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A Sequence Symmetry Analysis

Scott R. Garrison, MD; Colin R. Dormuth, ScD; Richard L. Morrow, MA; Greg A. Carney, BSc; Karim M. Khan, MD, PhD

Arch Intern Med. 2012;172(2):120-126. doi:10.1001/archinternmed.2011.1029

Background  The use of diuretics, statins, and inhaled long-acting β2-agonists (LABAs) is linked to muscle cramps but largely by anecdotal evidence. This study sought population-level data to better evaluate these associations.

Methods  Linked health care databases containing prescribing information (December 1, 2000, to November 30, 2008) about 4.2 million residents of British Columbia, Canada, were evaluated using sequence symmetry analysis to determine in adults 50 years or older whether new quinine prescriptions (initiations of cramp treatment) increase in the year following diuretic, statin, or LABA starts. The statistic of interest was the sequence ratio: the number of quinine starts in the year following index drug introduction compared with the number of quinine starts in the preceding year (adjusted for age and time trends in population prescribing).

Results  Adjusted sequence ratios (95% CIs) for the 3 drug classes were 1.47 (1.33-1.63 [P < .001]) for diuretics, 1.16 (1.04-1.29 [P = .004]) for statins, and 2.42 (2.02-2.89 [P < .001]) for LABAs. For diuretic subclasses, adjusted sequence ratios (95% CIs) were 2.12 (1.61-2.78 [P < .001]) for potassium sparing, 1.48 (1.29-1.68 [P < .001]) for thiazidelike, and 1.20 (1.00-1.44 [P = .07]) for loop. For LABA subclasses, adjusted sequence ratios (95% CIs) were 2.17 (1.56-3.02) for LABAs alone and 2.55 (2.06-3.12) for LABAs-corticosteroids (P < .001 for both).

Conclusions  Cramp treatment was substantially more likely in the year following introduction of LABAs, potassium-sparing diuretics, or thiazidelike diuretics, and 60.3% of quinine users (individuals experiencing cramp) received at least 1 of these medications during a 13-year period. In contrast, statin and loop diuretic associations were small. Physicians should be mindful that the use of these medications may worsen symptoms in patients experiencing nocturnal leg cramps.

Author Affiliations: Therapeutics Initiative (Drs Garrison and Dormuth and Messrs Morrow and Carney), Centre for Hip Health and Mobility (Drs Garrison and Khan), and Department of Anesthesiology (Dr Dormuth), University of British Columbia, Vancouver, Canada.

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