Navigante, A.H., Cerchietti, L.C., Castro, M.A., Lutteral, M.A., & Cabalar, M.E. (2006). Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. Journal of Pain and Symptom Management, 31, 38–47.

To assess the role of midazolam as adjunct therapy to morphine in patients with advanced cancer with severe dyspnea during their last week of life

 Patients randomly were assigned to one of three treatment groups.

• Group Mo (n = 35): morphine 2.5 mg every four hours around the clock (ATC) for opioid-naive patients or 25% above the daily dose for those receiving baseline opioids with midazolam 5 mg rescue doses for breakthrough dyspnea (BD)
• Group Mi (n = 33): midazolam 5 mg every four hours ATC with 2.5 mg morphine rescue doses for BD
• Group MM (n = 33): morphine ATC (same dose as Group Mo) plus midazolam 5 mg every four hours ATC with morphine 2.5 mg rescue doses for BD

All drugs were given subcutaneously through a butterfly needle in the infraclavicular space. Random assignments were performed using a random number generator in 1:1:1 ratio in blocks of nine.

• N = 101
• KEY DISEASE CHARACTERISTICS: Patients with advanced cancer experiencing severe dyspnea during their last week of life
• OTHER KEY SAMPLE CHARACTERISTICS: Eligible patients had to have low performance status (PS = 4), severe dyspnea, and life expectancy less than one week and had to be coherent (more than 23/30 on the mini-mental state examination [MMSE]).

• Randomized, single-blind

• Modified Borg scale was performed at baseline and 24 and 48 hours after randomization.
• The number of breakthrough dyspnea episodes was recorded daily.
• MMSE was used to monitor cognitive impairment daily.
• Pulse oximetry also was monitored.
• Common Toxicity Criteria for Adverse Events v2.0 was used to score adverse events.
• Study endpoints were dyspnea intensity (measured by Borg scale), dyspnea relief (yes-no) after the intervention, and number of episodes of breakthrough dyspnea requiring rescue medication.
• Side effects from rescue medication also were monitored.

A significant correlation existed between dyspnea and anxiety at baseline and 24 and 48 hours. No correlation existed between dyspnea and anxiety and the other variables. No significant difference was found in oxygen saturation among the groups. Also, the groups did not differ significantly with respect to dyspnea intensity. Dyspnea relief at 24 hours was 69% Mo, 46% Mi, and 92% MM (p = 0.0004 for MM versus Mi, p = 0.03 for MM versus Mo). Patients with no dyspnea relief were 12.5% Mo, 26% Mi, and 4% MM (p = 0.04 for MM versus Mi). Percentage of breakthrough dyspnea episodes were 34.3% Mo, 36.4% Mi, and 21.2% MM (p = not significant) at 24 hours and was 38%, 38.5%, and 21.2%, respectively, at 48 hours. Authors asserted that clinicians should prescribe the combination.

The addition of midazolam to morphine improved the control of baseline dyspnea.

• Single blinding was a potential limitation.
• The physician’s knowledge of the drug regimen that patients were receiving may have influenced the need for administering rescue medication for breakthrough dyspnea.

More evidence, in addition to this one randomized, uncontrolled trial, is needed to validate findings.