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Research Letter
May 9, 2017

Association Between Long-term Quinine Exposure and All-Cause Mortality

Author Affiliations
  • 1EA 7379 EpiDermE, Université Paris Est Créteil, Créteil, France
  • 2Department of Primary Care and Population Health, University College London, London, United Kingdom
JAMA. 2017;317(18):1907-1909. doi:10.1001/jama.2017.2332

Quinine has been used since the 1930s to treat idiopathic muscular cramps. However, in 2006, because of efficacy and safety issues, the US Food and Drug Administration cautioned about this off-label use of quinine, citing “665 reports of adverse events with serious outcomes…including 93 deaths.”1 Despite warnings, quinine is still prescribed to individuals with idiopathic muscular cramps. Furthermore, many drinks such as bitter lemon or tonic waters contain quinine, and hence, many may be exposed to quinine daily. This study explored the association between long-term quinine exposure and all-cause mortality.

This study used data recorded in The Health Improvement Network (THIN), a UK primary care database containing anonymized data on more than 12 million individuals representative of the UK population.2 The protocol for THIN to obtain and provide anonymous patient data was approved by a national ethics committee in 2002; need for informed consent was waived. Adults who received incident quinine salt (sulfate, bisulfate, dihydrochloride) prescriptions for idiopathic muscular cramps or restless leg syndrome for at least 1 year from January 1990 to December 2014 (last follow-up December 2015) at a mean dosage of 100 mg/d or more were considered to be exposed. This definition was chosen because the period of risk is unknown and most patients stopped quinine within weeks of death. The start date (ie, start of at-risk period) was defined as the first day of the first prescription of quinine. Individuals with muscular cramps or restless leg syndrome, never exposed to quinine or its derivatives, and with at least 1-year follow-up after a randomly selected start date were eligible to be included in the unexposed sample. Three unexposed individuals were selected for every exposed individual. The samples were stratified by sex and age. Group characteristics were compared using the χ2 test or the Wilcoxon rank-sum test. The primary outcome (all-cause mortality) was compared between the exposed and the unexposed populations using Cox proportional hazards models adjusted for sociodemographic data, underlying conditions, and concomitant prescriptions. Post hoc subgroup analyses were conducted by age and amount of exposure (averaged over the exposure period). The proportional hazards assumption for Cox models was checked graphically using the Schoenfeld residuals. Analyses were done using Stata (StataCorp), version 14.0. A 2-sided P value less than .05 denoted statistical significance.

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