Benzodiazepines, Codispensed Opioids, and Mortality among Patients Initiating Long-Term In-Center Hemodialysis

Abstract

Background and objectives: Mortality from benzodiazepine/opioid interactions is a growing concern in light of the opioid epidemic. Patients on hemodialysis suffer from a high burden of physical/psychiatric conditions, which are treated with benzodiazepines, and they are three times more likely to be prescribed opioids than the general population. Therefore, we studied mortality risk associated with short- and long-acting benzodiazepines and their interaction with opioids among adults initiating hemodialysis.

Design, setting, participants, & measurements: The cohort of 69,368 adults initiating hemodialysis (January 2013 to December 2014) was assembled by linking US Renal Data System records to Medicare claims. Medicare claims were used to identify dispensed benzodiazepines and opioids. Using adjusted Cox proportional hazards models, we estimated the mortality risk associated with benzodiazepines (time varying) and tested whether the benzodiazepine-related mortality risk differed by opioid codispensing.

Results: Within 1 year of hemodialysis initiation, 10,854 (16%) patients were dispensed a short-acting benzodiazepine, and 3262 (5%) patients were dispensed a long-acting benzodiazepine. Among those who were dispensed a benzodiazepine during follow-up, codispensing of opioids and short-acting benzodiazepines occurred among 3819 (26%) patients, and codispensing of opioids and long-acting benzodiazepines occurred among 1238 (8%) patients. Patients with an opioid prescription were more likely to be subsequently dispensed a short-acting benzodiazepine (adjusted hazard ratio, 1.66; 95% confidence interval, 1.59 to 1.74) or a long-acting benzodiazepine (adjusted hazard ratio, 1.11; 95% confidence interval, 1.03 to 1.20). Patients dispensed a short-acting benzodiazepine were at a 1.45-fold (95% confidence interval, 1.35 to 1.56) higher mortality risk compared with those without a short-acting benzodiazepine; among those with opioid codispensing, this risk was 1.90-fold (95% confidence interval, 1.65 to 2.18; P_interaction<0.001). In contrast, long-acting benzodiazepine dispensing was inversely associated with mortality (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.99) compared with no dispensing of long-acting benzodiazepine; there was no differential risk by opioid dispensing (P_interaction=0.72).

Conclusions: Codispensing of opioids and short-acting benzodiazepines is common among patients on dialysis, and it is associated with higher risk of death.

Keywords: Analgesics; Benzodiazepines; Cohort Studies; Follow-Up Studies; Medicare; Opioid; Opioid Epidemic; Prescriptions; Proportional Hazards Models; Records; dialysis; renal dialysis.

Graphical abstract

Figure 1.

Sixty-nine thousand, three hundred sixty-eight adults initiating hemodialysis between 2013 and 2014 were selected to be in the study sample. The dialysis initiation cohort was restricted to United States citizens aged 18 years old and older. MPAB, medicare part A and B; MPO, mediare primary, other.

Figure 2.

Benzodiazepine dispensing differed by geographic region among patients inititiating hemodialysis (n=69,368) between 2013 and 2014.

Figure 3.

Benzodiazepine dispensing barely changed over time among patients inititiating hemodialysis (n=69,368) between 2013 and 2014. Rates by quarter (Q) are presented as lorazepam milligram equivalent (LME) per 100 person-days.

Figure 4.

The cumulative incidence of time to first short-acting benzodiazepine prescription dispensed among patients initiating hemodialysis (n=69,368) between 2013 and 2014 differed by race and sex. (A) Cumulative incidence of short-acting benzodiazepine. Approximately 18.1% of white women, 12.5% of white men, 9.5% of nonwhite women, and 6.1% of nonwhite men had used a short-acting benzodiazepine within 6 months of initiating dialysis. (B) Cumulative incidence of long-acting benzodiazepine. Approximately 5.1% of white women, 3.4% of white men, 2.3% of nonwhite women, and 1.8% of nonwhite men had used a long-acting benzodiazepine within 6 months of initiating dialysis.