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and 3.4% (10.9 million), respectively, of the individuals in
2013 and 12.2% (39.3 million), 4.6% (14.8 million), and
3.6% (11.6 million), respectively, in 2014. In 2013, 1.6% of
the population were on double-threat and 0.53% of the population were on triple threat. In 2014, 1.9% of the population
are on double-threat and population on triple threat remained
at 0.53%.
Of the 9961 medication records in the study sample,
62.3% were opioids, 21.9% were benzodiazepines, and
15.8% were muscle relaxants. A total of 49 (0.5%) medication records were omitted due to missing medication quantity. Average days' supply per patient in 2013 for opioids was
18.9 days and in 2014 was 19.22 days. The average days'
supply per patient was 39.9 days in 2013 and 41.7 days in
2014 for benzodiazepines. Muscle relaxants' average days'
supply in 2013 was 27.8 days and in 2014 was 31.8 days.
Comparing 2013 to 2014, the prevalence of double-threat
patients rose from 5.13 million lives (1.59%) to 6.21 million
lives (1.93%), while the prevalence of triple-threat users
remained unchanged at 1.71 million lives (0.53%).

2013 Analysis
Patients on any of the study medications, double-threat, and
triple-threat were at increased probability of same year hospitalization in 2013 compared to individuals not using these
medications with triple-threat users at highest likelihood of
same year hospitalization. Opioid users had an OR of 5.63
(95% confidence interval [CI]: 5.62-5.64). Benzodiazepine
users had an OR of 3.67 (95% CI: 3.66-3.68). Muscle relaxant users had an OR of 2.42 (95% CI: 2.41-2.43). Doublethreat users had an OR of 5.71 (95% CI: 5.69-5.72).
Triple-threat users had an OR of 8.52 (95% CI: 8.50-8.55;
Table 1).

2014 Analysis
Similar to 2013 findings, patients on any of the study medications, double-threat, and triple-threat were at increased
probability of same year hospitalization in 2014 compared to
individuals not using these medications. Opioid users had an
OR of 6.72 (95% CI: 6.71-6.73). Benzodiazepine users had
an OR of 3.43 (95% CI: 3.42-3.44). Muscle relaxant users
had an OR of 1.11 (95% CI: 1.10-1.11). Double-threat users
had an OR of 11.47 (95% CI: 11.44-11.49). Triple-threat
users had an OR of 5.06 (95% CI: 5.04-5.08; Table 1).

2013 to 2014 Longitudinal Analysis
Patients exposed to the high-risk study medications in 2013
were at elevated likelihood in the following year compared
to those not on any of these medications. Opioid users had an
OR of 2.32 (95% CI: 2.32-2.32). Benzodiazepine users had
an OR of 3.11 (95% CI: 3.10-3.12). Muscle relaxant users
had an OR of 2.37 (95% CI: 2.36-2.38). Double-threat users

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had an OR of 5.59 (95% CI: 5.57-5.60). Triple-threat users
had an OR of 4.61 (95% CI: 4.59-4.63; Table 1).

Discussion
For the endpoint of hospitalization, this is the first comprehensive outcomes study of the additive probability for
patients with combined use of opioids, benzodiazepines, and
muscle relaxants using a US-representative, validated, longitudinal database from HHS. While a limited number of published studies have investigated the pharmacodynamics
salient to the additive toxicity of combined use of opioids,
benzodiazepines, and/or muscle relaxants, no health services
utilization studies have been completed.17,18 Exposure to the
multiple potentially inappropriate medications increased
hospitalization probability for patients. In 2013 and 2014,
patients on triple-threat had a minimum fourfold increased
odds of hospitalization compared to nonusers.
A limited set of prior studies have evaluated the additive
risks of prescribing benzodiazepine to patients on opioids.
The addition of concurrent muscle relaxant usage has not
been assessed to our knowledge for hospitalization endpoints
in a US national database. With growth in the number of prescriptions for benzodiazepines by 67% from 1996 to 2013,
the likelihood of concurrent use of opioids and benzodiazepines medications has also increased.17,19 Over the last decade,
deaths involving opioid overdose have more than doubled
leading to 28 647 deaths in 2014 alone.20 This number
increased to more than 42 000 deaths in 2016.21 Escalating
concurrent use of opioids, benzodiazepines, and muscle
relaxants portends growing risk of death due to additive CNS
and respiratory depression. To control combined CNS depressant use, the FDA has issued a boxed warning for combined
benzodiazepine and opioid use.22 Both the Centers for
Medicare and Medicaid Services (CMS) and the CDC have
initiated monitoring programs to detect and prevent avoidable
concurrent use of multiple CNS depressant medications.23,24
Several state-wide protocols and regulations have been
established to reduce the inappropriate use of these medications. The State of California has established a mandatory
prescription drug monitoring program (PDMP) to track
patients' dispensed controlled substances. The California
PDMP referred to as "The Controlled Substance Utilization
Review and Evaluation System" (CURES) documents
patients' dispensed controlled substances in the prior years to
provide clinicians a resource to monitor medication dispensing for possible risks. As implementation of this system,
CURES has been bolstered for integration in pharmacies
both inpatient and outpatient. Although CURES functions as
a record of the patterns of patients' prescribed medications,
this PDMP does not immediately alert the provider nor the
pharmacy of any concurrent use of these high-risk medications.25-26 Thus, medication reconciliation to address double
threat and triple threat remains constrained to the prescribers'
awareness and discretion.

Hospital Pharmacy - October 2020

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