Chronic Pain, Analgesics, and Cognitive Status: A Comprehensive Mendelian Randomization Study

Abstract

BACKGROUND: Observational studies have suggested an intricate relationship among chronic pain (CP), use of analgesics, and cognitive status, but it remains unclear whether these associations are of a causal nature. METHODS: To investigate the causal relationship among them, summary statistics of 9 types of CP (headache, hip, neck/shoulder, stomach/abdominal, back, knee, facial, general, and multisite CP), analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], opioids, salicylic acid and derivatives, and anilides), and cognitive status (cognitive function, Alzheimer’s disease [AD], vascular dementia, Lewy body dementia [LBD], and dementia) were included in this Mendelian randomization (MR) study. As both CP and analgesic use were associated with cognitive status and vice versa, we performed a bidirectional MR analysis between CP or analgesics and dementia using strong genetic instruments (P < .001) identified from genome-wide association studies (GWAS). The inverse-variance weighted method was applied to calculate estimates. The MR estimated odds ratio (OR) was interpreted as odds of outcome per unit increase in the exposure. The Benjamini-Hochberg method was applied to adjust the P value for multiple testing, and P < .05 means statistically significant. RESULTS: Multisite CP (MCP) was associated with worse cognitive function (OR [95% confidence interval], 0.69 [0.53–0.89], P = .043), but no significant reverse effect of cognitive status on CP was found. There were no significant associations observed between analgesics and cognitive status. Unexpectedly, patients with AD and LBD had significantly lower exposure to anilides (AD: OR = 0.97 [0.94–0.99], P = .034; LBD: OR = 0.97 [0.96–0.99], P = .012) and NSAIDs (AD: OR = 0.96 [0.93–0.98], P = .012; LBD: OR = 0.98 [0.96–0.99], P = .034). CONCLUSIONS: Our findings indicate that an elevated number of CP sites predict future cognitive decline. Patients with dementia had lower exposure to anilides and NSAIDs, suggesting that they might not be adequately medicated for pain.

Interpretation and Considerations in the Mendelian Randomization Study on Chronic Pain, Analgesics, and Cognitive Status

“…The authors concluded that multisite chronic pain is associated with a future decline in cognitive function while patients with dementia, especially Alzheimer's disease and Lewy body dementia, have a significantly lower prevalence of nonsteroidal anti-inflammatory drugs (NSAIDs) and anilides use, contributing greatly to our understanding of the comprehensive causality of chronic pain, analgesics, and cognitive status. 1 However, we have some concerns about the findings in this MR study.…”

“…To the Editor W e read with great interest the recently published Mendelian randomization (MR) study by Guo et al 1 entitled "Chronic pain, analgesics, and cognitive status: a comprehensive Mendelian Randomization study." The authors concluded that multisite chronic pain is associated with a future decline in cognitive function while patients with dementia, especially Alzheimer's disease and Lewy body dementia, have a significantly lower prevalence of nonsteroidal anti-inflammatory drugs (NSAIDs) and anilides use, contributing greatly to our understanding of the comprehensive causality of chronic pain, analgesics, and cognitive status.…”

“…Second, analgesics are given for pain, and pain might increase the risk of decline in cognitive function as author reported. 1 Besides, over the same period patients might take prescription opioid and other common pain medications, including anilides, salicylic acid, and NSAIDs, so that the synergy of them might contribute to the final association. The combination of pain medication with site-specific pain or multiple pains and the combined effect of prescribed opioid use with nonopioid pain medication on cognitive function may need to be considered to derive a more robust cause-and-effect relationship and genetic liabilities.…”

In Response

“…We appreciate the comments provided by Zhang et al 1 on our study. 2 In their comments, they highlighted the possibility of confounding factors, such as body mass index (BMI) and lifestyle, contributing to the inconsistent findings between our Mendelian randomization (MR) analyses and the observational studies on site-specific chronic pain in dementia. Confounders are usually third variables associated with both the exposure and outcome, which makes them seem related when they are not.…”

“…First, as it was reported in the existing observational studies, patients with chronic pain have poorer cognitive function and a higher risk of dementia, but the data in the MR study only showed that only MCP, but not site-specific chronic pain or general chronic pain. 2 The inconsistent findings of MR analyses and observational studies are worthy of thought. Some confounding factors such as body mass index, lifestyle (initiation of smoking, alcohol consumption, etc), and gender may mediate causal associations, as our previous MR study and others have found a causal relationship between multisite chronic pain and body mass index and smoking.…”