Transmucosal Fentanyl

To study the effect of fentanyl in preventing dyspnea before exertion.

Opiate-tolerant patients were given a six-minute walk test for baseline, then later given fentanyl or a placebo, waited 30 minutes, then repeated the six-minute walk test. Study measures were then taken between the two arms.

• N = 20 
• AGE: Average age = 55 years
• MALES: 40%  
• FEMALES: 60%
• CURRENT TREATMENT: Supportive care
• KEY DISEASE CHARACTERISTICS: 90% had metastatic disease. All had some concurrent scheduled medications for SOB besides opiates; 0% were used to taking 66-130 mg of morphine a day. SOB of 3-7 on a scale of 10 at rest.
• OTHER KEY SAMPLE CHARACTERISTICS: Karnofsky level mean was 71. Average fvc = 2.4 L, and fev1 = 1.7 L.

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: Supportive care clinics

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

Double blind randomized placebo controlled trial comparing baseline six-minute walk test and then a second six-minute walk test (6MWT) effects of placebo versus single dose of fentanyl buccal tablet 30 minutes prior to second walk.

Dyspnea was measured using a modified BORG scale from 0-10, with 10 indicating the worst score. Vital signs of BP: O₂ saturation, heart rate, respiratory rate taken before and after the six-minute walk test. Distance walked per minute was recorded. Lung function was only done at baseline. Neurocognitive testing was done before medication and after the second six-minute walk.

No difference with either arm seen for distance walked or fatigue, or vital signs other then respiratory rate between the first and second 6MWTs (mean change = 2.6, 95% CI [0.4, 4.7]) with a trend toward greater level of dyspnea relief compared with placebo (estimate = 0.25, p = 0.068).

Buccal fentanyl had a significant effect in reducing dyspnea then placebo after 30 minutes, when patients exerted themselves.

• Small sample (< 30)

Nurses caring for patients with dyspnea recognize the need to provide interventions that minimize dyspnea during daily activities, particularly when dyspnea interferes with ADLs and impacts patients' quality of life. Interventions such as prophylactic FBT may enable patients to participate in activities, regain independence, and improve their quality of life without experiencing adverse events such as dizziness, drowsiness, and nausea.

To evaluate the efficacy of oral transmucosal fentanyl citrate (OTFC) in the treatment of dyspnea on exertion in patients with advanced cancer

Subjects were chosen over the course of one year. The participants were assigned to one of two treatment groups. The study administered a dosage of 200 µg to patients who were not receiving opioid treatment and 400 µg to those using opioids for other cancer-related symptoms. Prior to testing, the patients remained at rest for five minutes. They were then given OTFC, and the 6-Minute Walk Test (6MWT) was carried out. During visit 2, patients who had been receiving the investigational product were given the placebos and vice versa. At least two days passed between visits 1 and 2 to perform the 6MWT. The follow-up of patients covered a maximum period of seven calendar days.

• N = 13
• MEAN AGE = 65.2 years
• MALES: 84.6% (n = 11), FEMALES: 15.4% (n = 2)
• KEY DISEASE CHARACTERISTICS: Average time after diagnosis was 1.88 years; locations of primary tumors were lung (n = 10; 76.9%), kidney (n = 1; 7.7%), breast (n = 1; 7.7%), and stomach (n = 1; 7.7%)
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria included moderate dyspnea defined as dyspnea caused by basic activities of daily living in the past 24 hours with an intensity of at least 3 on a scale from 0–10; Karnofsky index score > 50; hemoglobin levels within the past month exceeding 10 mg/dl; and SaO2 >90%. Exclusion criteria included patients with advanced chronic obstructive pulmonary disease. 

• SITE: Not stated/unknown  
• LOCATION: Not specified

• APPLICATIONS: Palliative care

Randomized, double-blinded, crossover, placebo-controlled clinical trial

• Edmonton System Assessment System (ESAS), a numeric rating scale to determine changes and severity of breathlessness.
• Dyspnea intensity scale, a numeric scale from 0–10 (0 = no dyspnea and 10 = maximum severity)
• Karnofsky Performance Status (KPS)

Patients were classified into three categories according to the differences observed in dyspnea before and after completion of the 6MWT. 1) Better response to the treatment obtained in the first period, 2) same response to both the periods, and 3) better response to the treatment obtained in the second period. No differences between treatments were demonstrated (P = 1). There were no differences between the change in oxygen saturation level before and after the 6MWT (P = 0.7541). The distance walked in the different sequences did not vary independently (P = 0.6550). There were no differences in the relation to the Edmonton Symptom Assessment System before or after the 6MWT (P = 0.1234). No secondary effects associated with the medication were observed. Type 2 error was ruled out with a confidence level exceeding 5%.

The study concluded that it could not demonstrate that OFTC improved exertion dyspnea in patients with advanced cancer. A placebo effect was observed in all the patients. This study had a small sample size of 13 patients. It was observed that OTFC may reduce dyspnea in the first three minutes of initiating the test, but this lacked statistical significance.

• Small sample (< 30)
• Measurement/methods not well described
• Findings not generalizable
• Other limitations/explanation: Study was costly because of the cost of developing a placebo with the characteristics of OTFC. Only a select number of laboratories agreed to manufacture the placebo, increasing the cost of the clinical trial. The study had a single point in time evaluation.

Dyspnea is one of the most common and distressing symptoms experienced by patients with advanced cancer. This study demonstrated some benefit of transmucosal fentanyl citrate on dyspnea with exertion in the first three minutes, but this result was not statistically significant. Overall, transmucosal fentanyl did not ffect dyspnea with exertion in these patients. This study was small with only 13 participants, and a placebo effect was observed in all patients.

To determine time to onset, efficacy, feasibility, and safety of transmucosal fentanyl (FBT) in comparison to immediate-release morphine (IRM) for the relief of episodic breathlessness.

Fentanyl buccal tablets 100 mcg and 2% immediate release morphine are titrated to 1/6th dosing based on their daily oral morphine equivalent (DOME) to start and increase up to 400 mcg fentanyl or 1/6th + 100% of DOME. Patients were to keep a diary of when dyspnea episode started and when medication taken, with various times to record effectiveness and oxygen saturation over one hour. Patients had twice-a-day safety checks by researchers. Actual doses used were 100-200 mcg of fentanyl and 6-36 mg morphine. Patients crossed over after five days (of a 10-day study).

• N = 6 patients completed the study
• AGE: Mean = 58 years old
• MALES: 60%
• FEMALES: 40%
• CURRENT TREATMENT: Palliative care
• KEY DISEASE CHARACTERISTICS: Patients with incurable cancer who had at least one month to live and SOB scores greater than 3 of 10.
• OTHER KEY SAMPLE CHARACTERISTICS: Older than age 18 years and opiate tolerant.

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Germany

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Elder care, palliative care

This is an open-label, randomized, active-controlled (morphine), crossover, phase II trial with an open label dose titration phase.

Oxygen saturation testing was done, stop watch, and a breathlessness scale of 0-10, with 10 being the worst score. Respiratory rate, Glasgow Coma Scale, and Karnofsky level.

The Breathlessness Index Difference (BID) was calculated.  At 10 minutes, the difference was p = 0.051, with mean time to onset of meaningful breathlessness relief was for FBT 12.7 minutes (plus or minus 10 minutes), and, for IRM, 23.6 minutes (plus or minus 15.1 minutes), with a mean difference of 10.9 minutes (95% CI [-24.5, 2.7], p = 0.094) in favor for FBT (FBT-IRM). Time of onset between morphine and fentanyl was a mean difference of 8.4 (95% CI [-18.8, 2.1], p = 0.085), which was not statistically significant.

Fentanyl was found to work quicker then MS, without any difference in side effects or satisfaction with the medications.

• Small sample (< 30)

For many patients, once SOB has started, time to relief can be an important factor in keeping the anxiety factor down. For some, the price of fentanyl outweighs the benefit against morphine as both have tolerated side effects for opiate-tolerant patients.