Opioid use in the elderly is associated with an almost 40% increased risk of dementia, in new findings that suggest exposure to these drugs may be another modifiable risk factor for dementia.

“Clinicians and others may want to consider that opioid exposure in those aged 75-80 increases dementia risk, and to balance the potential benefits of opioid use in old age with adverse side effects,” Stephen Z. Levine, PhD, professor, Department of Community Mental Health, University of Haifa, Israel, told Medscape Medical News.

The study was published online May 31 in The American Journal of Geriatric Psychiatry.

Widespread Use

Evidence points to a relatively high rate of opioid prescriptions among older adults. A Morbidity and Mortality Weekly Report (MMWR) noted 19.2% of the US adult population filled an opioid prescription in 2018, with the rate in those over 65 double that of adults aged 20-24 years (25% vs 11.2%).

Disorders and illnesses for which opioids might be prescribed, including cancer and some pain conditions, “are far more prevalent in old age than at a younger age,” said Levine.

This high rate of opioid use underscores the need to consider the risks of opioid use in old age, said Levine. “Unfortunately, studies of the association between opioid use and dementia risk in old age are few, and their results are inconsistent.”

The study included 91,307 Israeli citizens aged 60 and over without dementia who were enrolled in the Meuhedet Healthcare Services, a nonprofit health maintenance organization (HMO) serving 14% of the country’s population. Meuhedet has maintained an up-to-date dementia registry since 2002.

The average age of the study sample was 68.29 years at the start of the study (in 2012).

In Israel, opioids are prescribed for a 30-day period. In this study, opioid exposure was defined as opioid medication fills covering 60 days (or two prescriptions) within a 120-day interval.

The primary outcome was incident dementia during follow-up from January 1, 2013 to October 30, 2017. The analysis controlled for a number of factors, including age, sex, smoking status, health conditions such as arthritis, depression, diabetes, osteoporosis and cognitive decline, vitamin deficiencies, cancer, cardiovascular conditions, and hospitalizations for falls.

Researchers also accounted for the competing risk of mortality.

During the study, 3.1% of subjects were exposed to opioids at a mean age of 73.94 years and 5.8% of subjects developed dementia at an average age of 78.07 years.

Increased Dementia Risk

The risk of incident dementia was significantly increased in those exposed to opioids vs unexposed individuals in the 75-80–year age group (adjusted hazard ratio [AHR] 1.39; 95% CI, 1.01-1.92; Z-statistic = 2.02, P < .05).

The authors noted the effect size for opioid exposure in this elderly age group is like other potentially modifiable risk factors for dementia, including body mass index and smoking.

The current study could not determine the biological explanation for the increased dementia risk among older opioid users. “Causal notions are challenging in observational studies and should be viewed with caution,” noted Levine.

However, a plausible mechanism highlighted in the literature is that opioids promote apoptosis of microglia and neurons that contribute to neurodegenerative diseases, he said.

The study included 14 sensitivity analyses, including those that looked at females, subjects over age 70, smokers, and groups with and without comorbid health conditions. The only sensitivity analysis that didn’t have similar findings to the primary analysis looked at dementia risk restricted to subjects without a vitamin deficiency.

“It’s reassuring that 13 or 14 sensitivity analyses found a significant association between opioid exposure and dementia risk,” said Levine.

Some prior studies did not show an association between opioid exposure and dementia risk. One possible reason for the discrepancy with the current findings is that the previous research didn’t account for age-specific opioid use effects, or the competing risk of mortality, said Levine.

Clinicians have a number of potential alternatives to opioids to treat various conditions including acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), amine reuptake inhibitors (ARIs), membrane stabilizers, membrane stabilizers, muscle relaxants, topical capsaicin, botulinum toxin, cannabinoids, and steroids.

A limitation of the study was that it didn’t adjust for all possible comorbid health conditions, including vascular conditions, or for use of benzodiazepines, and surgical procedures.

In addition, since up to 50% of dementia cases are undetected, it’s possible some in the unexposed opioid group may actually have undiagnosed dementia, thereby reducing the effect sizes in the results.

Reverse causality is also a possibility as the neuropathological process associated with dementia could have started prior to opioid exposure. In addition, the results are limited to prolonged opioid exposure.

Interpret With Caution

Commenting on the study for Medscape, David Knopman, MD, a neurologist at Mayo Clinic in Rochester, Minnesota, whose research involves late-life cognitive disorders, was skeptical.

“On the face of it, the fact that an association was seen only in one narrow age range — 75+ to 80 years — ought to raise serious suspicion about the reliability and validity of the claim” that opioid use is a risk factor for dementia, he said.

Although the researchers performed several sensitivity analyses, including accounting for mortality, “pharmacoepidemiological studies are terribly sensitive to residual biases” related to physician and patient choices related to medication use, added Knopman.

The claim that opioids are a dementia risk “should be viewed with great caution” and should not influence use of opioids where they’re truly indicated, he said.

“It would be a great pity if patients with pain requiring opioids avoid them because of fears about dementia based on the dubious relationship between age and opioid use.”

Levine and Knopman report no relevant financial disclosures.

Am J Geriatr Psychiatry. Published online May 31, 2022. Source.

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