Radbruch, L., Torres, L.M., Ellershaw, J.E., Gatti, A., Luis Lerzo, G., Revnic, J., & Taylor, D. (2012). Long-term tolerability, efficacy and acceptability of fentanyl pectin nasal spray for breakthrough cancer pain. Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer, 20(3), 565–573.

To assess the long-term tolerability, acceptability, and consistency of fentanyl-pectin nasal spray (FPNS) in patients with breakthrough cancer pain

Newly enrolled patients participated in four study phases. Phase 1 was screening. Phase 2 consisted of dose titration based on the approach used in controlled trials: The lowest FPNS dose was uptitrated, one dose per episode of pain, to a maximum of 800 mcg per dose until two consecutive episodes of breakthrough cancer pain were successfully treated without causing adverse events. Phase 3 consisted of 16 weeks of open-label treatment: Patients were provided with a four-week supply of FPNS, either 100 mcg/spray or 400 mcg/spray, based on the findings in the titration phase. Patients self-administered FPNS. If FPNS was ineffective, patients could take their usual analgesia. Investigators initiated weekly calls to patients during the first four weeks. In these calls patients and investigators discussed progress, dose adjustments, and side effects. An investigator considered dose adjustment during the participant’s monthly visit. Consideration was based on information in an e-diary, which each patient submitted, and drug-related adverse events. Phase 4 was the end-of-treatment phase. Those previously enrolled in phase III CP043 (FPNS compared to placebo in the United States, Argentina, and Costa Rica) or CP044 (FPNS compared to immediate-release morphine sulphate in the European Union and India) went through phase 3 and phase 4.

• The sample was composed of 403 patients.
• Mean patient age was 53.8 years.
• Of all patients, 53.1% were male and 46.9% were female.
• Patients had to have a histologically confirmed diagnosis of cancer.  
• To be eligible, participants could have more than one type of breakthrough cancer pain or pain in multiple areas; however, only one location and cancer type were considered the target of the medication.
• Participants could not participate if they had
  • Uncontrolled or rapidly escalating background pain or were medically unstable
  • Breakthrough pain not primarily related to cancer
  • Inability to tolerate fentanyl or other opioids
  • History of alcohol or substance abuse
  • Been treated with monoamine oxidase inhibitors or with investigational drugs within the previous 30 days
  • Any disorder or medication use that would adversely affect the normal function of the nasal mucosa

• Multisite
• Outpatient
• A total of 91 centers in Argentina, Costa Rica, the Czech Republic, France, Germany, the United Kingdom, India, Italy, the Netherlands, Poland, Spain, and the United States
   

• Phases of care: multiple
• Clinical applications: late effects and survivorship, end of life, palliative care
   

Multicenter open-label study

• Episode acceptability assessment    
• Breakthrough pain questionnaire
• Electronic diary that recorded patient's overall satisfaction by means of satisfaction scales
• Survey of adverse events recorded in categories (mild, moderate, and severe)
• Objective nasal assessments
• Subjective nasal assessment
   

• Analysis for intent to treat and safety included 403 patients; 356 entered the treatment phase, and 110 completed the full 16 weeks.
• Approximately 25% of the 403 patients experienced treatment-related, treatment-emergent adverse events that were mild to moderate and typical of opioids. Twenty patients stopped treatment because of an adverse event, and nine stopped as a result of an adverse drug reaction.
• Nasal assessments revealed no significant effects.
• Of all treated episodes, 94% required no additional rescue medication. During the study, more than 90% of patients did not have to have their dose increased. Patients were satisfied with overall outcome for 90% of episodes. At 12 weeks, 97% were satisfied with the ease and convenience of FPNS.

Per patient reports, FPNS is generally easy to use and well tolerated for the treatment of breakthrough cancer pain. FPNS doses were relatively stable during this four-month study; typically, multiple dose changes were not required. Spray, as a means of delivery, is a benefit, especially to those who have difficulty taking pills. The FPNS had little effect on the nasal passages. The results of this study appear generalizable, and administration of fentanyl by means of a nasal spray appears to be acceptable in many institutions across the world. All these outcomes indicate that FPNS may be a helpful intervention for the treatment of breakthrough cancer pain.

• The study had a risk of bias due to no appropriate control group.
• Inclusion of individuals with multiple sites and multiple locations of pain and presentation of pain could have affected  outcomes: Focusing on a primary site of pain, for the purpose of a study, is difficult.
• The study was observational and did not include active comparators.
• Selection bias presents a concern, especially considering the acceptability analysis.
   

Education regarding nasal spray administration seems to play a large role in the effectiveness of a spray-delivered intervention. Further research should investigate adverse events, to ensure the well-being of patients.