Healthcare providers may be utilizing central nervous system (CNS) depressants to reduce opioid use due to recent changes in public policy. Combination use of these agents with opioids increases the risk of respiratory depression and death. Healthcare expenditures by individuals using these drug combinations have not been previously quantified. We sought to characterize healthcare costs and expenditures associated with a population reporting concurrent CNS depressants and opioid use compared with nonopioid analgesics in the United States from 2009 to 2019. A serial cross-sectional design was used to compare the healthcare expenditures of adult Medical Expenditure Panel Survey respondents who were prescribed nonopioid analgesics, opioids only, opioids/benzodiazepines (BZD), opioids/BZD/skeletal muscle relaxants (SMR), or opioids/gabapentin (gaba) using pooled data from 2009 to 2019. Expenditure (cost and resource utilization) categories included inpatient, outpatient, office-based, and prescription medicine. Average marginal effects were used to compare survey-weighted annual costs and resource utilizations across the groups as compared to nonopioid analgesic respondents, adjusted for covariates. A weighted total of 34 241 838 individuals were identified. Most were opioid-only respondents (46.5%), followed by nonopioid analgesic (43.4%), opioid/BZD (5.3%), opioid-gaba (3.5%), and opioid/BZD/SMR respondents (1.3%). In comparison to the study groups with nonopioid analgesics, opioid-gaba users had the highest significant incremental cost difference among the different pairings (+$11 684, P < .001). Opioid-gaba, opioid/BZD, and opioid/BZD/SMR respondents had significantly higher inpatient, emergency department, and prescription drug costs and use compared to nonopioid analgesic respondents. Opioid-only respondents had higher outpatient and office-based costs and visits compared to nonopioid analgesic respondents. As healthcare providers seek to utilize fewer opioids for pain management, attention must be paid to ensuring safe and effective use of concurrent CNS depressants to mitigate high healthcare costs and burden.
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