Navigante, A.H., Castro, M.A., & Cerchietti, L.C. (2010). Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated. Journal of Pain and Symptom Management, 39(5), 820-830.

The objective of this study was to assess the efficacy of a rapid titration of either morphine or midazolam for reduction of dyspnea.

Patients were randomized to receive oral morphine or oral midazolam. Starting dose of morphine was 3 mg, and midazolam was 2 mg. Two steps of 25% increases in dosage were given as needed to achieve 50% reduction in symptoms and to establish the “effective dose” for the follow-up period. Dyspnea relief was assessed 30 minutes after each medication dose during the rapid titration phase. In the follow-up phase, the effective dose was taken every four hours around the clock while awake. Breakthrough dyspnea was managed with rescue doses, and the dose was adjusted daily during the five-day follow-up period based upon need.

• The study reported on a sample of 63 participants.
• The mean age in the morphine arm was 55 years, with a range of 30–80 years.
• The mean age in the midazolam arm was 59 years, with a range of 36–82 years.
• Gender distribution was not reported.
• Of the participants, 16 of 63 had lung cancer, 15 of 63 had breast cancer, 6 of 63 had head and neck cancer, and 26 of 63 had other cancers.
• Other clinical contributing risk factors for dyspnea were present in most patients.
• Exclusion criteria included active or uncontrolled COPD, noncompensated heart failure, and severe renal or hepatic failure.

The study was conducted in a single outpatient setting in Buenos Aires.

Patients were undergoing end-of-life and palliative care.

The study was a random-assignment, single-blind intervention trial.

• Mini-mental status (MMS) exam for cognitive ability to participate in trial
• Dyspnea numeric rating scale (NRS) of 0–10 for breathlessness in which 0 means no breathlessness and 10 means worst possible breathlessness (used to establish baseline dyspnea and for follow-up phase)
• Dyspnea descriptors patients used first to characterize their dyspnea
• Semi-structured questionnaire for healthcare providers regarding possible active causes of dyspnea for each patient, dyspnea syndromes, and treatment or diagnostic approaches
• Dyspnea relief five-point scale (used only during rapid titration phase): none, slight, moderate, a lot, complete

• No serious adverse events required drug discontinuation, but about 50% in both arms developed mild somnolence.
• All patients in both arms of rapid titration were alleviated of dyspnea and continued into the follow-up phase
• Median intensity for dyspnea at baseline was 9 on NRS, and day one showed a significant decrease in dyspnea in both arms (morphine [9–6] and midazolam [9–4.5, p < .001]). Subsequent days continued to decrease or stayed low.
• The midazolam arm maintained significantly lower dyspnea levels as compared to the morphine arm on days three to five (p < .0002).
• Therapeutic failure (defined as less than 50% reduction in breathlessness) was seen in 20% of those on morphine and 0% of those on midazolam.

Midazolam alone or in combination with opioids may be beneficial for dyspnea management.

• The study had a limited sample size of less than 100 patients.
• Patients were eliminated if their symptoms were rated greater than or equal to 3/10, which is inconsistent with the stated criteria of moderate to severe dyspnea.
• Only patients and caregivers were stated to be blinded.
• No clear description was provided of whether patients could tell the difference in medications used.
• Patients were ambulatory and followed daily in the clinic; findings here may not apply to individuals with worse performance status.
• Though stated that patients could use rescue doses, no discussion ofuse of rescue medication took place between groups.
• Whether this was dypsnea at rest or dyspnea on exertion was unclear.
• Some patients on midazolam were also on opiods for other reasons, but no differentiation was made of these patients, and the number of the sample involved with use of both drugs was not described.

Midazolam may be useful in the management of dyspnea, but well designed clinical trials are needed to establish supporting evidence for this intervention.