Fentanyl Nasal Spray
Fentanyl Nasal Spray
Fentanyl nasal spray is used to treat breakthrough pain in cancer patients 18 years of age or older who are taking regularly scheduled doses of another narcotic pain medication. Fentanyl, an opiate analgesic with a relatively short half-life, can be rapidly absorbed via mucosa. Nasal fentanyl products deliver the drug in solution, in a fine mist. Various nasal-spray formulations may include other substances, such as pectin, as a delivery platform.
Recommended for Practice
Davies, A.N., Dickman, A., Reid, C., Stevens, A.M., Zeppetella, G., & Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. (2009). The management of cancer-related breakthrough pain: Recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. European Journal of Pain, 13(4), 331–338.doi: 10.1016/j.ejpain.2008.06.014
Purpose & Patient Population:
The Science Committee of the Association for Palliative Medicine of Great Britain and Ireland convened a task group to produce up-to-date, evidence-based clinical guidelines regarding the management of cancer-related breakthrough pain in adult patients. Literature review provided limited evidence, only case series and expert opinion, and the task group could make no recommendations about any particular intervention.
Type of Resource/Evidence-Based Process:
Face-to-face group meetings initiated the review process and determined the scope of work. A draft set of recommendations was circulated to group members, and all members were in agreement regarding content. Authors did not describe the process of evidence grading or how the recommendations were drafted. A final meeting was held to finalize results. The MEDLINE keywords searched to retrieve reviews were breakthrough pain, incident pain, and episodic pain. The search was for the years 1950–2007. In addition to the MEDLINE search, investigators manually searched reference lists of retrieved papers and major texts. Authors did not specify inclusion or exclusion criteria. Evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) system.
Results Provided in the Reference:
Authors noted these points regarding breakthrough pain:
- The definition the authors adopted of the term breakthrough pain was “a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.” (p. 332)
- Authors noted that no definition of breakthrough pain is common to much of the work in this area.
- Breakthrough pain was categorized as either idiopathic (unrelated to a precipitant) and unpredictable or incident (related to an identifiable precipitant).
- Authors noted that the guidelines they provided were based on consensus, not levels of evidence.
- Authors provided a simple algorithm of a dose-titration scheme for opioid rescue medications.
Guidelines & Recommendations:
The guidelines make the recommendations that follow.
- Patients with pain should be assessed for the presence of breakthrough pain. Differentiating between uncontrolled background pain and controlled background pain with breakthrough pain is important.
- Patients with breakthrough pain should be assessed specifically for breakthrough pain. Authors note that no assessment tool for breakthrough pain exists, so guidelines recommend assessing breakthrough pain by using standard means of pain assessment.
- Management of breakthrough pain should be individualized—that is, reflect patient-related factors and preferences. In many cases, however, options are limited by availability and affordability of interventions. Guidelines recommend balancing the cost of the intervention with the cost of uncontrolled breakthrough pain.
- Those who determine treatment should consider the underlying cause of pain. Evidence supports the efficacy of cancer treatment in the management of background pain, but no evidence relates to breakthrough pain specifically.
- Caregivers should consider the benefits of avoiding precipitating factors versus treatment of precipitating factors. For example, practical support with activities of daily living and simple adaptation of surroundings could mitigate movement-related pain.
Those who determine treatment should consider modifying the background analgesic regimen. Modification strategies could include
- Titration of opioid analgesics.
- Switching opioid analgesics.
- Addition of adjuvant analgesics (such as antieleptics for neuropathic pain or antispasmodics for visceral pain).
- Addition of other adjuvant drugs for relief from the side effects of pain medication.
- Other strategies (e.g., use of nonanalgesic drugs, anti-inflammatories).
- Opioids are the rescue medication of choice in the management of breakthrough pain. Decisions regarding specific preparations and routes should be based on pain characteristics and the patient’s previous response to opioids. Oral opioids may have a role in breakthrough pain but are not typically the optimal approach.
- Individual titration should determine the dose of opioid rescue medication. Guidelines suggest that the traditional approach—that the dose of opioid rescue medication should be a fixed proportion of the background medication—is not the most effective.
- Nonpharmacologic methods may be useful in the management of breakthrough pain episodes. Guidelines mention rubbing or massage, application of heat or cold, distraction techniques, and relaxation techniques, though authors note that little evidence shows that these methods are effective.
- Nonopioid analgesics may be useful in the management of breakthrough pain episodes. Interventions that have been used include nonsteroidal anti-inflammatory drugs, ketamine, midazolam, and nitrous oxide.
- Intervention techniques may be useful in the management of breakthrough pain. Interventions include neuraxial drug infusion, neural blockade, neuromodulation (e.g., transcutaneous electrical nerve stimulation, or TENS), and interventional radiologic techniques.
- Breakthrough pain, specifically, should be reassessed.
- Patients with pain that is difficult to manage should be referred in a timely manner to a pain specialist or palliative care specialist.
Three members of the task force consult for pharmaceutical companies.
Breakthrough pain is heterogeneous and highly individual; clinicians and caregivers should approach it with these facts in mind. Little evidence guides the management of breakthrough pain. Current teaching is not in concert with recommendations related to the usual practice of prescribing a fixed proportional dose of background opioids as rescue medications. Guidelines point to the need to consider breakthrough pain as an issue separate from background pain. The use of rescue medications is only one aspect of managing breakthrough pain; clinicians should remember other approaches, such as treatment of the underlying causes of the pain. The field of oncology needs research aimed specifically at the management of breakthrough pain.
Research Evidence Summaries
Fallon, M., Reale, C., Davies, A., Lux, A.E., Kumar, K., Stachowiak, A., & Galvez, R. (2011). Efficacy and safety of fentanyl pectin nasal spray compared with immediate-release morphine sulfate tablets in the treatment of breakthrough cancer pain: A multicenter, randomized, controlled, double-blind, double-dummy multiple-crossover study. Journal of Supportive Oncology, 9(6), 224–231.doi: 10.1016/j.suponc.2011.07.004
To compare the efficacy and tolerability of fentanyl-pectin spray (FPNS) with that of immediate-release morphine sulfate (IRMS) in the treatment of breakthrough cancer pain (BTCP)
Intervention Characteristics/Basic Study Process:
Patients in the study were experiencing 1–4 episodes of BTCP per day while taking at least 60 mg/day of oral morphine or equivalent for BTCP. Patients completing the titration phase continued to the double-blind, double-dummy phase: 10 episodes of BTCP were randomly treated with FPNS and oral capsule placebo (5 episodes) or IRMS and nasal spray placebo (5 episodes). The primary end point was pain intensity (PI) difference from baseline at 15 minutes. Secondary end points were onset PI decrease (≥ 1 point) and time to clinically meaningful pain relief. Safety and tolerability were evaluated by means of adverse events (AEs) and nasal assessments. By-patient and by-episode analysis were completed. Duration of follow-up was a maximum of 14 days in the open-label period.
- The sample was composed of 110 patients.
- Mean patient age at baseline was 55.9 years (SD = 12.3 years). Of all patients, 65.1% were 60 years old or younger.
- Of all patients, 53.8% were male and 46.2% were female.
- All patients received fixed-schedule opioid regimens consisting of a total dose equal to or greater than 60 mg/day oral morphine for BTCP. All patients had 1-4 episodes per day of BTCP.
Exclusion criteria barred participation of patients
- With uncontrolled or rapidly escalating background pain.
- Who were medically unstable.
- Who had breakthrough pain unrelated to cancer.
- With a past inability to tolerate fentanyl or other opioids.
- Who anticipated receiving therapy with any pain-affecting treatment (i.e., radiotherapy, chemotherapy) during the study or who had received treatment with another investigational drug within 30 days.
- With any disorder or using any medication likely to adversely affect normal functioning of the nasal mucosa.
- Multicenter (35 oncology centers)
Europe and India
Phase of Care and Clinical Applications:
- Phase of care: active treatment
- Clinical application: palliative care
Randomized, controlled, double-blind, double-dummy, multiple crossover trial
- 11-point numeric scale (0 = no pain, 10 = worst possible pain), to measure pain intensity.
- Nasal assessments performed by the study physician.
Four-point scale (0 = absent, 3 = severe) of subjective nasal assessment by the patient, who completed a 10-item questionnaire before the first use of the study drug, one hour after each dose of the study medication, and at the final study visit. Items rated included stuffy/blocked nose, runny nose, itching/sneezing, crusting/dryness, burning/discomfort, nosebleed, cough, postnasal drip, sore throat, and taste disturbance.
- Analysis of pain intensity difference pre- and post-treatment showed that FPNS provided a greater reduction in pain intensity than did IRMS, with mean ± SE 3.02 ± 0.21 for FPNS doses and 2.69 ± 0.18 for IRMS (p < 0.05). Statistical superiority of FPNS compared with IRMS, on patient-averaged PID scores, continued at each point 15–60 minutes (p < 0.05).
- After treatment, from 10 minutes onward, mean PI scores were lower for FPNS-treated episodes than for IRMS-treated episodes.
More treatment-emergent AEs occurred after FPNS than after IRMS treatment. A higher percentage of treatment-emergent AEs occurred after 400 mcg and 800 mcg doses of FPNS. Treatment-emergent AEs were mainly mild to moderate in severity and included vomiting, somnolence, dehydration, and nausea. Of all patients, 4.7% of patients withdrew from titration due to AEs.
The pain intensity difference associated with FPNS was greater than that associated with IRMS. The difference between the two measures of pain intensity was statistically significant (p < 0.05).
- The study was of short duration, only 14 days. This period is not long enough to evaluate potential long-term effects on the nasal mucosa.
- The study design did not include titration to an effective dose of IRMS.
For patients receiving around-the-clock opioid treatment for chronic cancer-related breakthrough pain, FPNS appears to be effective, safe, and well tolerated. The early reduction of pain that FPNS provided either matched or exceeded that provided by IRMS. Compared to IRMS, FPNS provided more complete pain relief. The effects of long-term use of FPNS have not been evaluated; nurses must be aware that long-term effects of FPNS on the nasal mucosa are unknown.
Kongsgaard, U.E., Eeg, M., & Greisen, H. (2014). The use of Instanyl® in the treatment of breakthrough pain in cancer patients: A 3-month observational, prospective, cohort study. Supportive Care in Cancer, 22, 1655–1662.doi: 10.1007/s00520-014-2128-0
To evaluate Instanyl® for breakthrough pain in patients with cancer in real-life settings
Intervention Characteristics/Basic Study Process:
This study followed adult patients with cancer receiving Instanyl® in seven countries at 61 centers. The Brief Pain Inventory Short Form (BPI) and patient Treatment Satisfaction Scale (TSS) questionnaires were used to assess patient satisfaction with pain management. Descriptive statistics of the patient population were also collected. The Instanyl® doses received by patients were 50, 100, and 200 micrograms, and data were collected at three time points: baseline, week 4, and week 13.
- N = 309 overall analysis (107 completed study)
- AVERAGE AGE = 60 years
- MALES: 56%, FEMALES: 44%
- KEY DISEASE CHARACTERISTICS: Metastases present
- SITE: Multi-site
- SETTING TYPE: Multiple settings
- LOCATION: Multiple study centers in Norway, Denmark, France, Greece, Ireland, Sweden, and the United Kingdom
Phase of Care and Clinical Applications:
- PHASE OF CARE: Mutliple phases of care
- APPLICATIONS: Elder care, adult care, palliative care
Observational prospective cohort study
The primary outcome variables were success of titration, measured by whether maintenance dose level was achieved, and the dose level of Instanyl® (maintenance dose). The secondary outcome variables measured were changes in maintenance dose and the level of background pain medication, severity and impact of pain on daily life (assessed by the BPI), and satisfaction with current pain medicine (assessed by the TSS). The BPI and TSS were only used in the United Kingdom and in France and were assessed at baseline and during week 4. Adverse drug reactions were measured as well as reasons for and time to Instanyl® termination.
The successful titration of Instanyl® to a maintenance dose was achieved in 84.5% of patients. There was a difference noted between different countries with successful titration rates highest in Greece and Norway and lowest in France and the United Kingdom. The majority of the patients who were successfully titrated achieved this with 50 micrograms of fentanyl, which was the lowest dose. Most patients showed no change in the maintenance dose strength throughout the study even though disease progression was expected. 49.8% of patients were successfully titrated at 50 micrograms, the lowest dose. Treatment was followed to the duration of 13 weeks. In 4.5% of patients, termination was due to lack of efficacy; in 2.3% it was due to adverse effects; and in 7.1% it was due to the inability to successfully titrate the medication. Patients' worst-pain scores, pain severity, and pain interference with activities declined significantly within the first four weeks (p < .001).
The rate of successful titration and pain management using Instanyl® was high in this study, and successful titration was often achieved with the lowest possible dose of Instanyl®. Patients were more satisfied with their pain management and had reductions in pain severity, worst-pain score, and pain interference with daily activities.
- Risk of bias (no control group)
- Risk of bias (no blinding)
- Risk of bias (no random assignment)
- Risk of bias (no appropriate attentional control condition)
- Subject withdrawals ≥ 10%
- Other limitations/explanation: Only about 35% of patients completed the study, there was a lack of a comparison arm, and adverse drug reactions were not reported.
This study adds to the body of evidence regarding the efficacy of opioid nasal spray for breakthrough pain. The authors suggest that patients who did not respond were likely those for whom titration to full dosage was not achieved. Nurses need to be aware of full dosage needs for efficacy. There continues to be a lack of evidence regarding the long-term effects and any potential adverse effects on the nasal cavity for this medication type.
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.doi: 10.1016/j.clinthera.2009.05.022
To assess the efficacy and long-term tolerability of infranasal fentanyl spray (INFS)
Intervention Characteristics/Basic Study Process:
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.
- 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.
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.doi: 10.1185/03007990903336135
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
Intervention Characteristics/Basic Study Process:
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.
- Inpatient and outpatient
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.
Portenoy, R.K., Burton, A.W., Gabrail, N., Taylor, D., & Fentanyl Pectin Nasal Spray 043 Study Group. (2010). A multicenter, placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer pain. Pain, 151(3), 617–624.doi: 10.1016/j.pain.2010.07.028
To demonstrate the safety and efficacy of fentanyl-pectin nasal spray (FPNS) in the treatment of breakthrough cancer pain
Intervention Characteristics/Basic Study Process:
Consenting patients entered an open label-titration phase for determination of effective dose of FPNS. Effective dose was defined as a dose that achieved successful treatment of two breakthrough episodes. In the titration phase, if pain relief was unacceptable at 30 minutes, the patient was able to take his or her previous rescue medication. Doses were sequentially increased up to 800 mcg. Individuals who achieved an effective dose were eligible to continue in the double-blind stage. Patients received randomly assigned separate bottles, identified by number. Patients were instructed to use the bottles in the order designated. Each breakthrough episode was treated with a single dose. Pain that continued to require treatment after 30 minutes was treated with the patient’s usual rescue medication. Electronic diaries were used for data collection. Patients recorded pain intensity and pain relief at 5, 10, 15, 30, 45, and 60 minutes. Adverse events were recorded throughout the study, and visual nasal assessments were performed by the study physician at baseline and at the end of treatment. Maximum study duration was eight weeks.
- Seventy-three patients were in the intent-to-treat analysis.
- Mean patient age was 53.8 years (SD = 1 year).
- Of all patients, 46.9% were female and 53.1% were male.
- The study included multiple tumor types. The most common were lung, breast, reticuloendothelial, and bowel.
- All patients were receiving, on a regular basis, opioids for the treatment of pain. The most common opioids for the treatment of background pain were morphine, fentanyl, oxycodone, and methadone. Of all patients, 26% were taking multiple opioids.
Multisite (26 in the United States and 2 in other countries)
Randomized double-blind placebo-controlled crossover study
- 11-point scale, to measure pain intensity
- Five-point scale, to measure overall satisfaction
- Five-point scale, to measure ease of use
- Five-point scale, to rate nasal symptoms
- Thirteen patients (15.7% of those randomized) withdrew from the study because of lack of efficacy or adverse effects.
- At 5 minutes and sustained over all other time points, the mean pain-intensity score for FPNS-treated episodes was significantly lower (p = 0.03) than that for placebo-treated episodes. At 5 minutes, 33% of patients reporting on FPNS-treated episodes noted a drop of one point or more. At 10 minutes, 61% of patients reporting on FPNS-treated episodes noted a drop of one point or more; at 30 minutes, 73% noted a drop of one point or more.
- Of all FPNS-treated episodes, 90.6% did not require additional rescue medication. Of all placebo-treated episodes, 80% did not require additional rescue medication.
- Authors noted significantly lower pain intensity (p < 0.0001) with FPNS at 60 minutes.
- Clinical assessment of each patient's nose revealed no changes.
- In regard to adverse events, authors noted no significant differences between treatments.
- In an open label extension after study conclusion, 87% of patients chose to continue use of FPNS.
FPNC is effective and well tolerated for treatment of breakthrough cancer pain.
- The study had a small sample size, with fewer than 100 patients.
- Authors noted a high response to placebo.
- The study period was relatively short. Whether nasal complications might occur with long-term treatment with FPNS is unclear.
FPNS is an effective approach to the management of the breakthrough pain of patients with cancer who are taking opiods for relief of background pain. FPNS can be a useful alternative in situations where clinicians want to reduce the number of oral medications. Studies of the use of nasal sprays have been relatively brief, so nurses must remain aware of the need to assess the patient’s nares and related symptoms.
Portenoy, R.K., Raffaeli, W., Torres, L.M., Sitte, T., Deka, A.C., Herrera, I.G., . . . Fentanyl Nasal Spray Study 045 Investigators Group. (2010). Long-term safety, tolerability, and consistency of effect of fentanyl pectin nasal spray for breakthrough cancer pain in opioid-tolerant patients. Journal of Opioid Management, 6(5), 319–328.doi: 10.5055/jom.2010.0029
To evaluate the safety and tolerance of fentanyl-pectin nasal spray for cancer-related breakthrough pain
Intervention Characteristics/Basic Study Process:
Patients completed an open dose-titration phase for dose determination and then entered a 16-week open label treatment phase. Patients were instructed to administer the effective dose from titration for a maximum of four episodes of breakthrough pain per day. If pain relief was inadequate after 30 minutes, patients could take the prestudy rescue medication. Investigators contacted patients at least weekly to review appropriate use of study medication, to discuss the need for dose adjustment and nasal symptoms, and to review use of rescue medication. Patients also rated nasal symptoms by using a 10-point questionnaire. A physician performed graded nasal assessments at baseline, week 8, and week 16.
- Authors reported that 110 patients completed the entire 16 weeks of the study.
- Authors reported 42,227 breakthrough pain episodes in 403 patients included in the analysis.
- Mean patient age was 53.8 years. The age range was 21–84 years.
- Of all patients, the percentage of females was 46.9% and the percentage of males was 53.1%.
- Authors did not report diagnosis information.
- Of all patients, 59.8 % were on morphine; 31.5%, on fentanyl; and 14.4%, on oxycodone. These drugs were used for the treatment of background pain.
- Multiple countries
Open label trial
- Nasal-symptom questionnaire, offering a four-point assesment scale for each of the following: stuffy/blocked nose, runny nose, itching/sneezing, crusting/dryness, burning/discomfort, nose bleeding, cough, postnasal drip, sore throat, and taste disturbance
- Measures of the neeed for rescue medication other than the study drug
- Authors reported that 110 patients completed the full 16-week extension trial.
- Of all patients, 24.6% had treatment-related adverse events. The most common adverse events were dizziness, vomiting, constipation, and somnolence, which occurred in 3.5%–5.2% of patients.
- Doses of fentanyl spray were 100–800 micrograms. Authors did not relate overall dose to adverse events.
- For most patients, the results of nasal examination at the end of the study were normal. Authors observed no consistent pattern in patient-reported nasal symptoms.
- Of the 42,227 breakthrough episodes, 94% did not require additional rescue medication to be resolved.
Fentanyl-pectin nasal spray for cancer-related breakthrough pain appears to be well tolerated over a use period of four months.
The study has a risk of bias due to no appropriate control group.
This study showed that, over a four-month period, patients tolerated the fentanyl-pectin nasal spray well. This study suggests that long-term use is not associated with significant adverse nasal events. Fentanyl-pectin nasal spray used as specified, for the treatment of breakthrough cancer-related pain, was effective for the majority of patients. Fentanyl-pectin nasal spray is a rapidly acting treatment for breakthrough pain that can be particularly helpful to patients who have difficulty with oral intake.
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.doi: 10.1007/s00520-011-1124-x
To assess the long-term tolerability, acceptability, and consistency of fentanyl-pectin nasal spray (FPNS) in patients with breakthrough cancer pain
Intervention Characteristics/Basic Study Process:
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
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
Phase of Care and Clinical Applications:
- 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.
Taylor, D., Galan, V., Weinstein, S.M., Reyes, E., Pupo-Araya, A.R., Rauck, R., & Fentanyl Pectin Nasal Spray 043 Study Group. (2010). Fentanyl pectin nasal spray in breakthrough cancer pain. The Journal of Supportive Oncology, 8(4), 184–190. Retrieved from http://jso.imng.com/jso/journal/articles/0804184.pdf
To determine the efficacy and tolerability of intranasal fentanyl spray (INFS) in the treatment of cancer-related breakthrough pain
Intervention Characteristics/Basic Study Process:
Eligible patients went through an open dose-titration phase to determine an effective individual dose of the study drug. In the double-blind phase, patients were given 10 “blinded” bottles containing either the determined dose of INFS or placebo. The bottles were in a randomly assigned sequence. Each patient self-administered a maximum of four doses per day. If relief was inadequate at 30 minutes or if a separate episode of breakthrough pain occurred within a four-hour period, patients could take their usual rescue medication for analgesia. After each treatment episode, subjects recorded relief scores at timed intervals and rated overall satisfaction by means of an electronic diary. Self-reported adverse events were recorded throughout the study, and the study clinician directly assessed nasal condition at the beginning and end of the study.
- Seventy-six patients completed the study.
- Mean patient age was 53.8 years (SD = 11.6 years).
- Authors did not report information about the gender of participants.
- Patients were not receiving active chemotherapy or radiation therapy and did not have unstable clinical conditions or rapidly escalating or uncontrolled pain.
- The mean baseline pain-intensity score was 6.89 (SD = 1.7) across INFS-treated episodes and 6.96 (SD = 1.83) for placebo-treated episodes.
- The state of Georgia, United States
Randomized double-blind, placebo-controlled multiple-crossover study
- Numeric pain-intensity scale (0 = no pain, 10 = worst possible pain)
- Five-point pain-relief scale
- Nasal assessment questionnaire, to identify of nasal symptoms
- Of patients in the open label-titration phase, 72.8% found an effective and tolerable dose of IFNS. Of patients who withdrew from the titration phase, 11.4% withdrew because of adverse events or lack of efficacy.
- The analgesic effect of INFS was consistently better than that of placebo at all time points measured. At 15 minutes from the beginning of the pain episode, 73% had an observed pain-reduction effect (P < 0.0001 compared to placebo). Reduction of pain in INFS episodes was clinically meaningful (pain-reduction score ≥ 2-point reduction) at all time points (p < 0.0001 versus placebo)
- Of all episodes of breakthrough pain treated with INFS, 90% did not require additional rescue medication. Of all episodes of breakthrough pain treated with placebo, 80% required rescue medication (p < 0.001).
- Speed of relief was better with INFS than with placebo (p < 0.0001).
- The most common side effects of INFS were vomiting, nausea, dizziness, epistaxis, nasopharyngitis, somnolence, and headache. Most nasal events were mild.
INFS is effective for the relief of breakthrough cancer pain for some patients and, as administered in this study, is not associated with severe and prevalent adverse effects.
- The study has a small sample size, with fewer than 100 patients.
- The duration of the study was short, so efficacy and tolerability over a long term are unknown.
- The study comprised a relatively healthy population, and patients were not under treatement. As a result, the results of this study may not be applicable to other patients and other situations.
- The length of time a patient had chronic pain prior to study participation is not provided, and the range of regular opioid doses is not provided. These factors may have effects.
- The fact that the fentanyl was associated with more taste disturbance than was placebo suggests that patients may not have been unaware of the drug they were using.
For the short term, INFS is effective for the management of breakthrough pain episodes for some patients with cancer. Nurses should be aware of the need for assessment of nasal symptoms with INFS use. The fact that slightly more than 20% of patients did not find an effective and tolerable dose of INFS is a reminder that effective pain management, which includes management of breakthrough episodes, needs to be highly individualized to be effective. INFS appears to be a useful part of the set of strategies to manage cancer-related pain. Despite strong evidence from this study, in regard to the immediate effect of INFS, research has not ascertained the effects of long-term INFS use.
Vissers, D., Stam, W., Nolte, T., Lenre, M., & Jansen, J. (2010). Efficacy of intranasal fentanyl spray versus other opioids for breakthrough pain in cancer. Current Medical Research and Opinion, 26(5), 1037–1045.doi: 10.1185/03007991003694340
To compare the effectiveness of oral morphine to that of rapid-onset opioids, intranasal fentanyl spray (INFS), oral transmusocal fentanyl citrate, and fentanyl buccal tablets in the management of breakthrough cancer pain (BTCP)
Databases searched were MEDLINE, EMBASE, and BIOSIS Citation Index. The search was for the period 1996–October 2007. In addition, investigators searched conference proceedings. Pre-published data regarding INFS were included.
Search keywords included the generic and brand names of opioids and combinations of generic and brand names and pain and episodic, breakthrough, transient, flare, incident, exacerbation and transitory, cancer, malignant, tumor, and neoplasia.
Studies were included if they were
- Randomized controlled trials (RCTs)
- Involved the management of BTCP
- Studies involving adult patients with cancer, with breakthrough pain, who were being treated with opioids for the management of background pain
- Studies that measured pain intensity difference (PID) at specified time points at the start and after the start of the pain episode
The initial review was of 128 abstracts. Assessment of abstracts and full articles, according to inclusion criteria, identified six RCTs for analysis.
- The sample across all studies was composed of 594 patients.
- The range of sample sizes was 77–139 patients.
- Samples included both males and females.
- The range of mean patient age, across all studies, was 53.9 years (SD = 11.3 years) through 62 years (SD = 11.6 years).
- The range of pain intensity at baseline across studies was 5.9–6.9 (SD = 0.2) on a 10-point scale.
PID was measured at various time points across studies. Meta-analysis demonstrated that INFS provided the greatest reduction in pain within 15 minutes, with a 99% probability in all comparisons. Oral morphine was no better than placebo within the first 45 minutes of a breakthrough episode. Oral morphine was only better than placebo after 45 minutes. INFS provided better relief than did buccal fentanyl before 45 minutes and better relief than did oral transmucosal fentanyl citrate for the first 60 minutes.
Findings show that INFS provides better rapid-onset pain relief for BTCP than does oral morphine, transmucosal oral fentanyl, and buccal fentanyl tablets. Oral morphine showed the same level of pain relief as placebo for the first 30 minutes, showing that oral morphine is an inappropriate treatment for BTCP.
All studies involved an initial period in which appropriate dosing of INFS was established for each patient. Effective use of INFS necessitates determination of individualized dose.