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\begin{document}

\title{Skeletal Muscle Relaxant Drug-Drug-Drug Interactions and Unintentional
Traumatic Injury: Screening to Detect Three-Way Drug Interaction Signals}



\author[1]{Cheng Chen}%
\author[1]{Sean Hennessy}%
\author[1]{Colleen Brensinger}%
\author[1]{Ghadeer Dawwas}%
\author[1]{Emily Acton}%
\author[1]{Warren Bilker}%
\author[2]{Sophie Chung}%
\author[3]{Sascha Dublin}%
\author[4]{John Horn}%
\author[1]{Todd Miano}%
\author[1]{Thanh Phuong Pham Nguyen}%
\author[1]{Samantha Soprano}%
\author[1]{Charles Leonard}%
\affil[1]{University of Pennsylvania}%
\affil[2]{Athenahealth Inc}%
\affil[3]{Kaiser Permanente Washington Health Research Institute}%
\affil[4]{University of Washington}%


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  \date{May 20, 2024}


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\begin{abstract}
Background and Purpose. Skeletal muscle relaxants (SMRs) are commonly
co-prescribed with potentially interacting medications that may
contribute to increased risk of unintentional traumatic injury
(hereafter, injury). While prior research has investigated clinical
outcomes for some pairwise drug interactions involving SMRs, drug
interactions involving more than two drugs, such as drug triads (3DIs),
largely remain unexamined. We sought to identify SMR 3DI signals
associated with injury via automated high-throughput
pharmacoepidemiologic screening of 2000--2019 healthcare data for
members of commercial and Medicare Advantage health plans. Experimental
Approach. We performed a self-controlled case series study for each drug
triad consisting of an SMR base pair (i.e., concomitant use of an SMR
with another medication), and a co-dispensed medication (i.e., candidate
interacting precipitant) taken during ongoing use of the base pair. We
included patients aged [?]16 years with an injury occurring during base
pair-exposed observation time. We used conditional Poisson regression to
calculate adjusted rate ratios (RRs) with 95\% confidence intervals
(CIs) for injury with each SMR base pair + candidate interacting
precipitant (i.e., triad) versus the SMR-containing base pair alone. Key
Results. Among 58,478 triads, 29 were significantly positively
associated with injury; confounder-adjusted RRs ranged from 1.39 (95\%
CI=1.01--1.91) for tizanidine+omeprazole with gabapentin to 2.23 (95\%
CI=1.02--4.87) for tizanidine+diclofenac with alprazolam. Most
identified 3DI signals are new and have not been formally investigated.
Conclusions and Implications. We identified 29 SMR 3DI signals
associated with increased rates of injury. Future etiologic studies
should confirm or refute these SMR 3DI signals.%
\end{abstract}%



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