Charles, M. A., Reymond, L., & Israel, F. (2008). Relief of incident dyspnea in palliative cancer patients: a pilot, randomized, controlled trial comparing nebulized hydromorphone, systemic hydromorphone, and nebulized saline. Journal of Pain and Symptom Management, 36, 29–38.

To compare the efficacy of nebulized hydromorphone, systemic hydromorphone, and nebulized saline for incident dyspnea in patients with advanced cancer.

On three occasions when patients requested treatment for incident breathlessness, they randomly received one of the following:

• 5 mg of nebulized hydromorphone
• A systemic breakthrough dose of hydromorphone
• 3 mL of nebulized saline and an agent to maintain double blinding.

If patients felt the intervention was not effective, they could ask for additional pharmaceutical interventions. Patients scored breathlessness at 10, 20, 30, and 60 minutes from completion of treatment. Treatment order was randomized.

• The sample was comprised of 20 patients (11 men, 9 women) receiving palliative care.
• Mean age was 69 years (range 48–83). 
• Diagnoses included primary lung cancer or secondary lung pathology, including lung metastases, pleural effusion, or pulmonary emboli.
• To be eligible, patients had to have Mini Mental State Exam (MMSE) results of at least 24 out of 30.
• Thirteen patients were on continuous oxygen.
• Mean baseline total opioid dose in morphine equivalent mg was 82 (range 10–540).

• Inpatient- and community-based hospice service in Brisbane, Australia
• Single site

Patients were undergoing the palliative and end of life phases of care.

The study was a pilot, double-blind, randomized, crossover, controlled trial.

• Perceived intensity of breathlessness was measured on a vertical 100-mm visual analog scale (VAS).
• Pulse rate and peripheral oxygen saturation were measured with a pulse oximeter.
• Respiratory rate was counted by the research nurse over two 30-second intervals.

There were no differences between treatments in improvement scores. Improvement in breathlessness at 10 minutes post intervention completion was seen in each of the treatment conditions. Improvement considered to be clinically significant (≥1 cm on the VAS) was only seen with the nebulized hydromorphone. Respiratory rate improved over time from 10 to 60 minutes (p < 0.05), with no difference between treatments. There were no clear, consistent preferences among patients for any particular intervention.

The results suggest that nebulized saline provides relief of incident breathlessness; its effect is ongoing and does not differ significantly from the effects of nebulized opioid treatments.

• The study was appropriately powered to answer the study questions, but the study had a small sample size.
• A change of 1 cm on the VAS was used as a clinically significant symptom change, in concert with the work of others.
• Further research to define clinically significant differences in patient perception would be beneficial.
• It is not clear if higher doses of hydromorphone might yield differences across groups.
• The authors suggested that improvements in respiratory rates and peripheral oxygen over time likely represent Type I error in this study because the patients had a background of irreversible baseline dyspnea.
• The presence of the research nurse, to specifically administer this protocol, may have had an effect in terms of reassuring patients and confounded the overall results. Similar research having patients self-administer treatments might address this aspect.
• It is unclear if findings represent placebo effects.