Simon, S.T., Koskeroglu, P., & Bausewein, C. (2012). Pharmacological therapy of refractory dyspnoea: A systematic literature review. [Medikamentose therapie der refraktaren atemnot: Eine systematische literaturubersicht] Schmerz, 26, 515–522.

STUDY PURPOSE: Evaluate the four most commonly used pharmacologic therapy options for the management of breathlessness in patients with advanced cancer and non-cancerous diagnosis

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Ovid, PubMed, Medline, Cochrane

YEARS INCLUDED: (Overall for all databases) 1950 to 2012

INCLUSION CRITERIA: Randomized controlled trials, controlled clinical trials, and systematic literature reviews and meta-analyses that were published in German or English of patients who experienced continued breathlessness despite treatment for the underlying disease including cancer, COPD, chronic heart failure, ALS, MS, and HIV/AIDS, and received pharmacologic treatment with opioids, benzodiazepines, corticosteroids, or oxygen which the intensity of breathlessness could be measured. 

EXCLUSION CRITERIA: Studies with the use of nebulized or oral steroids as a basic treatment for COPD and studies including oxygen for patients with hypoxic COPD.

TOTAL REFERENCES RETRIEVED: 2,029

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Database search yielded 2,559 reviews; after review for duplicates, the references were 2,029. Two reviewers independently searched and analyzed the title, abstract, and study for inclusion criteria, which left 65 references. The reviewers then conducted a full-text review, leaving seven references which made up the final inclusion along with eight references from experts. The final number of studies included 5 systematic reviews and 10 randomized controlled trials.

FINAL NUMBER STUDIES INCLUDED: 15

TOTAL PATIENTS INCLUDED IN REVIEW: 2,125

SAMPLE RANGE ACROSS STUDIES: Patients with advanced cancer, cancer, CHF, COPD

KEY SAMPLE CHARACTERISTICS: Included nine studies, one systematic review and eight RCT/CCT, on efficacy of opioids. Two studies, one systematic review, and one RCT/CCT on efficacy of benzodiazepines. Four studies (three systematic reviews and one RCT) on efficacy of oxygen.

PHASE OF CARE: Multiple phases of care     

APPLICATIONS: Elder care, palliative care

Results are categorized in three medication groups and oxygen. No results are available for corticosteroids because there were no studies identified. Two reviews for benzodiazepines were conducted. A systematic review of seven studies, including 200 patients in which 6 of the 7 studies did not show efficacy for the use of benzodiazepines for breathlessness (effect size = -0.32 with 95% CI [-0.89, -0.24]). The second review was a RCT comparing temazepam to placebo with no difference in relief of breathlessness between the two groups. The strongest evidence is from the nine reviews (one systematic literature review and eight RCT) for studies using opioids. Significant efficacy was reported from the systematic literature review of 18 RCT and 293 patients with oral/parenteral morphine (effect size = -0.4 with 95%CI [-0.63, 0.17], p = 0.0006). All eight reviews of RCT were positive, with three showing morphine significantly better than placebo and five showing relief of breathlessness. There were four reviews (three systematic reviews and one RCT) for the efficacy of oxygen identified. The three systematic reviews all compared oxygen to room air. Two did not show significant improvement, however, in one study of 702 non-hypoxemic COPD patients, oxygen showed significant improvement of breathlessness (effect size = -0.37 with 95% CI [-0.5, -0.24]). The RCT compared oxygen to room air in 239 patients. Breathlessness was improved in both the morning and evening by 0.9 and 0.7 points, however, there was no significant difference between the two groups.

The review emphasizes the treatment of breathlessness is still a challenge with evidence varying and partly limited. However, opioids are recommended as a first choice for the treatment of breathlessness for patients with cancerous and non-cancerous advanced diseases. Benzodiazepines are recommended as a second choice for the co-existing management of panic symptoms, anxiety, and breathlessness. Oxygen is not proven to be effective in the non-hypoxic patient with cancer and the use of hand-held fans should be offered.

• Limited search
• Limited number of studies included
• The search strategy was not specific, including only studies written in English or German, excluding studies in other languages. Studies with uncontrolled study designs were also excluded.

Findings show that only opioids offer benefit to patients experiencing breathlessness and should be considered as first-line therapy. However, there are several other nursing implications provided by this review. A smaller dose of opioid is effective in relieving breathlessness and, whenever possible, should be started low and go slow. The fear of respiratory depression with the use of opioids is not warranted based on results of several studies. This finding should be communicated to nurses with education provided to patients and families. Although benzodiazepines are commonly used for breathlessness, efficacy has not been established. However, nurses must recognize the benefit of reducing anxiety and possibly allowing for lower doses of opioids. Lastly, the use of hand-held fans producing an air stream across the patient’s midface and over the nasal mucosa is an intervention nurses may easily use to reduce breathlessness.