Midazolam as Adjunct Therapy to Morphine in the Alleviation of Severe Dyspnea Perception in Patients with Advanced Cancer

Abstract

The mainstay of dyspnea palliation remains altering its central perception. Morphine is the main drug and anxiolytics have a less established role. This trial assessed the role of midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in terminally ill cancer patients. One hundred and one patients with severe dyspnea were randomized to receive around-the-clock morphine (2.5 mg every 4 hours for opioid-naïve patients or a 25% increment over the daily dose for those receiving baseline opioids) with midazolam rescue doses (5 mg) in case of breakthrough dyspnea (BD) (Group Mo); around-the-clock midazolam (5 mg every 4 hours) with morphine rescues (2.5 mg) in case of BD (Group Mi); or around-the-clock morphine (2.5 mg every 4 hours for opioid-naïve patients or a 25% increment over the daily dose for those receiving baseline opioids) plus midazolam (5 mg every 4 hours) with morphine rescue doses (2.5 mg) in case of BD (Group MM). All drugs were given subcutaneously in a single-blinded way. Thirty-five patients were entered in Group Mo, 33 entered in Mi, and 33 entered in MM. At 24 hours, patients who experienced dyspnea relief were 69%, 46%, and 92% in the Mo, Mi, and MM groups, respectively (P = 0.0004 and P = 0.03 for MM vs. Mi and MM vs. Mo, respectively). At 48 hours, those with no dyspnea relief (no controlled dyspnea) were 12.5%, 26%, and 4% for the Mo, Mi, and MM groups, respectively (P = 0.04 for MM vs. Mi). During the first day, patients with BD for the groups Mo, Mi, and MM were 34.3%, 36.4%, and 21.2%, respectively (P = NS or not significant), whereas during the second day, these percentages were 38%, 38.5%, and 24%, respectively (P = NS). The data demonstrate that the beneficial effects of morphine in controlling baseline levels of dyspnea could be improved with the addition of midazolam to the treatment.

Symptom Management in Metastatic Breast Cancer

“…Although small series describe relief of dyspnea with the administration of nebulized opioids [65], randomized controlled trials and a Cochrane review did not show that nebulized opioids are effective for dyspnea [66]. Benzodiazepines may be helpful in some patients when dyspnea is related to a panic disorder or severe anxiety, and corticosteroids may be effective in dyspnea re-lated to carcinomatous lymphangitis or treatment-related pneumonitis [61,67,68].…”

Dyspnea Management in Patients with Cancer

“…They found that the combination of this benzodiazepine with morphine had a positive effect on dyspnea with minimal effect on somnolence. [11] In contrast to these results, Simon and et al (2010) stated that there is no evidence to support the efficacy of benzodiazepines in the palliation of dyspnea in their metaanalysis. [5,12] More randomized, controlled studies aimed at assessing the efficacy of benzodiazepines used in conjunction with other opioids need to be performed.…”

The Evidence Base for Oxygen for Chronic Refractory Breathlessness: Issues, Gaps, and a Future Work Plan

“…There is one study which shows that morphine and midazolam give additional benefit when administered together in dyspnoeic patients in the dying phase (last hours of days of life), compared with giving midazolam alone (56). Although morphine alone gave more relief than midazolam alone, the combination was still the more efficacious option.…”