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Could Chronic Pain Increase Risk of Cognitive Decline?

November 5, 2020
Clinical understanding of Alzheimer’s disease in relation to pain is growing – and may soon help clinicians provide more thorough assessments and treatment plans.

Chronic pain is common in elderly patients, including those with neurodegenerative conditions such as Alzheimer’s disease. However, recent data point to a potential link by which the presence of chronic pain actually may increase one’s risk for developing Alzheimer’s disease (AD) and similar cognitive problems in later life.

However, recent data point to a potential link by which the presence of chronic pain actually may increase one’s risk for developing Alzheimer’s disease and similar cognitive problems in later life. (Image: iStock)


Basis in Brain Biology

Data on the biologic relationship between pain and AD were recently published in the Journal of Neuroinflammation. The paper described the interaction of two processes: locus coeruleus noradrenergic system dysfunction and neuroinflammation caused by microglial pro-inflammatory activity in the brain.1

In the review, Song Cao, MD, of the Affiliated Hospital of Zunyi Medical University, Guizhou, China, and colleagues, wrote that “chronic pain is associated with increased self-rated and objective cognitive deficits,” although these deficits were not specific to a particular pain modality. His team discussed the potential mechanism behind the connection of chronic pain and AD and explained that “Chronic pain induces pathological activation of the locus coeruleus (LC)-noradrenaline (NE) system.” The resulting increase in noradrenaline in certain areas of the brain (eg, the prefrontal cortex and hippocampus) “could be one of the mechanisms of chronic pain-induced microglial pro-inflammatory activation,” they stated.

The team further hypothesized that this pro-inflammatory activation could contribute to the development of Alzheimer's through various avenues, including accumulation of amyloid-β peptide (Aβ) aggregates, loss of synaptic function, and cytokine-induced neuron death.

However, “Whether chronic pain induces neuronal loss in the LC has not been reported yet, but it is possible, especially with long-lasting pain (defined as > 3 months),” the researchers noted, recommending: 

“Studies to examine whether chronic pain can induce or aggravate cognitive deficits as well as behavioral and psychiatric symptoms in aged and AD models would be helpful in beginning to confirm a causal relationship, and tracking AD-related biomarkers and pro-inflammatory factors released from activated microglia in brain regions related to AD pathogenesis, such as the PFC and hippocampus, would further help define pathological mechanisms.”

Clinical Data Support Pain and AD Connection

Data from a separate population-based cohort study published in the International Journal of Environmental Research and Public Health in 2020 showed an association between non-cancer chronic pain conditions (NCPC) at baseline and increased risk for incident AD and related dementias (ADRD) two years later.2 The longitudinal study included 11 pooled cohorts for the years 2001 to 2013 from the US Medicare Current Beneficiaries Survey for a total of 1,934 adults aged 65 years and older in the United States. The participants were free of ADRD at baseline, and the prevalence of NCPC was 36%.

After controlling for variables including sociodemographics, lifestyle characteristics, medications and medical history, NCPC was significantly associated with increased risk for ADRD after two years, with an adjusted odds ratio of 1.21 for any NCPC vs. no NCPC.2

Sumaira Khalid, MSPH, PharmD, of the West Virginia University School of Public Health, Morgantown, and colleagues, noted that the association increased significantly with the number of NCPCs, with an OR of 1.91 for four or more NPCs compared with zero, but was partly mediated by mood and sleep disorders. (Of note, Dr. Khalid’s study was supported by the National Institutes of Health and Alzheimer’s Research and Prevention Foundation.)

Although the researchers noted that prospective studies are needed to confirm their findings, “a growing literature suggests chronic pain can disrupt neurocognitive function and may increase risk for cognitive decline and incident dementia, whereas evidence for an inverse relationship remains sparse,” they wrote.

In a separate study published in 2019 in Osteoarthritis Cartilage, Mohammed Ikram, M.Pharm, MBA, of the West Virginia School of Pharmacy in Morgantown, and colleagues examined the possible association between pain interference from osteoarthritis and an increased risk for AD and related dementias (ADRD).3  Ikram’s team conducted a retrospective cross-sectional study of US adults aged 65 years and older. The study population included 25,009 individuals pooled from 2009-2015 Medical Expenditure Panel Survey (MEPS) data.

Overall, 27.1% of their sample had OA and 47.6% of these individuals reported pain interference, defined as frequent pain interfering with normal activities (PIA).3

After adjusting for multiple factors including demographics, socioeconomic status, behavior and lifestyle, type of insurance, chronic health conditions, medication use, region, and year, ADRD was found to be significantly more prevalent among individuals with PIA, with or without OA, compared to those with no OA (adjusted odds ratios of 1.37 and 1.86, respectively, P = 0.041) or PIA (aOR 1.44 and 1.82, respectively, P < 0.003).3

The data from this published population-based cross-sectional study of pain and ADRD in the United States reflect findings from similar studies in other countries, the researchers shared.

While mechanisms underlying the observed association of OA and PIA to ADRD remain unknown, OA and PIA may contribute to cognitive decline and subsequent development of ADRD via both direct and indirect pathways,” Ikram’s team wrote. “For example, as discussed above, pain, both in the presence and absence of OA, may lead to adverse changes in brain structure and function and in CNS activation and sensitivity that increase risk for cognitive dysfunction and ultimately, ADRD.”

Challenges of Alzheimer's Diagnosis and Treatment in Patients with Chronic Pain

A 2019 review published in Pain Therapy examined key challenges of pain management in elderly adults with cognitive decline.4 In this population, pain is often underestimated, underreported, misdiagnosed, and undertreated, wrote Luca Cravello, MD, of Passirana di Rho Hospital, Milan, Italy, and colleagues in their paper.

“The complexity of patients with dementia makes it difficult not only to make a correct diagnosis of pain but also to start adequate treatment,” Dr. Cravello emphasized.To help make a correct diagnosis, the reviewers advised using validated and standardized pain assessment scales. Self-assessment scales are appropriate for those with mild to moderate cognitive impairment, while observational scales can be used for those with more severe impairment.

When it comes to treating pain in adults with cognitive impairment, “The first consideration is to use appropriate pain assessment methods and to correctly set the diagnosis in order to choose the most appropriate drug therapy and avoid the use of inappropriate, potentially harmful drugs,” Dr. Cravello said. Clinical trial data on the effectiveness of treatment strategies in this patient population are limited, so most guidance is based on clinical experience, he noted.

Effective strategies should involve “careful training of caregivers, analyzing the patient’s risk factors and comorbidities, and carefully monitoring the patient over time,” and can include both pharmacologic and nonpharmacologic elements, Dr. Cravello added.

Further Considerations and Future Directions

It is worth remembering that chronic pain can have different meanings, noted Glenn J. Treisman, MD, PhD, a professor of psychiatry and medicine at Johns Hopkins University in Baltimore, in an interview with PPM.

Chronic pain may emerge as a result of tissue that is damaged, and also from an adaptation in the nervous system, he clarified. The inflammatory system is a processor, like the brain, and exploration of the relationship between the brain and inflammatory system is “a very exciting area of medicine right now,” he added.

“We used to think that AD was purely a result of the development of sheets of protein, the amyloid plaques in the brain,” said Dr. Treisman. However, recent research suggests that there is more of a role for other cells, the microglia, and that inflammatory damage plays a role, he explained. This evolution has sparked the development of new drugs for Alzheimer's that are directed at changing inflammation cascades, he explained.

“The studies referenced here are well done because they are stacked towards more elucidation of the relationship between the inflammation and later dementia,” he said.

When it comes to patient care, clinicians need to adopt a comprehensive approach, said Dr. Treisman. In individuals with chronic pain, treatment includes not only getting the pain and related symptoms under control but helping the person to follow a healthier diet and lifestyle to help diminish the effects of inflammation that may contribute to diseases including AD.

“When you have a new patient, you examine the whole patient,” Dr. Treisman emphasized. “Everyone should be screened for cognitive impairment, and there are some simple tests depending on how functional the patient is.”

Specifically, Dr. Treisman recommends the Mini-Mental State Examination (MMSE), which is sensitive to cognitive impairment and considered an AD screener. However, clinicians need to look at other forms of cognitive function in their patients as well, such as how well they can read or process information. Providers who are especially concerned about cognitive impairment can administer the Montreal Cognitive Assessment (MoCA), which also assesses executive functions, language, and short-term memory, he advised.

“Chronic pain itself can be a risk factor for chronic impairment,” Dr. Treisman said. “Pain makes inflammatory symptoms worse (as illustrated in the study of pain and osteoarthritis) and when you add in cognitive impairment, it makes treatment that much harder.”

Areas for additional study on the link between chronic pain and cognitive impairment, including Alzheimer's disease, should involve interstitial medicine, the medicine between subspecialties, including work on the interaction between dementia and inflammation, he suggested. “For example, heart disease has an inflammatory component, and we are just starting to understand how some of these conditions go together to explore more options for cures.”

Last updated on: November 6, 2020
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