Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Public Health

Major Professor

Janice Zgibor, Ph.D.

Committee Member

Henian Chen, M.D., Ph.D.

Committee Member

Kathleen O'rourke, Ph.D.

Committee Member

Chigaf Bakour, M.D., Ph.D.

Committee Member

Kaarin J. Anstey, Ph.D.

Keywords

Aging, Potentially Inappropriate Medications, Brain Atrophy, Cognitive Function

Abstract

Introduction: Multiple comorbidities are common among older adults. Pharmaceutical interventions are the most common form of medical management of the multiple health conditions that the older adult population faces. Almost 90% of adults aged 65 years and above take at least one prescription medication. Polypharmacy (5 medication or more) occurs with 50% of the older adult population. Most medications used to treat common ailments affecting the geriatric population have anticholinergic properties. These medications are known to cause a range of side effects from peripheral effects to central nervous system effects. These adverse effects are of particular concern in the older population due to age related changes that increases vulnerability to these side effects. Persistent pain is one of the most common complaint among older adults. While not the first choice of treatment for pain in this population, the use of opioids is increasing in the older adult population. Similar to anticholinergics, opioids cause multiple side effects that may be amplified in older adults. The overarching goal of this dissertation was to (1) Examine and describe the prescribing trend of anticholinergics and opioids in a population of community dwelling older adults (2) Assess the effect of anticholinergics on cognitive function and brain volume of the study population and (3) Assess the effect of opioids on cognitive function and brain volume of the study population.

Methods: For this dissertation, data from the 60+ cohort of the Personality and Total Health (PATH) Through Life study (Wave 1 (year 2005/2006) to Wave 4 (year 2014/2015)) were used. Medication data of study participants were obtained from the Pharmaceutical Benefits Scheme, which captures prescription data during the study period for all participants. Medications with anticholinergic properties were identified using the Anticholinergic Risk Scale, the Anticholinergic Drug Scale, and the American Geriatrics Society 2012 Beers Criteria. Medications classified as opioids in the World Health Organization Anatomical Therapeutic Chemical (ATC) classification was included in this dissertation. To assess the effect of opioids and anticholinergics on cognition and brain volume, exposure to these medications were quantified. Exposure to cumulative anticholinergic use was quantified to Total Standardized Daily Dose (TSDD) and exposure to cumulative opioid use was quantified to Total Morphine Equivalent Dose (MED). Cognitive measures were obtained from neuropsychological battery assessment, while magnetic resonance imaging (MRI) was used to obtain volumetric brain measures. Temporal trends of prescriptions for anticholinergics and opioids from 2004 to 2015 were examined using joinpoint regression analysis. The association between change in cognitive function and brain volume measures from baseline (wave 2) to 4-year follow-up (wave 3), and cumulative use of anticholinergics and opioids was assessed through generalized linear models. Three models were assessed. Model 1 was an unadjusted model, Model 2 adjusted only for demographic confounders, and Model 3 adjusted for multiple known confounders. Effect modification of Apolipoprotein E (APOE) epsilon 4 (ε-4) genotype was also assessed. Statistical significance was determined at p<0.01 to account for potential Type 1 error due to multiple assessments.

Results: The baseline characteristics of the PATH Through life study were: mean age of 66.6 ± 1.5 years, 51.6% male and mean years of education 13.9 ± 2.6 years. We found that the trend for anticholinergic prescriptions in the study population increased in 2004 to 2015 with an annual percent of change (APC) of 3.4%. While the trend for opioid prescriptions increased from 2004 to 2011 (APC of 11.3%) this trend changed and a decline in prescriptions of opioids was observed from 2011 to 2015 (APC of -4.4%). Cumulative use of anticholinergics over a period of 4 years which exceed a TSDD of 1095 was significantly associated with decline in Trail Making Test Part B (Model 1: β=5.77, Model 2: β=5.33, Model 3: β=8.32, p<0.01). No significant association was seen between anticholinergic use and brain volume. Among those exposed to anticholinergics amounting to a TSDD between 366 to 1095, compared to those without the APOE ε-4 allele, individuals with 2 alleles experienced a significant decline in their Trail Making Test Part B performance (β=78.82, p<0.01). Compared to those not on opioids, individuals exposed to opioids resulting in total MED of greater than 2940 had significantly lower scores in the Mini Mental State Examination (Model 1: β= -0.34, Model 2: β= -0.35, and Model 3: β= -0.39, p<0.01). Among those with this highest level of cumulative opioid exposure, individuals with two APOE ε-4 alleles had significantly greater decline in their Immediate Recall ( β= -5.71, p<0.01) and Delayed Recall (β= -7.38, p<0.001) assessments compared to those without the alleles. Opioid use was not significantly associated with changes in brain volume and white matter hyperintensities during the study period.

Conclusion: Results from this dissertation show that among older adults, chronic exposure to high doses of anticholinergics and opioids result in greater cognitive decline. While pharmaceutical management of co-morbidities in this population is inevitable, these findings support the need to approach the use of these medications with caution in geriatric populations to avoid adversely affecting healthy aging trajectories and cognitive health of older adults.

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