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Signals of Muscle Relaxant Drug Interactions Associated with Unintentional Traumatic Injury: A Population-Based Screening Study

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Abstract

Background

Use of muscle relaxants is rapidly increasing in the USA. Little is understood about the role of drug interactions in the known association between muscle relaxants and unintentional traumatic injury, a clinically important endpoint causing substantial morbidity, disability, and death.

Objective

We examined potential associations between concomitant drugs (i.e., precipitants) taken with muscle relaxants (affected drugs, i.e., objects) and hospital presentation for unintentional traumatic injury.

Methods

In a series of self-controlled case series studies, we screened to identify drug interaction signals for muscle relaxant + precipitant pairs and unintentional traumatic injury. We used Optum’s de-identified Clinformatics® Data Mart Database, 2000–2019. We included new users of a muscle relaxant, aged 16–90 years, who were dispensed at least one precipitant drug and experienced an unintentional traumatic injury during the observation period. We classified each observation day as precipitant exposed or precipitant unexposed. The outcome was an emergency department or inpatient discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to estimate rate ratios adjusting for time-varying confounders and then accounted for multiple estimation via semi-Bayes shrinkage.

Results

We identified 74,657 people who initiated muscle relaxants and experienced an unintentional traumatic injury, in whom we studied concomitant use of 2543 muscle relaxant + precipitant pairs. After adjusting for time-varying confounders, 16 (0.6%) pairs were statistically significantly and positively associated with injury, and therefore deemed signals of a potential drug interaction. Among signals, semi-Bayes shrunk, confounder-adjusted rate ratios ranged from 1.29 (95% confidence interval 1.04–1.62) for baclofen + sertraline to 2.28 (95% confidence interval 1.14–4.55) for methocarbamol + lamotrigine.

Conclusions

Using real-world data, we identified several new signals of potential muscle relaxant drug interactions associated with unintentional traumatic injury. Only one among 16 signals is currently reported in a major drug interaction knowledge base. Future studies should seek to confirm or refute these signals.

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Author information

Authors and Affiliations

  1. Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA

    Ghadeer K. Dawwas, Sean Hennessy, Colleen M. Brensinger, Emily K. Acton, Warren B. Bilker, Todd A. Miano, David W. Oslin, Thanh Phuong Pham Nguyen, Samantha E. Soprano & Charles E. Leonard

  2. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Ghadeer K. Dawwas, Sean Hennessy, Colleen M. Brensinger, Emily K. Acton, Todd A. Miano, Thanh Phuong Pham Nguyen, Samantha E. Soprano, Douglas J. Wiebe & Charles E. Leonard

  3. Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA, USA

    Ghadeer K. Dawwas, Sean Hennessy, Douglas J. Wiebe & Charles E. Leonard

  4. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Sean Hennessy

  5. Translational Center of Excellence for Neuroepidemiology and Neurology Outcomes Research, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Emily K. Acton & Thanh Phuong Pham Nguyen

  6. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Warren B. Bilker & David W. Oslin

  7. AthenaHealth, Inc., Watertown, MA, USA

    Sophie Chung

  8. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    Sascha Dublin

  9. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA

    Sascha Dublin

  10. Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA

    John R. Horn

  11. Department of Pharmacy Practice, McWhorter School of Pharmacy, Samford University, Birmingham, AL, USA

    Melanie M. Manis

  12. Mental Illness Research, Education, and Clinical Center, Corporal Michael J. Crescenz Veterans Administration Medical Center, Philadelphia, PA, USA

    David W. Oslin

  13. Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Thanh Phuong Pham Nguyen

  14. Penn Injury Science Center, University of Pennsylvania, Philadelphia, PA, USA

    Douglas J. Wiebe

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  1. Ghadeer K. Dawwas
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  2. Sean Hennessy
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  7. Sascha Dublin
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  15. Charles E. Leonard
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Corresponding author

Correspondence to Charles E. Leonard.

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Funding

The US National Institutes of Health supported this work (R01AG060975, R01DA048001, R01AG064589, and R01AG025152).

Conflict of interest

GKD receives funding from the American Society of Hematology and the National Institutes of Health. CEL is an Executive Committee Member of the University of Pennsylvania’s Center for Pharmacoepidemiology Research and Training. The Center receives funds from Pfizer and Sanofi to support pharmacoepidemiology education. CEL recently received honoraria from the American College of Clinical Pharmacy Foundation and the University of Florida College of Pharmacy. CEL receives travel support from John Wiley and Sons. CEL is a Special Government Employee of the US Food and Drug Administration; he consults for their Reagan-Udall Foundation. CEL’s spouse is employed by Merck; neither she nor CEL holds stock in the company. JRH is a coauthor and publisher of The Top 100 Drug Interactions: A Guide to Patient Management and a consultant to Urovant Sciences and Seegnal US. WBB serves on multiple data safety monitoring boards for Genentech. SD has research funding from GlaxoSmithKline. SH has consulted for multiple pharmaceutical companies, and directs the University of Pennsylvania’s Center for Pharmacoepidemiology Research and Training. CMB, EKA, SC, MMM, TAM, DWO, TPPN, SES, and DJW declare no competing interests for this work.

Data availability

Data are not publicly available.

Code availability

Codes are available upon request from the corresponding author.

Author contributions

GKD wrote the manuscript. CEL, SH, and WBB designed the research. GKD, SH, CMB, EKA, WBB, SC, SD, JRH, MMM, TAM, DWO, TPPN, SES, DJW, and CEL performed the research. CMB and WBB analyzed the data. CMB and WBB contributed analytic tools. All authors approve the final version of the manuscript and agree to be accountable for the work.

Ethics approval

At the University of Pennsylvania, studies using Optum are deemed exempt by the Institutional Review Board (protocol #819924).

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Dawwas, G.K., Hennessy, S., Brensinger, C.M. et al. Signals of Muscle Relaxant Drug Interactions Associated with Unintentional Traumatic Injury: A Population-Based Screening Study. CNS Drugs 36, 389–400 (2022). https://doi.org/10.1007/s40263-022-00909-1

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