Mercadante, S., Radbruch, L., Davies, A., Poulain, P., Sitte, T., Perkins, P., . . . Camba, M.A. (2009). A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: An open-label, randomised, crossover trial. Current Medical Research and Opinion, 25(11), 2805–2815.

To compare the effectiveness of intranasal fentanyl spray (INFS) with that of oral transmucosal fentanyl citrate (OTFC) for relief of breakthrough pain in patients with cancer

The study had three phases. In the screening phase, patients recorded pain intensity, characteristics of breakthrough episodes, and use of rescue medications. Then they received a test dose of INFS. If the patients had no reactions to the dose, they were randomized to receive INFS followed by OTFC or vice versa. In the titration phase, the study drug was used to treat four breakthrough pain episodes, to determine effective dose. In the efficacy phase, six episodes of breakthrough pain were treated with the effective dose of the study drug. The efficacy phase lasted two weeks or less. Following the efficacy phase, the titration and efficacy phases were repeated, with the patient using the alternate study drug. In the efficacy phase, the patient recorded, for each episode of breakthrough pain, time to onset of meaningful pain relief, pain intensity, and use of rescue medication. To measure time to relief, the patient used a stopwatch. Doses of INFS were 50, 100, or 200 micrograms taken as a single dose in one nostril. If a second dose was required, it was allowed after 10 minutes and administered in the other nostril. OTFC doses of 200, 400, 600, 800, 1200 or 1600 micrograms were in the form of a single compressed lozenge. If required, a second dose of OTFC was used 30 minutes after the first. Patients could use rescue analgesics as needed, 45 minutes after one OTFC dose or 60 minutes later, if a second OTFC dose was used. Up to four episodes of breakthrough pain per day were treated with the study drugs. Pain intensity was recorded at multiple time intervals for each breakthrough episode.

• Eighty-six patients completed all phases. INFS efficacy data were for 101 patients; OTFC efficacy data, for 100 patients.
• Mean patient age was 62 years. The age range was 22–94 years.
• Of all patients, 43.2% were female and 56.8% were male.
• All patients were Caucasian.
• Authors did not provide information about specific diagnoses.
• Patients had a life expectancy of three months or longer and were receiving stable opioid therapy for background pain, at a dose equivalent to 60–500 mg/day morphine, for at least one month prior to the study.
• Patients were excluded if they had had recent cancer treatment or if treatment was scheduled within the next eight weeks.

• Multisite
• Inpatient and outpatient
• Europe

Open-label crossover trial

• Stopwatch, to measure time to onset of meaningful pain relief
• 11-point numeric scale, to measure pain intensity
• Five-point Likert-type scale, to rate general impression of efficacy
• Five-point Likert-type scale, to rate ease of drug administration

• Authors reported that 85.1% of patients achieved an effective INFS dose and 87.9% achieved an effective OTFC dose in titration.
• Results revealed that 73.6% obtained faster onset of pain relief with INFS (p < 0.001) than with OTFC.
• After onset of the breakthrough pain episode, INFS produced a significantly larger mean decrease in pain intensity (p < 0.001) in the first 15 minutes and the first 60 minutes. Compared to OFTC, INFS was associated with a higher rating of efficacy (p < 0.001).
• Onset of relief was faster with INFS; however, at 60 minutes results tended to converge.
• The majority of adverse events were not considered to be related to the study drugs. Prevalence of adverse events of the nasal cavity was low, with one patient experiencing a nasal ulcer. General adverse events were similar in both groups. The most frequent adverse events were nausea, vomiting, and constipation. These occurred in less than 9% of patients.

More patients experienced faster relief of cancer-related breakthrough pain with INFS than with OTFC.

• Duration of INFS use was two weeks or less; potential adverse events of the nasal cavity, related to long-term use of INFS, are unknown.
• Although INFS was associated with faster onset of pain relief, the difference in the effect of the two drugs became less clear at 60 minutes. The percentage of patients who used rescue medication was higher with INFS than with OTFC. Whether these facts were due to real differences in effect or to the study design, which allowed patients taking INFS to take rescue medication earlier than patients taking OTFC, is unclear.
• Patients used the study drugs to treat up to four episodes daily. Authors provided no information about how many daily episodes total that patients experienced or how either study drug might fit into a comprehensive pain management plan.

Study results show INFS to be an effective treatment for the short-term management of breakthrough cancer-related pain; INFS is associated with rapid relief. Potential adverse events with long-term use and more frequent daily use are unknown. Further study, involving long duration and frequent use, are needed to determine the optimal role of INFS in a comprehensive pain management plan.