Kress, H.G., Oronska, A., Kaczmarek, Z., Kaasa, S., Colberg, T., & Nolte, T. (2009). Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: A phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Clinical Therapeutics, 31(6), 1177–1191.

To assess the efficacy and long-term tolerability of infranasal fentanyl spray (INFS)

In an initial titration phase, the effective dose of INFS was determined for each patient. An effective dose was defined as one that was successful in treating three of four episodes of breakthrough pain. If pain relief was insufficient, an additional dose was administered in the alternate nostril. Titration was repeated if the patients’ background opioid dosage was adjusted during the trial. During the efficacy phase patients received, in randomized double-blind sequence, the titrated effective dose of INFS or placebo for administration at home. Patients were randomized to treatment sequences for eight episodes of breakthrough pain. Patients used a diary to record pain intensity at 0, 10, 20, 40, and 60 minutes after administration. Pain ratings were according to a numeric rating scale. Patients were monitored during the 10-month open-label extension phase. Patients received 30-day supplies of INFS, in appropriate doses, during monthly clinic visits. Weekly telephone contact provided data about adverse events, concurrent medications, and INFS efficacy.

• In all,120 patients were enrolled and achieved an effective dose; 113 were randomized and 111 were included in the intent-to-treat analysis.
• Mean patient age was 60.6 years. Age range was 35–79 years.
• Of all patients, 49.5% were female and 50.5% were male.
• The study included patients with multiple cancer sites. Most frequent diagnoses were breast, lung, colon-rectal, and female genital cancer. All patients in whom race was reported were white. Of all patients, 54% received fentanyl for background pain and 43% received morphine sulfate. The other subjects received other opioids.

• Multisite
• Outpatient
• Anesthesiology departments, palliative care units, and oncology clinics in Austria, Denmark, France, Germany, and Poland

Double-blind randomized, double-dummy two-way crossover study

• 11-point numeric rating scale (0–10) of pain intensity
• Five-point scale (0 = poor, 5 = excellent) that provided patient's general impression of treatment efficacy
   

• INFS was associated with pain intensity decreases that were significantly greater than those associated with placebo (p < 0.001).
• Compared with placebo, INFS pain reduction improved with increases in dose related to time after administration (p < 0.0001). Rating of general impression of efficacy at 60 minutes after use was significantly higher (p < 0.001) with INFS than with placebo.
• During the efficacy phase, 22 patients experienced adverse events. Most common effects were nausea and vertigo.

INFS titrated to an effective dose demonstrated some effectiveness in relieving breakthrough pain in this group of patients. Long-term tolerability could not be clearly determined because of the small number of patients who completed the extension phase of the study. Most patients appeared to tolerate IFNS well.

• Approximately one-third of patients who entered the extension phase of the trial withdrew consent. Reasons for withdrawal were not cited, and findings did not include withdrawals as adverse events. Lacking details about withdrawals, the actual prevalence and types of adverse events associated with long-term INFS use are unknown.
• Authors considered a small numeric reduction in pain scores—from baseline to 10 minutes, a difference of 0.5 or a change greater than 2—to mean that the treatment was clinically effective. Whether a patient would consider such levels of change indicative of effective treatment is unknown.

Findings suggest that INFS may be a useful adjunctive approach to deal with the breakthrough pain of patients with cancer who have chronic opioid-managed pain. INFS may be more useful as a short-term, rather than a long-term approach; the matter of long-term efficacy and tolerability requires further study.