Ben-Aharon, I., Gafter-Gvili, A., Paul, M., Leibovici, L., & Stemmer, S.M. (2008). Interventions for alleviating cancer-related dyspnea: A systematic review. Journal of Clinical Oncology, 26(14), 2396-2404.

The objective of this study was to systematically review the evidence for the efficacy of pharmacologic and nonpharmacologic treatments in alleviating dyspnea in patients with terminal cancer.

Databases searched were Cochrane Library up to 2007, MEDLINE (PubMed) (1966–2007), American Society of Clinical Oncology conference proceedings, and references of all included documents. In addition to databases, the search included the reference lists of key studies, the reference lists of 16 review articles on the topic, reference lists from 16 textbooks, and seven websites. Authors (15) of main investigations were contacted, and all members of the Association of Palliative Care and users of the www.palliativedrugs.com bulletin board were contacted for additional information and unpublished data.

Search keywords were opiate, opioid, morphine, benzodiazepine, furosemide, steroids, corticosteroids, oxygen, nonpharmacological, acupuncture, nursing, cancer, carcinoma, malignancy, dyspnea and breathlessness. 

Studies were included in the review if they were a randomized controlled trial assessing dyspnea in patients with terminal cancer in which any intervention for dyspnea relief was compared with no intervention, placebo, or another intervention.

Studies were excluded if they were nonrandomized studies or trials in which only a minority of the patients had a cancer diagnosis.

Literature evaluated included 37 studies, plus one abstract initially reviewed. A final set of 18 studies was included; 7 assessed opioids, 6 assessed oxygen- or helium-enriched air, 1 assessed furosemide, and 4 assessed nonpharmacologic interventions. Meta-analysis was not completed due to the paucity of studies and heterogeneous outcome measures.

Sample Size Across Studies:

• Opioid intervention = 256 patients
• Oxygen or helium = 148 patients
• Furosemide intervention = 7 patients
• Nonpharmacologic intervention = 403 patients

Sample Range Across Studies:

• Opioids = 9–101 patients
• Oxygen or helium = 12–51 patients
• Nonpharmacologic = 34–203 patients

With respect to gender, age, and diagnosis within the sample, the opioids subgroup included both genders. The median age range was 56–73 years. The majority had primary lung cancer, and both opioid-tolerant and opioid-naïve participants were included.

The oxygen or helium subgroup included both genders. The median age range was 64–72 years. The majority had primary lung cancer.

No comment was available on gender or age for the nonpharmacologic subgroup, but the primary diagnosis was lung cancer.

The primary outcome was subjective dyspnea relief according to the visual analog scale (VAS) or dyspnea intensity according to the modified Borg scale. The secondary outcome was oxygen saturation and adverse effects.

Opioid Intervention:

• The administration of subcutaneous morphine resulted in significant reduction in dyspnea according to the VAS compared with placebo.
• Nebulized morphine versus placebo failed to demonstrate a significant effect of nebulized morphine. No difference in dyspnea VAS score was observed in one trial when nebulized morphine was compared with subcutaneous morphine, although patients preferred the nebulized route.
• In one trial, the addition of benzodiazepines (midazolam) to morphine was significantly more effective than morphine alone, without additional adverse effects.

Oxygen Intervention:

• Oxygen was not superior to medical air for alleviating dyspnea, except for patients with hypoxemia.

Furosemide Intervention:

• One small trial assessed the use of nebulized furosemide with a trend toward worsening dyspnea.

Nonpharmacologic Interventions:

• Nurse-led interventions improved breathlessness.
• Acupuncture was not beneficial.
• Nurse-led interventions encompassed routine follow-up by nurses performing methods of counseling and relaxation and teaching coping strategies.
• The nurse-led breathlessness rehabilitation techniques and education and advice regarding coping with the psychological aspects of the symptoms assessed the primary outcome of dyspnea relief after weeks.
• All nurse-led interventions proved to be beneficial, improving breathlessness and quality of life in terms of physical, psychological, and emotional aspects.

• No evidence supports subcutaneous morphine as effective in treating dyspnea in patients with advanced cancer.
• Use of oxygen to alleviate dyspnea in nonhypoxic patients with cancer cannot be recommended. Supplemental oxygen is expensive and can restrict mobility with possible decrease in quality of life. Use of medical air (78.9% nitrogen, 21.1% oxygen) was shown to be effective in reducing the sensation of dyspnea. However, this intervention is not used routinely in care settings.
• This review recommended integration of pharmacologic and nonpharmacologic interventions, such as those used in nurse-led programs to relieve dyspnea.

Acknowledging the paucity of evidence from randomized controlled trials to support the interventions is important.

Limitations of this review were

• Few randomized controlled trials
• Small studies
• Short follow-up in opioid studies
• Lack of consistency regarding opioid doses.

A major research opportunity exists to further document outcomes from nurse-led dyspnea interventions.