Patients with chronic obstructive pulmonary disease (COPD) who are taking benzodiazepines have a more than doubled risk of suicide, compared with similar patients not taking the medications.
The risk of all-cause mortality in , according to the results of research published in the Annals of the American Thoracic Society.
Benzodiazepines were often prescribed for people with COPD to manage chronic symptoms of anxiety, dyspnea, and insomnia that affect quality of life, Lucas M. Donovan, MD, of the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle, and his colleagues noted.
However, there were documented concerns that the class of medications could lead to respiratory depression and increase the risk of exacerbations. According to the authors, one particular area of controversy was the long-term use of benzodiazepines, with up to 40% of COPD patients using them on a long-term basis against the advice of clinical guidelines.
They noted that benzodiazepines were also often used to treat dyspnea, a fact which had the potential to introduce confounding into research as the symptom was linked to increased mortality, nonfatal respiratory events, and suicidal ideation.
“One strategy to reduce confounding is to examine risks of benzodiazepines in a sample of patients who are likely to be prescribed benzodiazepines to manage nonrespiratory symptoms, and patients with comorbid posttraumatic stress disorder (PTSD) provide one such opportunity,” they wrote.
In the current study, the research team therefore used data from a nationwide cohort of patients with comorbid COPD and PTSD identified from the Veteran’s Health Administration administrative data between 2010 and 2012. The primary outcome was all-cause mortality in the 2 years following index among propensity-matched veterans with long-term benzodiazepine use, compared with nonusers.
Of 44,555 patients with COPD and PTSD included in the analysis, 29,237 had no benzodiazepine use, 4,782 patients had short-term use (less than 90 days’ supply), and 10,536 patients had long-term use (equal to or more than 90 days).
With a matched sample of 19,552 patients who did not receive benzodiazepines, the risk of all-cause mortality was not significantly different among those with long-term benzodiazepine use relative to those without use (hazard ratio, 1.06; 95% confidence interval, 0.95-1.18).
Furthermore, the specific relative risks of death related to obstructive lung disease and accidental overdose did not differ between the two groups.
Among matched and unmatched patients, short-term benzodiazepine use (HR, 1.16; 95% CI, 1.05-1.28), but not long-term use (HR, 1.03; 95% CI, 0.94-1.13) was associated with increased mortality. However, the authors said it was “worth noting that the associations with short-term use were found in analyses with unmatched patients and may be confounded by the specific episodic reasons for short-term benzodiazepine use such as acute illnesses not captured in our data.”
According to the research team, the most “consistent” and “striking” finding in their analysis was the link between benzodiazepine use and suicide.
They saw a substantially greater risk for death by suicide among those with long-term benzodiazepine use (HR, 2.33; 95% CI, 1.14-4.79). After adjusting all analyses by propensity score for any benzodiazepine exposure, individuals with both short-term and long-term use of benzodiazepines were at a greater risk of suicide (short-term: HR, 2.46; 95% CI, 1.16-5.26; long-term: HR, 2.35; 95% CI, 1.33-4.16).
“Similar to other estimates of the suicide rate within the veteran population (0.3 per 1,000 person-years), the rate of suicide among those without benzodiazepine use (0.4-0.5 per 1,000 person-years) in our sample was greater than the rate in the civilian population (0.1 per 1,000 person-years). However the risk of suicide was substantially greater among those with short- and long-term benzodiazepine use (1.1 per 1,000 person-years),” they wrote.
The use of long-acting benzodiazepines, such as diazepam, chlordiazepoxide, and flurazepam, was also positively associated with suicide (HR for every 10 days of exposure, 1.07; 95% CI, 1.01-1.13), and higher prescribed doses were associated with an increased risk of accidental overdose (HR for every 10 mg of diazepam equivalents, 1.19; 95% CI, 1.07-1.31).
The findings suggested that long-acting agents could pose a particular suicide risk but also “may relate to the sustained half-life of medication or the more severe and sustained mental health symptoms that prompt the use of long-acting agents,” the investigators wrote.
Concomitant opioid use was associated with increased risk of overall mortality (HR for every 10 days of exposure, 1.02; 95% CI, 1.01-1.02) and accidental overdose (HR, 1.11; 95% CI, 1.04-1.18). Individuals with long-term benzodiazepine use also had a higher rate of psychiatric admissions (incidence rate ratio, 1.37; 95% CI, 1.14-1.65).
The researchers concluded that, overall, their results did not suggest that discontinuation of long-term benzodiazepines would reduce overall mortality or death related to obstructive lung disease or overdose.
However, they advised that providers consider discontinuing benzodiazepines in patients already at high suicide risk as well as avoiding the concomitant use of opioids.
“Furthermore, providers should be aware of the risks that new benzodiazepine prescriptions may present to patients with COPD and PTSD without prior exposure to these medications,” they added.
The study was funded by several National Institutes of Heath grants, the ASPIRE (Academic Sleep Pulmonary Integrated Research/Clinical) Fellowship, and a VA grant.
SOURCE: Donovan LM et al. Ann Am Thorac Soc. 2018 Oct 12. doi: 10.1513/AnnalsATS.201802-145OC. Epub ahead of print.