Opioids Tied to Higher Dementia Risk, but Only After a Point

After a certain threshold, cumulative opioid use was associated with higher dementia risk, a study of adults over age 60 in Denmark showed.

In a nested case-control study, opioid use above 90 total standardized doses (TSDs) was associated with increased all-cause dementia risk, reported Nelsan Pourhadi, MD, of Copenhagen University Hospital Rigshospitalet in Denmark, and co-authors.

Cumulative opioid exposure of 91 to 200 TSDs yielded an increased dementia incidence rate ratio (IRR) of 1.29 (95% CI 1.17-1.42) for people diagnosed with dementia at ages 60-69, Pourhadi and colleagues wrote in JAMA Network Open. Exposure greater than 500 TSDs had an IRR of 1.59 (95% CI 1.44-1.76).

Corresponding IRRs were 1.16 (95% CI 1.11-1.22) and 1.49 (95% CI 1.42-1.57) for people diagnosed with dementia at ages 70-79, and 1.08 (95% CI 1.03-1.14) and 1.21 (95% CI 1.16-1.27) for those diagnosed at ages 80-89.

There was no significant association between opioid use below 90 TSDs and dementia incidence, the researchers said. The threshold of 90 TSDs corresponded to 90 treatment days of a standard dose of opioids at 30 morphine milligram equivalents per day.

The overall relationship between exposure above 90 TSDs and dementia persisted among individuals with chronic noncancer pain diagnoses and those who used weak opioids only.

“Opioids are widely used for chronic noncancer pain, yet their long-term effect on cognition and dementia are not fully understood,” Pourhadi told MedPage Today.

“Our study by its observational nature cannot infer causality, but I hope it inspires further research into the long-term impact of opioids on cognition and dementia,” he added.

Some earlier studies have found slightly positive correlations between heavy opioid use and dementia, and some have not. Other research has tracked chronic pain and cognitive function.

Pourhadi and co-authors conducted a nested case-control study using data from national Danish registers of people ages 60 and older without previous dementia, cancer, opioid addiction, or opioid use in terminal illness. They matched individuals who developed dementia during follow-up with five dementia-free controls.

Cumulative opioid exposure was based on filled prescriptions from 1995 through 2020. The researchers used a 5-year lag-time window to address possible reverse causality and omitted opioid prescriptions redeemed within 5 years of index date (date of dementia diagnosis).

About 1.9 million people were included in the study. Of these, 93,638 (5.0%) developed dementia during follow-up; they were matched with 468,190 controls. Both groups included 55% women. Median age at opioid initiation was about 66, median follow-up time was 11.8 years, and median age at dementia diagnosis was 78. Results were adjusted for demographic and health-related confounders.

Cumulative opioid exposure up to 90 TSDs was not consistently associated with dementia risk, the researchers pointed out. Opioid use also did not show a statistically significant association with dementia that occurred at age 90 or older.

The strong opioids used most frequently in the study were oral morphine and oxycodone. The weak opioid used most often was oral tramadol. Exclusive use of weak opioids was associated with increased IRRs of dementia, ranging from 1.15 (95% CI 1.08-1.22) for dementia diagnoses at ages 60-69 to 1.07 (95% CI 1.03-1.11) for diagnoses at ages 80-89.

Information about opioid exposure before 1995 was not available and the cumulative amount of opioids used in this study may have been underestimated, Pourhadi and colleagues acknowledged.

The researchers also could not differentiate between opioid use and underlying disorders that led to treatment. Information about the severity and duration of chronic pain also was unavailable.