Opioids, Benzodiazepines Linked to Higher Mortality in Older Patients With COPD

Opioid use, with or without benzodiazepine use, was associated with increased long-term all-cause mortality in patients with chronic obstructive pulmonary disease (COPD) aged older than 60 years, according to a study published today in the International Journal of Chronic Obstructive Pulmonary Disease.¹

The researchers explained that the primary goal of pharmacological treatment for COPD is to improve patients’ quality of life and manage their symptoms while decreasing exacerbation frequency.² Therefore, opioid-based therapy is conditionally recommended for patients with COPD experiencing advanced refractory dyspnea. Also, benzodiazepines are prescribed for anxiety, chronic breathlessness, or insomnia associated with or caused by COPD.³

Current data indicate that about 40% of patients with advanced COPD are prescribed opioids.¹ Conversely, although 65% of patients with COPD suffer from anxiety or depressive disorders, only 31% receive treatment for these conditions. Also, the researchers noted that co-prescribing opioids and benzodiazepines may increase overdose risk, and their respiratory effects may especially raise mortality risk in patients with COPD, making it easy to attribute the increased mortality risk in this population to these drugs.

However, it is still not clear whether using these drugs directly contributes to long-term mortality among patients with COPD or just indicates advanced illness. Consequently, they assessed the association between opioid use, with or without benzodiazepine use, and long-term all-cause mortality among adults with COPD.

Opioid use, with or without benzodiazepines, significantly increases long-term mortality risk in patients with chronic obstructive pulmonary disease (COPD) over the age of 60. | Image Credit: Feng Yu - stock.adobe.com

To do so, the researchers collected data on patients aged 20 years or older with COPD within the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES) cycles; NHANES contains a nationally representative sample of US patients. The primary outcome was all-cause mortality, assessed by linking the NHANES data to the National Death Index (NDI); mortality data, which extended through 2019, was collected after the initial home interview. 

Therefore, annual prescription medication data was collected from participants through face-to-face interviews. Patients were asked to present containers with all medications used in the last 30 days; if unavailable, interviewers recorded the medication name as stated by the patient. The researchers then matched the reported medication to the Multum Lexicon Plus drug database to classify them into therapeutic medication categories.

Based on prior research, they identified 23 types of benzodiazepines and over 60 types of opioid narcotics, which were used to identify opioid and benzodiazepine users. However, those using opioids to manage opioid dependence or withdrawal were excluded from the prescription opioid user category.

Of the 30,442 patients who completed the NHANES home interview and physical examination, 1063 were diagnosed with COPD. The final study population consisted of 811 patients, representing an estimated 10.84 million US patients with COPD. The mean (standard deviation [SD]) age of patients was 58.7 (0.6) years, and the population consisted of mostly White (84.7%) and male (60.6%) patients.

Based on the estimated representation number, 2,107,463 patients (19.4%; 95% CI, 15.2-23.7) received only opioids, 542,155 (5.0%; 95% CI, 3.0-7.0) received only benzodiazepines, and 507, 554 (4.7%; 95% CI, 2.7-6.6) received both. Conversely, the remaining 7,680,826 patients (70.9%; 95% CI, 66.2-75.6%) were not prescribed either drug.

The study population had a median follow-up duration of 9.6 years (range, 1.1-13.3 years), with 4,719,004 (43.5%) being followed for more than 10 years, equating to 7269 person-years. During follow-up, 255 deaths were recorded, resulting in an overall mortality rate of 35.1 events per 1000 person-years.

More specifically, the mortality rates were 45.7 per 1000 person-years (19 deaths) among those with co-prescriptions, 41.3 per 1000 person-years (15 deaths) among benzodiazepine-only users, 57.8 per 1000 person-years (86 deaths) among opioid-only users, and 27.0 per 1000 person-years (135 deaths) in those not using either medication.

Through the unadjusted weighted Cox proportional hazard regression models, the researchers found that patients who were prescribed only opioids (HR, 2.42; 95% CI, 1.69-3.46) or co-prescribed opioids and benzodiazepine (HR, 2.30; 95% CI, 1.35-3.91) had an increased mortality risk than those not receiving either medication.

After adjusting for all covariates, this increase in mortality risk remained significant in patients who only used opioids (adjusted HR, 1.68; 95% CI, 1.13-2.49). Similarly, the use of both opioids and benzodiazepines was associated with a significant, although smaller, all-cause mortality increase (adjusted HR, 1.76; 95% CI, 1.11-2.78).

Lastly, subgroup analyses revealed an elevated mortality risk among patients aged over 60 years prescribed only opioids (adjusted HR, 2.00; 95% CI, 1.29-3.09) or both opioids and benzodiazepines (adjusted HR, 1.89; 95% CI, 1.20-2.97). Although these patterns were not found in younger patients, the researchers discovered an increased mortality risk in patients aged 60 years or younger prescribed only benzodiazepines (adjusted HR, 4.29; 95% CI, 1.27-14.55).

The researchers acknowledged their limitations, one being that the NHANES does not provide detailed data on drug use indication, duration, or dosage. This limited their ability to distinguish between new and long-term users, high and low dosages, or short- and long-term exposure to opioids or benzodiazepines. Despite their limitations, the researchers made future treatment suggestions based on their findings.

“Given the lack of comprehensive opioid prescription guidelines for COPD patients using sedatives and hypnotics, managing the co-prescription of opioids and benzodiazepines is a major challenge for physicians,” the authors concluded. “To address this, collaborative efforts involving clinicians, scientists, and policymakers are essential to reduce the overprescription of these drugs for COPD patients, identify high-risk individuals, and develop specific interventions.”

References

1. Jiang H, Zhang X, Zhang J, Liang J, Wang L. Association between opioid and benzodiazepine use and all-cause mortality in individuals with chronic obstructive pulmonary disease: a prospective cohort study. Int J Chron Obstruct Pulmon Dis. 2024;19:2181-2192
   doi:10.2147/COPD.S467131
2. Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of chronic obstructive pulmonary disease. an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(9):e56-e69. doi:10.1164/rccm.202003-0625ST
3. Currow DC, Agar MR. Benzodiazepine prescribing in people with chronic obstructive pulmonary disease: clinical considerations. Drugs Aging. 2020;37(4):263-270. doi:10.1007/s40266-020-00756-z