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Table 1.  
Characteristics of REGARDS Study Participants
Characteristics of REGARDS Study Participants
Table 2.  
Association of Opioid Use With Atrial Fibrillation in REGARDS Participants
Association of Opioid Use With Atrial Fibrillation in REGARDS Participants
1.
Parsells Kelly  J, Cook  SF, Kaufman  DW, Anderson  T, Rosenberg  L, Mitchell  AA.  Prevalence and characteristics of opioid use in the US adult population. Pain. 2008;138(3):507-513.
PubMedArticle
2.
Lendeckel  U, Müller  C, Röcken  C,  et al.  Expression of opioid receptor subtypes and their ligands in fibrillating human atria. Pacing Clin Electrophysiol. 2005;28(suppl 1):S275-S279.
PubMedArticle
3.
Howard  VJ, Cushman  M, Pulley  L,  et al.  The reasons for geographic and racial differences in stroke study: objectives and design. Neuroepidemiology. 2005;25(3):135-143.
PubMedArticle
4.
Soliman  EZ, Howard  G, Meschia  JF,  et al.  Self-reported atrial fibrillation and risk of stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Stroke. 2011;42(10):2950-2953.
PubMedArticle
5.
Woodcock  J.  A difficult balance—pain management, drug safety, and the FDA. N Engl J Med. 2009;361(22):2105-2107.
PubMedArticle
6.
Holmuhamedov  EL, Wang  L, Terzic  A.  ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria. J Physiol. 1999;519(pt 2):347-360.
PubMedArticle
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Research Letter
June 2015

Association Between Opioid Use and Atrial FibrillationThe Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study

Author Affiliations
  • 1Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
  • 2Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
  • 3School of Medicine, Department of Medicine, University of Alabama at Birmingham
  • 4School of Public Health, Department of Biostatistics, University of Alabama at Birmingham
  • 5School of Public Health, Department of Epidemiology, University of Alabama at Birmingham
  • 6Epidemiological Cardiology Research Center, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
JAMA Intern Med. 2015;175(6):1058-1060. doi:10.1001/jamainternmed.2015.1045

It has been estimated that more than 4.3 million adults in the United States are taking opioids regularly in any given week.1 Opioid receptors are downregulated in animal models of atrial fibrillation (AF).2 However, to our knowledge, the association between opioid use and AF has not been examined in population-based studies. We examined the cross-sectional association between prescription opioid use and AF using data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.3

Methods

Details of the REGARDS study and its design have been published.3 Briefly, between January 25, 2003, and October 30, 2007, a total of 30 239 participants were recruited using postal mailings and telephone calls from across the United States. Demographic information, medical histories, blood tests, and electrocardiograms were obtained using a computer-assisted telephone interview system and in-home study visits by trained staff. The study was approved by the institutional review boards at all participating centers. Oral informed consent was obtained; the participants received financial compensation. Atrial fibrillation was identified by electrocardiogram and self-reported history of a previous physician-determined diagnosis.4 Opioid use was ascertained by pill-bottle review during the in-home visit. The association between opioid use and AF was examined in multivariable adjusted logistic regression models using SAS, version 9.3 (SAS Institute Inc). Subgroup analyses were performed.

Results

A total of 24 632 participants (mean [SD] age, 65 [9.4] years; 54.0% women; 40.2% black) were included in the analysis. A total of 1887 participants (7.7%) reported opioid use, and 2086 individuals (8.5%) had AF. The most commonly used opioid was hydrocodone (779 [41.3%] of opioid users), followed by propoxyphene (470 [24.9%] of opioid users) and tramadol (378 [20.0%] of opioid users). Several differences were observed between opioid users and nonusers. Opioid users were slightly younger and more likely to be female, black, and have cardiovascular comorbidities (Table 1). The prevalence of AF was higher in opioid users than nonusers (12.5% vs 7.6%; P < .001). As reported in Table 2, opioid use was associated with increased odds of AF (odds ratio [OR], 1.35 [95% CI, 1.16-1.57]) after adjustment for potential confounders, and the results were consistent in several subgroups of the REGARDS study participants. Since it is possible that this association could be confounded by substance abuse, we further adjusted for benzodiazepine and alcohol use. The association remained statistically significant (OR, 1.29 [95% CI, 1.11-1.51]). In addition, given the known cardiotoxic effects of propoxyphene, we excluded 434 participants receiving this drug in a sensitivity analysis, and the association remained statistically significant (OR, 1.33 [95% CI, 1.11-1.58]).

Discussion

In this analysis of data from the REGARDS study, opioid use was independently associated with increased prevalence of AF. Propoxyphene has been linked with fatal cardiac arrhythmias that led to cessation of its sales in the United States.5 However, chronic arrhythmias (eg, AF) have not been linked with opioid use. Endogenous opioid peptides open mitochondrial potassium adenosine triphosphate channels, making mitochondria resistant to oxidative stress during episodes of ischemia. Loss of this protective mechanism against oxidative stress may render atrial myocytes amenable to damage, leading to AF.6

Our study has limitations, including the cross-sectional design, possibility of residual confounding by unmeasured factors, and lack of data on opioid dosage and length of therapy. In addition, the use of self-reported history of a previous physician diagnosis as one of the methods to ascertain AF is subject to recall bias.

Using data from the REGARDS study, we have shown that opioid use is associated with an increased prevalence of AF. During the past 2 decades, there have been significant increases in both opioid use and AF in the United States. These increases represent a parallel temporal trend that needs further investigation.

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Article Information

Corresponding Author: Waqas T. Qureshi, MD, Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157 (wqureshi@wakehealth.edu).

Published Online: April 27, 2015. doi:10.1001/jamainternmed.2015.1045.

Author Contributions: Drs Khodneva and Soliman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Qureshi, Safford, Soliman.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Qureshi, O’Neal, Safford, Soliman.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: O’Neal, Khodneva, Muntner.

Obtained funding: Judd, Safford, Soliman.

Administrative, technical, or material support: Judd, Safford, Muntner.

Study supervision: Qureshi, Safford, Soliman.

Conflict of Interest Disclosures: None reported.

Funding/Support: The REGARDS study is supported by cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services.

Role of the Funder/Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Virginia Howard, PhD, and George Howard, PhD (Department of Epidemiology University of Alabama at Birmingham), helped in drafting, supervising, and providing guidance in performing this study. They received no financial compensation. We thank the investigators, staff, and participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org.

References
1.
Parsells Kelly  J, Cook  SF, Kaufman  DW, Anderson  T, Rosenberg  L, Mitchell  AA.  Prevalence and characteristics of opioid use in the US adult population. Pain. 2008;138(3):507-513.
PubMedArticle
2.
Lendeckel  U, Müller  C, Röcken  C,  et al.  Expression of opioid receptor subtypes and their ligands in fibrillating human atria. Pacing Clin Electrophysiol. 2005;28(suppl 1):S275-S279.
PubMedArticle
3.
Howard  VJ, Cushman  M, Pulley  L,  et al.  The reasons for geographic and racial differences in stroke study: objectives and design. Neuroepidemiology. 2005;25(3):135-143.
PubMedArticle
4.
Soliman  EZ, Howard  G, Meschia  JF,  et al.  Self-reported atrial fibrillation and risk of stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Stroke. 2011;42(10):2950-2953.
PubMedArticle
5.
Woodcock  J.  A difficult balance—pain management, drug safety, and the FDA. N Engl J Med. 2009;361(22):2105-2107.
PubMedArticle
6.
Holmuhamedov  EL, Wang  L, Terzic  A.  ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria. J Physiol. 1999;519(pt 2):347-360.
PubMedArticle
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