Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. Effects of clorazepate on breathlessness and exercise tolerance in patients with chronic airflow obstruction. Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. Effect of alprazolam on exercise and dyspnea in patients with chronic obstructive pulmonary disease.
Fifteen out of 18 "pink and puffing" patients completed a double-blind, placebo-controlled cross-over trial of diazepam and promethazine for breathlessness and reduced exercise tolerance. Dosages were 25 mg and 125 mg daily, respectively, and each course lasted two weeks. Patients with psychiatric or other major medical histories were excluded. Of the three patients who did not complete the trial, one died during an exacerbation of breathlessness while taking diazepam, one was withdrawn because of mild hypercapnia while taking placebo, and one suffered intolerable drowsiness while taking diazepam. Of the remaining 15 patients, six needed a reduction in dosage because of drowsiness: one of these was taking promethazine and five diazepam. Diazepam had no effect on breathlessness and noticeably reduced exercise tolerance. Promethazine reduced breathlessness and improved exercise tolerance without altering lung function. From these results diazepam is contraindicated for breathlessness and reduced exercise tolerance in fixed airways obstruction, but promethazine may be beneficial. Five patients with severe chronic lung disease were given placebo or 7.5 mg of clorazepate, a benzodiazepine, at bedtime for two weeks using a double-blind cross-over study design. Exercise tolerance, arterial blood gases, pulmonary function tests, self-rated breathlessness, and self-administered depression and anxiety scores were similar during drug treatment, placebo treatment, and washout periods. Higher doses of clorazepate were not tolerated by three of five patients. Nonanxious patients with chronic lung disease seem not to benefit subjectively or objectively from a low-dose benzodiazepine regimen. 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. To evaluate the efficacy of a mild anxiolytic, alprazolam, in relieving dyspnea, we conducted a randomized, placebo-controlled double-blind study on patients with chronic obstructive lung disease. Twenty-four patients had alprazolam (0.5 mg bid) or placebo administered for one week, followed by placebo for one week, then either placebo or alprazolam for the third week. Assessment tests were performed at the outset, end of the first and second weeks, and finally end of the third week. The parameters measured were: pulmonary function, exercise testing on a bicycle ergometer, and the distance covered in a 12 minute walk. Subjective sensations of dyspnea at rest and during guarded exercise, as well as subjective feelings of calmness or anxiety were also recorded. There was no difference in mechanical lung function, but the PO2 tended to decrease and PCO2 to increase after alprazolam administration. The maximum exercise level attained and the distance covered in the 12 minute walk was unchanged. The subjective perception of dyspnea was the same before and after alprazolam, at rest and during exercise. We conclude that alprazolam is not effective in relieving exercise dyspnea in patients with obstructive lung disease.
There is no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in patients with advanced cancer and COPD. There is a slight but non-significant trend towards a beneficial effect but the overall effect size is small. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. These results justify considering benzodiazepines as a second or third-line treatment within an individual therapeutic trial, when opioids and non-pharmacological measures have failed to control breathlessness. Although a few good quality studies were included in this review, there is still a further need for well-conducted and adequately powered studies.