities of daily living in the past 24 hours with an intensity of at least 3 on a scale from 0–10; Karnofsky index score > 50; hemoglobin levels within the past month exceeding 10 mg/dl; and SaO2 >90%. Exclusion criteria included patients with advanced chronic obstructive pulmonary disease. 

• SITE: Not stated/unknown  
• LOCATION: Not specified

• APPLICATIONS: Palliative care

Randomized, double-blinded, crossover, placebo-controlled clinical trial

• Edmonton System Assessment System (ESAS), a numeric rating scale to determine changes and severity of breathlessness.
• Dyspnea intensity scale, a numeric scale from 0–10 (0 = no dyspnea and 10 = maximum severity)
• Karnofsky Performance Status (KPS)

Patients were classified into three categories according to the differences observed in dyspnea before and after completion of the 6MWT. 1) Better response to the treatment obtained in the first period, 2) same response to both the periods, and 3) better response to the treatment obtained in the second period. No differences between treatments were demonstrated (P = 1). There were no differences between the change in oxygen saturation level before and after the 6MWT (P = 0.7541). The distance walked in the different sequences did not vary independently (P = 0.6550). There were no differences in the relation to the Edmonton Symptom Assessment System before or after the 6MWT (P = 0.1234). No secondary effects associated with the medication were observed. Type 2 error was ruled out with a confidence level exceeding 5%.

The study concluded that it could not demonstrate that OFTC improved exertion dyspnea in patients with advanced cancer. A placebo effect was observed in all the patients. This study had a small sample size of 13 patients. It was observed that OTFC may reduce dyspnea in the first three minutes of initiating the test, but this lacked statistical significance.

• Small sample (< 30)
• Measurement/methods not well described
• Findings not generalizable
• Other limitations/explanation: Study was costly because of the cost of developing a placebo with the characteristics of OTFC. Only a select number of laboratories agreed to manufacture the placebo, increasing the cost of the clinical trial. The study had a single point in time evaluation.

Dyspnea is one of the most common and distressing symptoms experienced by patients with advanced cancer. This study demonstrated some benefit of transmucosal fentanyl citrate on dyspnea with exertion in the first three minutes, but this result was not statistically significant. Overall, transmucosal fentanyl did not ffect dyspnea with exertion in these patients. This study was small with only 13 participants, and a placebo effect was observed in all patients.