Skeletal muscle relaxant drug–drug–drug interactions and unintentional traumatic injury: Screening to detect three‐way drug interaction signals

Abstract

The aim of this study was to identify skeletal muscle relaxant (SMR) drug-drugdrug interaction (3DI) signals associated with increased rates of unintentional traumatic injury. Methods:We conducted automated high-throughput pharmacoepidemiologic screening of 2000-2019 healthcare data for members of United States commercial and Medicare Advantage health plans. 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.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.

Antidepressant drug–drug–drug interactions associated with unintentional traumatic injury: Screening for signals in real‐world data

“…Within each individual, the outcome rate during exposed person‐days was compared with unexposed person‐days, and an increased outcome rate signaled for potential 3DIs. This study design is well‐suited for 3DI screening as it controls for the effects of confounding variables that do not change over time, is highly computationally efficient, and has previously been used in high‐throughput pharmacoepidemiologic screening to identify drug interaction signals associated with injury 10,17–20 …”

“…This study design is well‐suited for 3DI screening as it controls for the effects of confounding variables that do not change over time, is highly computationally efficient, and has previously been used in high‐throughput pharmacoepidemiologic screening to identify drug interaction signals associated with injury. 10 , 17 , 18 , 19 , 20 …”

Skeletal muscle relaxants for the treatment of myofascial pelvic pain and high tone pelvic floor disorders

“…These overdose deaths mostly occur in combination with opioids, with benzodiazepines enhancing respiratory depression [28,29]. Growing data suggest that drug interactions may be responsible for much of the known association between opioid use and unintentional traumatic injury, resulting in morbidity, disability, and death [30]. Opioids such as hydrocodone, tramadol, and oxycodone have been studied to be significantly positively associated with unintentional traumatic injury [32].…”

Thinking Three‐Dimensionally: A Self‐ and Externally‐Controlled Approach to Screening for Drug–Drug–Drug Interactions Among High‐Risk Populations

“…Self‐controlled crossover observational pharmacoepidemiologic (SCOPE) designs have been proposed as potentially high‐efficiency strategies for DDI screenings. Studies using different variations of core SCOPE methods have supported their feasibility and validity in this application through successful detection of biologically plausible and/or previously established DDIs and 3DIs across a range of clinical areas 4–17 . We seek to expand on this work by testing a novel approach to screening for 3DIs that focuses on those already taking a set of purportedly interacting medications.…”

“…Studies using different variations of core SCOPE methods have supported their feasibility and validity in this application through successful detection of biologically plausible and/or previously established DDIs and 3DIs across a range of clinical areas. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] We seek to expand on this work by testing a novel approach to screening for 3DIs that focuses on those already taking a set of purportedly interacting medications. As there are a multitude of clinical scenarios that lead to the chronic co-prescription of drugs with established or suspected interactions, the goal of our approach would be to analyze the role additional drug exposures play as acute triggers for major adverse outcomes among this high-risk population.…”