Effectiveness Not Established

Fentanyl (Subcutaneous)

for Dyspnea

Fentanyl is an opioid analgesic drug. Subcutaneous fentanyl can be considered for patients in whom subcutaneous morphine is contraindicated. It has been investigated as an intervention to relieve breakthrough dyspnea in patients who have cancer. Healthcare professionals should be aware of the different formulations for these medications, the length of their half-life, and the onset of action.

Systematic Review/Meta-Analysis

Simon, S.T., Koskeroglu, P., Gaertner, J., & Voltz, R. (2013). Fentanyl for the relief of refractory breathlessness: A systematic review. Journal of Pain and Symptom Management, 46, 874–886.

Purpose

PURPOSE: To evaluate current evidence for the use of fentanyl for the relief of breathlessness
 
TYPE OF STUDY: Systematic review

Search Strategy

DATABASES USED: MEDLINE, EMBASE, Cochrane Library, and International Pharmaceutical Abstracts
 
KEYWORDS: Fentanyl and dyspnea (and dyspnea synonyms) 
 
INCLUSION CRITERIA: All types of studies containing original information about fentanyl (including drugs belonging to the pharmacologic group of fentanyl) and breathlessness; studies including healthy volunteers as well as patients (irrespective of disease); studies including breathlessness as a secondary as well as a primary outcome  
EXCLUSION CRITERIA: Literature reviews 

Literature Evaluated

TOTAL REFERENCES RETRIEVED: 622
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: The evaluation was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendation for systematic reviews. The search and study evaluation methods were transparent and valid.  

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 13 
  • TOTAL PATIENTS INCLUDED IN REVIEW = 88
  • SAMPLE RANGE ACROSS STUDIES: 1–35 patients
  • KEY SAMPLE CHARACTERISTICS: Two randomized, controlled trials ([RCTs] one RCT only had a sample size of two patients), two nonrandomized before–after studies, and nine case studies; majority of patients were inpatients with lung cancer or chronic obstructive pulmonary disease and constant or episodic (four studies) breathlessness receiving fentanyl (oral, IV, or transdermal) 

Phase of Care and Clinical Applications

PHASE OF CARE: Multiple phases of care 

APPLICATIONS: Elder care, palliative care

Results

All studies reported the successful relief of breathlessness after fentanyl application, but the only RCT (N = 12) failed to demonstrate a statistically significant difference when fentanyl was compared to a placebo. The nature and incidence of fentanyl-related adverse events such as somnolence and dizziness were comparable to other opioids, and no respiratory depression was observed.

Conclusions

There is no conclusive evidence about use of fentanyl to relieve breathlessness because of the lack of sufficiently powered, controlled studies. The descriptive and quasi-experimental studies included in this review show promising results for the use of fentanyl for breathlessness. All studies reported an improvement in breathlessness, but a fully powered RCT to conclusively determine the effect of fentanyl on breathlessness is warranted.

Limitations

The descriptive and quasi-experimental studies included were at-risk for bias because of the lack of a control. The doses of fentanyl varied considerably, which limits conclusions about the appropriate dose. Missing data included the time of response after the administration of fentanyl, which is important when comparing fentanyl to other opioids.

Nursing Implications

The clinical experience of fentanyl for breathlessness is promising. Considering emerging data, which suggests that breathless episodes often last less than 10 minutes, the current standard (immediate-release morphine) has a longer onset of action than the symptom episode duration. Fentanyl's time of onset still is unknown, but it may better match the characteristics of breathlessness episodes, which is clinically important.

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Research Evidence Summaries

Benitez-Rosario, M.A., Rosa-Gonzalez, I., Gonzalez-Davila, E., & Sanz, E. (2018). Fentanyl treatment for end-of-life dyspnoea relief in advanced cancer patients. Supportive Care in Cancer, 27, 157–164.

Study Purpose

The purpose of the study was to assess the effects of subcutaneous or IV fentanyl on dyspnea in patients with advanced cancer.

Intervention Characteristics/Basic Study Process

Subcutaneous or IV fentanyl for breathlessness at rest or with minimal exertion for patients with (a) decline in renal function and escalating doses transdermal fenatanyl/ or other opioid, and (b) alternative to transdermal fentanyl at discharge

Sample Characteristics

  • N = 72    
  • AGE: 50% younger than 75 years old, 21% = 75-80 years old, 29% = 81 or older 
  • MALES: 65%   
  • FEMALES: 35% 
  • CURRENT TREATMENT: Other
  • KEY DISEASE CHARACTERISTICS: Mixed diagnoses 
  • OTHER KEY SAMPLE CHARACTERISTICS: All patients with advanced cancer

Setting

  • SITE: Single site   
  • SETTING TYPE: Inpatient    
  • LOCATION: Spain

Phase of Care and Clinical Applications

PHASE OF CARE: End-of-life care
APPLICATIONS:  Pediatrics, elder care, palliative care

Study Design

Retrospective cohort study

Measurement Instruments/Methods

Breathlessness was measured on a 0-4 scale, other symptoms were measured with ESAS, MMSE/Pfeiffer, and Likert scales

Results

Total percent of responders to fentanyl was 76%. Fentanyl efficacy was not statistically related to age, gender, cancer type, previous opioid treatment, steroid and midazolam doses, and PPS. The median fentanyl dose in responders was 25 mcg/h (interquartile range = 12–70). It was significantly related to age (37 versus 12 mcg/h, for ≤ 75 versus > 75 years, respectively; p = 0.02). There was not a significant difference between fentanyl doses of responders and non-responders. 36, 23, and 15 patients had sustained improvements in dyspnea over 48, 72, and 96 hours. Fentanyl had no significant toxicity.

Conclusions

Subcutaneous and IV fentanyl may be associated with dyspnea relief in patients with advanced cancer. No severe adverse effects were noted.

Limitations

  • Small sample (< 100)
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Subject withdrawals ≥ 10%
  • Other limitations/explanation: Single center experience

Nursing Implications

Subcutaneous and IV fentanyl may be related to dyspnea at rest relief in patients with advanced cancer. Additional research is need to confirm these results.

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Hui, D., Xu, A., Frisbee-Hume, S., Chisholm, G., Morgado, M., Reddy, S., & Bruera, E. (2013). Effects of prophylactic subcutaneous fentanyl on exercise-induced breakthrough dyspnea in cancer patients: A preliminary double-blind, randomized, controlled trial. Journal of Pain and Symptom Management, 47, 209–217. 

Study Purpose

To study the feasibility of a randomized, controlled trial exploring the effects of fentanyl on breakthrough dyspnea, walking distance, vital signs, and adverse events in patients with cancer

Intervention Characteristics/Basic Study Process

Participants performed a baseline 6-Minute Walk Test (6MWT) without any medications followed by a rest period during which their levels of dyspnea were assessed every five minutes for one hour. When dyspnea levels were less than or equal to baseline dyspnea of +1, patients were given either a single dose of subcutaneous fentanyl or a placebo containing 0.9% preservative-free normal saline. Another 6MWT was performed 15 minutes later when the fentanyl was expected to reach its median peak concentration. 
 
Patients and research clinicians were blinded to the study intervention and randomization sequence. A study pharmacist randomly assigned patients to either intervention in a 1:1 ratio using a computer-generated randomization scheme. Participants enrolled in the fentanyl arm received a parenteral fentanyl dose based on a sliding scale intended to achieve 15%–25% of the morphine equivalent daily dose (MEDD) based on the rescue opioids for breakthrough dyspnea. 

Sample Characteristics

  • N = 20  
  • MEDIAN AGE = 55 years (range = 27–75 years) (mean age was 55 years in the fentanyl group 54 years in the placebo group)
  • MALES: 45% (n = 9), FEMALES: 55% (n = 11)
  • KEY DISEASE CHARACTERISTICS: Breast (5), gastrointestinal (1), genitourinary (3), gynecologic (2), lung (4), and sarcoma (5); other diseases were chronic obstructive pulmonary disease, heart failure, asthma, and bronchiectasis
  • OTHER KEY SAMPLE CHARACTERISTICS: Patients were included if they had a cancer diagnosis, were aged 18 years or older, had average intensity breakthrough dyspnea of three or more on a 10-point Numeric Rating Scale, spoke English or Spanish, were ambulatory with or without an assistive device, had a Karnofsky Performance Status of 50% or more, and were on a stable dose of strong opioids with a MEDD of 30–580 mg. Patients were excluded if their dyspnea scores at rest were seven or more out of 10, they used more than 6 L per minute of supplemental oxygen, they experienced delirium (Memorial Delirium Assessment Scale > 13 out of 30), they were allergic to fentanyl, they had history of substance abuse, they had a recent history of coronary artery disease, and if they had uncontrolled tachycardia or hypertension at the time of assessment.

Setting

  • SITE: Single site  
  • SETTING TYPE: Outpatient  
  • LOCATION: Supportive Care Center at the MD Anderson Cancer Center

Phase of Care and Clinical Applications

  • PHASE OF CARE: Multiple phases of care
  • APPLICATIONS: Palliative care

Study Design

Double-blinded, placebo-controlled, randomized trial

Measurement Instruments/Methods

  • Numeric Rating Scale (NRS) to measure dyspnea from 0–10 (0 = no shortness of breath and 10 = worst possible shortness of breath)
  • Borg scale to assess fatigue level
  • Global Symptom Evaluation (GSE) to evaluate change in dyspnea following interventions
  • Edmonton Symptom Assessment Scale (ESAS) and Cancer Dyspnea Scale (CDS) at baseline to assess the quality of dyspnea over the previous few days

Results

This study achieved its primary outcome of a 100% participant retention rate. Baseline levels of dyspnea were higher in the placebo group compared to the fentanyl group. All patients were able to walk the full 6MWT during each walk test. Twelve patients returned to their baseline levels of dyspnea within five minutes of rest, five returned within 10 minutes, and three returned within 15 minutes.
 
Significant improvements in dyspnea scores were observed among participants who received subcutaneous fentanyl (mean was -1.8 at end of test compared to -0.9 at rest before test) as well as Borg scale fatigue scores at the end of the 6MWT (mean was -1.3), 6MWT distance (mean distance 37.2 m, 95% CI = 5.8), and respiratory rate (mean was -2.4; 95% CI = -4.5, -0.3).
 
According to the authors, a statistically insignificant improvement also was observed among patients in the placebo arm in regard to dyspnea scores at the end of the 6MWT, dyspnea scores at rest before the 6MWT, Borg scale fatigue scores at the end of the 6MWT, 6MWT distance, and respiratory rate. There were no significant differences in physiologic measures between baseline and the second 6MWT in either study group. No statistically significant differences in any outcome measures were observed when fentanyl and the placebo were compared. Both were tolerated well. 
 
Six of the 10 patients receiving fentanyl reported improved dyspnea during the second walk test compared to the first walk test while three found no change and one felt worse. Similarly, in the placebo group, eight, one, and one patients (respectively) reported that their dyspnea was improved, was the same, or was worse, respectively. No statistically significant differences were observed between the study interventions (P = 0.78).

Conclusions

The prophylactic administration of subcutaneous fentanyl appears to be a safe and well-tolerated method for reducing dyspnea, fatigue, and respiratory rate while also enhancing physiologic function and activity levels among patients with cancer. However, the generalizability of these findings are limited because of the small sample size.

Limitations

  • Small sample (< 30)
  • Findings not generalizable
  • Intervention expensive, impractical, or training needs
  • Other limitations/explanation: The statistically insignificant improvement of dyspnea and fatigue among patients in the placebo arm was attributable to a placebo effect. According to the authors, a placebo effect within the context of this study may have been caused by a reporting bias, interviewer bias, or period/training effects. This suggests a need for the standardization of patient encounter experience and the stratification of baseline dyspnea levels. Also, routine subcutaneous administration may not be practical, and it requires some degree of training. The authors suggested rapid-onset fentanyl via transmucosal or intranasal routes as more practical alternatives.

Nursing Implications

Given the high, relatively fast enrollment and high completion rates of this study, the authors cite the feasibility of performing a more adequately powered, placebo-controlled, double-blinded, randomized, controlled trial with higher fentanyl doses to establish the prophylactic management of dyspnea with opioids. In addition, it would be beneficial to assess how long opioid effects last, what kinds of patients and cancer types would benefit more, and the most practical and cost-effective route of opioid administration (e.g., subcutaneous, oral).
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