Thronaes, M., Popper, L., Eeg, M., Jaatun, E., Kvitberg, M., & Kaasa, S. (2015). Efficacy and tolerability of intranasal fentanyl spray in cancer patients with breakthrough pain. Clinical Therapeutics, 37, 585–596. 

To assess the efficacy and 12-week tolerability of intranasal fentanyl spray (INFS) in patients with cancer-related breakthrough pain

Doses were titrated to achieve efficacy. Patients with doses titrated to 200–400 mcg were entered into an efficacy phase in which eight episodes of breakthrough pain were treated. Episodes were randomly treated with INFS or a placebo. Patients with doses titrated to 50 or 100 mcg were directly entered into a tolerability phase. Patients with titrated doses of 200 or 400 mcg entered a tolerability phase after the treatment of eight breakthrough episodes. Patients recorded pain, adverse effects, and impressions of efficacy daily in a diary. Pain was recorded at baseline and at two, 10, 30, and 60 minutes after taking INFS. Local nasal tolerability was assessed by an otorhinolaryngologist at baseline and at the end of the study.

• N = 46
• MEDIAN AGE = 61 years (range = 38–79 years)
• MALES: 32.6%, FEMALES: 67.4%
• KEY DISEASE CHARACTERISTICS: Most frequent tumor types were breast, urothelial, and gastrointestinal; 54% had bone metastases

• SITE: Multi-site  
• SETTING TYPE: Not specified  
• LOCATION: Several European countries

Double-blinded, placebo-controlled, crossover trial

• 11-point Numeric Rating Scale (NRS)  
• The difference between pain ratings at baseline and each time point for breakthrough episodes was calculated.
• Clinical nasal examination

Mean differences in pain were greater for INFS compared to a placebo at 10, 30, and 60 minutes (p < 0.02). In total, 61% of patients receiving 400 mcg responded at five minutes. The most common adverse nasal events were change in mucosa color, runny nose, inflammation, stuffed nose, and edema, which occurred in four to five cases. None were considered serious. Other events reported were dizziness, nausea, fatigue, and vomiting. Half of these were considered to be treatment-related. The adverse event profile was similar for all dose levels.

INFS was effective for the management of breakthrough pain compared to a placebo, and it was not associated with severe nasal side effects over a 12-week period. Other side effects seen were those typical of opioid treatment.

• Small sample (< 100)
• Measurement validity/reliability questionable
• Other limitations/explanation: Reliance on patient diaries for pain reporting at specific time points; adherence and missing data were not discussed

This study added to the body of evidence showing that INFS is effective in the management of breakthrough pain. The rapid, effective relief of breakthrough pain is an important goal for pain management. The examination of the nasal cavity in this study added to relevant information, showing its overall tolerability over a 12-week period. Ongoing research with longer periods of follow-up are needed.