The Cumulative Use of Muscle Relaxants and the Risk of Alzheimer's Disease: A Nationwide Case-Control Study

Background: Use of pharmacological treatments is one possible modifiable risk factor for cognitive disorders. Objective: To investigate if the use of muscle relaxants is associated with the risk of Alzheimer's disease (AD). Methods: The study was performed in a nested case-control design. Altogether 70,718 community-dwelling residents of Finland who received AD diagnosis in 2005-2011 were included as cases (the MEDALZ study). Each case was matched with four controls without AD by age, sex, and region of residence (N= 282,858). Data was extracted from Prescription register (1995-2012), Special Reimbursement register (1972-2012), and Hospital Discharge register (1972-2012). Drug use periods were modeled with PRE2DUP-method. Defined daily dose (DDD) was used to quantify the use. Analyses were conducted for any muscle relaxant use, and drug specific analyses were done for orphenadrine and tizanidine. A five-year lag window prior to the diagnosis was used, and results analyzed with conditional logistic regression. Results: The use of any muscle relaxant was associated with the risk of AD, aOR (95% CI) 1.04 (1.02-1.07). Stronger associations were observed with longer use (>366 days, aOR 1.12 (1.03-1.21)) than shorter use (1-365 days aOR, 1.04 (1.02-1.06)) compared to non-users. Dose-response was not observed. Tizanidine was not associated with AD, whereas cumulative exposure of orphenadrine (>= 101 DDDs) was associated with the risk of AD, aOR 1.19 (1.07-1.32). Conclusion: Muscle relaxant use was associated with the risk of AD and higher exposure to orphenadrine showed increased risk. Further studies on higher doses and longer durations of use are warranted.