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Watanabe and Yang	
to 17% in 2013.7 An analysis between 2001 and 2010 found
benzodiazepines were co-prescribed with opioids in 8.1% of
acute pain visits and 15.5% of chronic pain visits with no
evidence of decreased co-prescribing during the analysis
period.8 Benzodiazepines increase the level of the inhibitory
neurotransmitter gamma-aminobutyric acid (GABA) in the
brain resulting in sedation, respiratory depression, and cognitive impairment.9 Muscle relaxants function at a different
binding domain of the GABA receptor, but similarly generate the neuromuscular suppressive effects of benzodiazepines.10 The combination of benzodiazepines and/or muscle
relaxants potentiates the respiratory depression attributable
to opioids at the medullary respiratory centers of the brain
increasing lethal risk. Combinations of these agents also synergize the euphoria of opioids via enhanced agonism of the
µ1-opioid receptor and possibly by potentiation of the dopaminergic activity of the opioids.11
The goal of this study was to use US Department of
Health & Human Services (HHS) Medical Expenditure
Panel Survey (MEPS) datasets to quantify the increased likelihood of hospitalization for US users of opioids, concurrent
opioid and benzodiazepine use (commonly called "doublethreat"), and opioid, benzodiazepine, and muscle relaxant
use ("triple threat") compared to a reference group of nonusers of these agents in the United States.12

Methods
The 2013 and 2014 MEPS-Panel 18 longitudinal dataset and
affiliated Prescribed Medicines Files were used for this retrospective analysis.13 The MEPS database was designed and
validated to produce a national reflection of family and individual health services usage for people living in the United
States.14 The MEPS Household Component files are data
from a sample of families and individuals in selected communities across the United States, drawn from a nationally
representative subsample of households that participated in
the National Health Interview Survey from the prior year.15
The cohort surveyed in MEPS has been weighted to be
reflective of the actual US population in the years 2013 and
2014. The finalized analysis dataset was used to quantify the
relationship between opioid, benzodiazepine, muscle relaxant, double-threat, and triple-threat usage and odds of hospitalization in people living in the United States.

Longitudinal Analysis of Benzodiazepine, Opioids,
and Muscle Relaxant Usage
The prescribed medicines in MEPS were combined with the
longitudinal MEPS-Panel 18 by linking study subject numbers. Medications that were not designated as muscle relaxants, benzodiazepines, and opioids were removed from the
medication list for this study. All prescriptions of the same
medications prescribed per patient within a specified round
were summed to provide total day supply per round by

dividing total dose quantity per round by defined daily dose
for each study medication.16

Prevalence Estimation of "Double-Threat" and
"Triple-Threat"
Using the finalized analysis set, concurrent use of muscle
relaxants, benzodiazepines, and/or opioids were categorized
as either "double-threat" and/or "triple-threat." Concurrent
use of opioids and benzodiazepines was defined as "doublethreat" and the concurrent use of opioids, benzodiazepines,
and muscle relaxants as "triple threat."

Association of Medication Exposures With
Hospitalizations
Separate analyses were performed to measure the association
via odds ratio (OR) between exposures of opioids, benzodiazepines, muscle relaxants, double-threat, and triple-threat
using a reference group of nonusers of these medications
with the outcome of hospitalization. To evaluate the relationship within the same year of exposure and outcome, we completed an analysis of 2013 exposure and 2013 outcome and
performed a separate analysis of 2014 exposure and 2014
outcome. Finally, to examine the relationship of prior year
exposure of the study medications to hospitalization in the
succeeding year, the association was measured of 2013 medication exposure with hospitalization in 2014.

Statistical Analysis Plan
Logistic regression applying the subject-level MEPS survey
weights was performed to measure association via ORs of
medication exposures with the outcome of all-cause hospitalization. Study subjects were categorized into exposure
groups as nonusers (nonuse of opioids, benzodiazepines, or
muscle relaxants), opioid users, benzodiazepine users, muscle relaxant users, double-threat users, and triple-threat users.
For purposes of regression analysis estimation function, all
exposure groups were mutually exclusive. Analyses were
conducted using RStudio® 1.1.5 (Boston, MA) with α level
= 0.05 for all comparisons.

Results
Prevalence Analysis
A total of 16 715 individuals were survey-weighted to represent the US population of 321 million in 2013. Of the 16 715
individuals, 9857 were between 18 and 64 years of age representing a population of approximately 196 million or
61.4% of the total population. Of the 321 million represented,
2.28 million (0.7%) individuals had missing age values.
Opioids, benzodiazepines, and muscle relaxants were prescribed in 11.9% (38.4 million lives), 4.2% (13.5 million),
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