Prevalence and characteristics of patients prescribed opioids and central nervous system depression agents on discharge to hospice care

Introduction

Chronic liver disease is increasingly prevalent in the United States and with than 4.5 million adults have been diagnosed with liver disease, it is the fourth leading cause of death for persons between the ages of 45 and 64 years (1-3). Patients with end-stage liver disease (ESLD) suffer from an array of symptoms including pain, insomnia, delirium, dyspnea, and anxiety requiring a multimodal medication regimen for symptom management. However, with the pharmacokinetic and pharmacodynamic challenges associated with liver dysfunction, there are risks and potentially harmful medication-related events and toxicity, particularly with opioids and concurrent central nervous system (CNS) depressants (4,5). In addition to the complexity of pain and symptoms of advanced illness in hospice patients, patients with ESLD experience liver-specific symptoms such as hepatic encephalopathy, which may be attributable to medication toxicity or worsening of hepatic function.

Drug metabolism is altered in ESLD, requiring drug dose reduction or discontinuation. An analysis of Veterans’ Health Administration data of 1,877,841 patients with an opioid prescription found multiple variables, including liver disease and impaired drug metabolism or excretion, highly associated with opioid-induced respiratory or CNS depression (6). Further analysis of this study revealed that comorbid conditions such as liver disease were significantly associated with opioid-related toxicity and overdoses (7,8). Unfortunately, little is known about the frequency of opioid and CNS depressant prescribing in patients with ESLD in the hospice setting.

In this study, we aimed to investigate the frequency of opioid and concomitant CNS depressant prescribing in patients with ESLD and compare it to other common hospice diagnoses such as cancer, chronic obstructive pulmonary disorder (COPD), heart failure, and end-stage renal disease. We present this article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-23-537/rc).

Methods

This retrospective cross-sectional study utilized data from a national for-profit hospice chain across the United States, including 19 states, between January 1, 2010, and December 31, 2019. Before data acquisition, the University of Maryland, Baltimore, and Oregon Health & Science University institutional review boards deemed this study was not a human research subject because all patients were deceased at the time of data collection. Hospice decedents who died while receiving hospice care were included in the analysis if they were 18 years of age and had a primary diagnosis of ESLD, cancer, cardiovascular, or respiratory disease. We identified the primary hospice diagnoses at the time of hospice admission using International Classification of Diseases (ICD) versions 9 and 10 codes. Patients were excluded if they did not meet the inclusion criteria. Patient demographics collected included demographics (e.g., age, sex, race/ethnicity), hospice service site (e.g., assisted living facility, home, hospital, inpatient hospice, nursing home), hospice length of stay, and primary hospice admitting diagnosis.

We used medication utilization data to estimate the prevalence of scheduled and pro re nata (PRN) opioids, benzodiazepines, and adjuvant analgesics, including gabapentinoids prescribed at admission, at any time during hospice care, and at discharge or death for each admitting diagnosis. These data were extracted from the hospice electronic medical record data which contained the patient’s clinical and pharmacy records, including primary diagnosis and medication name, dosage, formulation, strength, and frequency. Medications were grouped by their pharmacological class. The medications included were within the hospice organization formulary or preferred drug list in their respective pharmacological class (Table 1).

Adjuvant analgesic, opioid, benzodiazepine, and gabapentinoid prescribing were collected for each study group. We excluded intravenous infusions that did not have information on medication administration and titrations throughout hospice admission. CNS depressants included in this study were benzodiazepines, gabapentinoids, and opioids. The frequency of patients prescribed an opioid with a gabapentinoid, opioid with a benzodiazepine, and opioid with a benzodiazepine and gabapentin medication order was evaluated and compared between each disease group. Opioid utilization was evaluated as total daily oral morphine equivalent (OME), which includes scheduled and all possible PRN dosages patients are able to receive, at admission and discharge. Total daily OME calculations were determined using the most recently published opioid equianalgesic conversion table (8) (Table 2).

Statistical analysis

We used descriptive statistics, including means and standard deviations, 95% confidence intervals (CIs), medians, interquartile ranges (IQRs), and percentages. In addition, we stratified patients by primary diagnoses of the liver, cardiovascular, respiratory, and cancer disease to compare the differences in opioid, adjuvant analgesics, benzodiazepine, and gabapentinoid utilization between subgroups. All analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

This study included 119,424 hospice decedents in the analysis, with the most prevalent hospice diagnoses being cancer (46.2%) and about 2.2% of the patients with ESLD. Overall, the mean age was 77.9 years, and 54.6% were female. More than half of the patients were non-Hispanic white (58.9%). The median hospice length of stay measured by days of overall hospice decedents was 9 (IQR, 3–33). The majority of patients referred to hospice care resided at home (36.1%) or at an inpatient hospice facility (24.4%) (Table 3).

The prevalence of prescribing a scheduled regimen and scheduled and PRN regimen consisting of adjuvant analgesics, benzodiazepine, and opioid prescriptions at admission, during hospice stay, and discharge are shown in Table 4. Although patients with ESLD were less frequently prescribed a scheduled benzodiazepine and adjuvant analgesic, they were more frequently prescribed a scheduled opioid compared to patients with cardiovascular and respiratory disease at any time (39.4% vs. 36.4%, 95% CI for difference: 0.01 to 0.05; and 41.8%, 95% CI for difference: 0.25 to 0.29).

The prevalence of patients with ESLD prescribed a scheduled and PRN benzodiazepine was less than patients with cancer, cardiovascular, and respiratory disease at admission (67.3% vs. 71.7%, 95% CI for difference: −0.07 to −0.03; 68.1%, 95% CI for difference: −0.03 to 0.01; and 68.0%, 95% CI for difference: −0.03 to 0.01). However, patients with ESLD were prescribed a scheduled and PRN benzodiazepine more frequently than those with respiratory disease at any point during hospice stay (75.0% vs. 74.9%, 95% CI for difference: −0.02 to 0.02). Patients with ESLD were more frequently prescribed a scheduled and PRN opioid than patients with cardiovascular and respiratory diseases at admission (78.3% vs. 76.0%, 95% CI for difference: 0.01 to 0.04; and 75.9%, 95% CI for difference: 0.01 to 0.04) and patients with respiratory disease at any time (84.2% vs. 82.6%, 95% CI for difference: 0.002 to 0.03) and discharge (80.5% vs. 77.8%, 95% CI for difference: 0.01 to 0.04).

The prevalence of patients with concurrent CNS depressant prescriptions, including an opioid, gabapentinoid, and benzodiazepine, were collected at admission and discharge. It was found that patients with ESLD received concurrent opioid and benzodiazepine prescriptions similarly to those with cardiovascular and respiratory disease at admission (65.4% vs. 63.9%, 95% CI for difference: −0.003 to 0.03; and 64.9%, 95% CI for difference: −0.01 to 0.03) and those with respiratory disease at discharge (68.4% vs. 67.6%, 95% CI for difference: −0.01 to 0.03). Patients prescribed all three CNS depressants, an opioid, benzodiazepine, and gabapentinoid prescription at admission (4.4%) and discharge (4.2%) were compared between disease groups. Patients admitted with a diagnosis of ESLD receiving all three pharmacologic categories had a similar frequency as those admitted with respiratory disease on admission (3.6%, 95% CI for difference: −0.002 to 0.014) (Table 5).

Opioid utilization was collected at admission and discharge and presented in Table 6 with median OME (IQR). From hospice admission to hospice discharge, overall OME increased across all disease groups. The median OME (IQR) was the same between ESLD, cancer, and respiratory disease, but the OME utilization was higher in ESLD than in cardiovascular disease (120 OME vs. 75 OME).

Discussion

Liver disease has been identified as one of the highest risk factors for opioid-related toxicity and overdoses (6,7,9-12). High opioid and benzodiazepine utilization in patients with ESLD is problematic due to impaired hepatic metabolism and elimination. While multiple studies have demonstrated high utilization of opioid and concurrent benzodiazepine prescriptions in liver disease, this is the first study to assess the prevalence of opioid and CNS depressant prescribing in the hospice setting and patients with ESLD. This is important because patients in the hospice setting are often prescribed multiple medications to treat suffering pain, anxiety, and insomnia, and changes in pharmacokinetics and pharmacodynamics must be considered.

A previous study has demonstrated patients with ESLD to have a high burden of mortality and morbidity and approximately 72% of patients report an overall poor quality of life. Pain, dyspnea, insomnia, and daytime sedation were reported in more than 75% of patients (13). Therefore, symptomatic management of patients with ESLD will require multiple interventions including non-pharmacological and pharmacological agents. This study found a high prevalence of opioid and CNS depressant utilization, as evidenced by a prescription in patients with ESLD compared to other common hospice diagnoses. As evidenced by previous studies, these results were not surprising given the high prevalence of pain and anxiety that patients with ESLD experience at the end of life (14-17). Our findings reveal that hospice patients with ESLD were frequently prescribed a scheduled and PRN opioid regimen at any time during their hospice length of stay (39.4%) at very high doses, typically defined as 90 or more OME, similar to other common hospice diagnoses (18). Commonly utilized opioids at the end of life, include morphine, hydromorphone, methadone, and oxycodone. These opioids are significantly metabolized by the liver, therefore hepatic impairment may result in greater plasma concentrations and prolonged half-lives (19-26). Given the high prevalence of pain, patients with ESLD are started on multiple analgesics, including opioids, non-steroidal anti-inflammatory agents, gabapentinoids, and antipyretic agents. A large nationwide database of insured US patients demonstrated higher rates of prescription opioids and benzodiazepines for patients with cirrhosis than other chronic diseases, which is concerning in the face of impaired drug metabolism in hepatic dysfunction (14). This study adds to the existing literature by presenting a large, national hospice patient population database and the high prevalence of CNS depressing agents and adjuvant analgesics prescribed to patients with ESLD and compared to other common admitting diagnoses with significant symptom burden. Considering the safety of opioids in patients with ESLD and impaired hepatic metabolism, opioid prescribing should be considered carefully. It is advisable to consult a pharmacist or clinician with extensive training in pharmacology to adjust medications to lower dosages, extended dosing frequencies, and continual monitoring.

Patients with ESLD often experience anxiety and agitation throughout their disease trajectory and especially at the end-of-life (16). Benzodiazepine prescribing was prevalent among all disease groups (74.9%), including ESLD (75.0%), with a scheduled and PRN benzodiazepine regimen at any time of hospice stay. Providing appropriate symptom management with minimal side effects with pharmacological agents at the end of life is challenging. Our results demonstrate the comparable prevalence of concomitant CNS depressant prescribing (e.g., opioid, gabapentinoid, and benzodiazepine) between diseases. However, in the face of hepatic dysfunction and ESLD, given the extensive hepatic biotransformation of benzodiazepines, clinicians must consider the implications of these pharmacokinetic changes (27,28).

This study had some limitations. The study population included hospice decedents from a single hospice provider in the United States, which may not be generalizable to all hospice and end-of-life patients. The study did not include data before hospice admission; therefore, the investigators were unaware of acute or chronic medications starting before hospice admission. When calculating the assumed total daily OME, all possible PRN dosages were included which may not account for all actual doses patients were taking. Lastly, study investigators were unable to identify medications that were part of the emergency kit (or comfort pack), so we could not specifically exclude the medications but included those medications as other PRN medications. This study’s strengths are the large sample size, including hospice admissions across all admission locations over 10 years, and the extensive medication database.

Conclusions

In conclusion, this study demonstrated the significant opioid, benzodiazepine, and gabapentinoid prescribing among hospice patients with ESLD compared to other common admitting diagnoses. These findings should be further studied in other patient populations and monitored for adverse effects that may occur. It is essential to take additional precautions in prescribing medications for patients with ESLD and impaired hepatic metabolism. Furthermore, clinicians should consult pharmacists to individualize pharmacological treatment plans and minimize symptom burden.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-23-537/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-23-537/dss

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-23-537/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-23-537/coif). J.P.F. serves as an unpaid editorial board member of Annals of Palliative Medicine from June 2023 to May 2025. He also serves as an unpaid board member of Oregon Hospice and Palliative Care Association, unpaid member of Diversity, Equity, and Inclusion Committee and editor of Diversity, Equity, and Inclusion LAB of the American Academy of Hospice and Palliative Medicine, and unpaid member of eLearning Continuing Education subcommittee and paid Statistical of the Society of Healthcare Epidemiology of America. J.P.F. received research funding from federal sponsors for other activities: First, AHRQ R01HS027820. This is a multi-site project using a mixed methods approach to develop, implement, and evaluate novel antibiograms to improve antibiotic prescribing in nursing homes, developing a novel antibiogram tool to improve empiric antibiotic prescribing in nursing homes. Second, Agency for Healthcare Research and Quality R01HS026747. This project utilizes a mixed methods approach to develop interventions to improve antibiotic prescribing among hospitalized inpatients on discharge to nursing homes, optimizing antibiotic prescribing on discharge to long-term care facilities. Third, Centers for Disease Control and Prevention Contract 75D30122F00001. This is a multisite study to develop knowledge and infrastructure to respond to public health emergencies in the nursing home setting, and nursing home public health response network. Last, National Institutes of Health R01AG079555. This is for Decision trajectories of patients at the end of life: An epidemiological exploration of MAID and the impact on caregivers and clinicians. This is a multisite longitudinal cohort study to understand quantitative and qualitative outcomes of seriously ill persons pursuing MAID as well as their caregivers, and health care providers. None represent any conflicts of interest related to this article. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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