Hardy, J., Randall, C., Pinkerton, E., Flatley, C., Gibbons, K., & Allan, S. (2016). A randomised, double-blind controlled trial of intranasal midazolam for the palliation of dyspnoea in patients with life-limiting disease. Supportive Care in Cancer, 24, 3069–3076. 

To investigate the effect of a short-acting intranasal benzodiazepine on dyspnea, which is extremely common in those with life-limiting disease and negatively impacts quality of life (QOL)

Participants were given six identical bottles of nasal spray, three of which contained a placebo and three of which contained midazolam (benzodiazepine being studied) with the concentration of 0.5 mg per spray. The bottles were numbered one through six  in random sequence. Patients were instructed to inhale a total of three times on each occasion of use with the total dose of active drug delivered being 1.5 mg. The participants were asked to use bottle number 1 on the first day, number 2 on the second day, and so on, using no single nasal spray for more than 24 hours. The dosages were not to be delivered more frequently than every four hours, and if participants did not experience dyspnea on a certain day, they were not required to use a nasal spray that day. The participants were formally assessed by investigators at baseline, day 7, and day 14. The participants were also contacted by phone throughout the study on specific days to ensure compliance. The participants formally scored the first dose administered each day, and at the end of each study day, participants documented how many times they used the nasal spray and if there was any benefit using a variety of tools and surveys.

• N = 62
• MEDIAN AGE = 70 years
• AGE RANGE = 62–78 years
• MALES: 48%, FEMALES: 52%
• CURRENT TREATMENT: Not applicable. Patients were instructed to continue baseline medications and treatment of underlying condition, and no further information on this matter was collected.
• KEY DISEASE CHARACTERISTICS: Participants were from two different countries—participants in New Zealand had a greater proportion of participants with cancer, and participants in Austrailia had a larger proportion of participants with respiratory diseases. 
• OTHER KEY CHARACTERISTICS: All participants had dyspnea related to either a life-limiting disease or the treatment of the disease with the average score being > 3/10 on a scale of 1–10 with 10 being the worst breathlessness. All participants had an adequate performance status and were able to operate the nasal spray independently. Study participants were in or outpatients recruited across four sites in Australia and New Zealand. Any participants receiving sustained-release opioids were to continue to take these medications throughout the study period and any of those on dependent supplemental oxygen were also instructed to continue at the same flow rate for the duration of the study.

• SITE: Multi-site
• SETTING TYPE: Blend of inpatients and outpatients
• LOCATION: The participants were recruited from an oncology/palliative care department in a hospital in Australia and from three palliative care services in New Zealand.

• PHASE OF CARE: Symptom management, palliation, end of life
• APPLICATIONS: Palliative care

• Randomized, double-blind, placebo-controlled crossover design with participants taking both placebo or the trial medication at various times

The Covi Anxiety Scale (CAS) and the Cancer Dyspnea Scale (CDS) were completed by clinicians and examined verbal reports, patient behaviors, and somatic symptoms of anxiety. Participants documented how many times they had used the nasal spray in 24 hours and if they found any benefit in a daily log. Participants rated dyspnea, anxiety, and drowsiness on an 11-point numerical rating scale (NRS).

No significant benefit of the intranasal midazolam on anxiety scores was noted. No difference at any time point of investigation existed between the midazolam and the control group, and no difference in the dyspnea scores or positive change in dyspnea existed between the control bottles of nasal spray and the midazolam when looking closer into age, gender, baseline anxiety, depression, and disease. The greatest benefit was seen at 30 minutes after the use of both the control spray and the midazolam, with no difference between the two groups. When questioned about adverse events, participants revealed that side effects worse than they were at baseline were low grade and most likely from the use of the nasal spray, with the most common being nasal cavity irritation and sinus reactions.

The study failed to demonstrate a meaningful benefit of intranasal midazolam on dyspnea or anxiety. Though the nasal cavity is thought to be a good way to deliver the effects of medications quickly, intranasal midazolam did not effectively relieve the participants’ dyspnea.

• Small sample (< 100)
• Baseline sample/group differences of import: The sample contained patients with a variety of diseases, with the majority having cancer or respiratory diseases. Further studies should target a single disease type because of the differences in characteristics and presentations of dyspnea.
• The sample size was limited because participants had to be able to operate the nasal spray device and have an adequate performance status; this is unfortunate since many terminally ill patients needed to be excluded from the study. 
• The study participants had low anxiety scores at baseline, which may have affected the study results of the intervention in question, and measures may have been subject to floor effects.
• Many of the older adult patients in the study found the nasal sprays difficult to use, and several of the bottles were faulty and did not delivery a reliable spray, which may have resulted in a less-than-planned dose delivered.

The study findings demonstrated that intranasal midazolam was not effective in relieving dyspnea. This study magnified the importance of finding ways to better control dyspnea in terminally ill patients and the impact on quality of life if not done. The effectiveness of benzodiazepines on dyspnea needs further investigation, and nurses should continue with the administration of low-dose opioids to treat patient dyspnea, as this remains the evidence-based medication of choice.