The Potential Contribution of Chronic Pain and Common Chronic Pain Conditions to Subsequent Cognitive Decline,New Onset Cognitive Impairment,and Incident Dementia: A Systematic Review and Conceptual Model for Future Research

Burden and epidemiology of Alzheimer’s disease and related dementias

Prevalence of Alzheimer’s disease and related dementias (ADRD), which encompass a range of progressive and devastating neurodegenerative disorders, continues to increase steeply in both developing and developed countries, paralleling the rapid aging of populations worldwide and constituting a serious and growing global public health crisis. A leading cause of disability, institutionalization, and death globally, ADRD imposes an enormous clinical, societal, and economic burden [1–3]. Even in high-income countries, the economic costs and associated societal burden of dementia threaten to overwhelm existing resources as the population ages and longevity increases [4].

The development of ADRD is generally insidious, with onset of clinical signs preceded years earlier by perceived and/or objective cognitive decline [5]. With effective disease-modifying treatments for cognitive impairment (CI) or ADRD still lacking after decades of disappointing clinical trials, research is shifting increasingly to prevention and early intervention [6, 7], with large-scale risk reduction trials now underway in multiple countries [7–11], including the U.S. [7, 12]. Although still incompletely understood, the development of late onset ADRD, which account for the vast majority of ADRD cases, is thought to reflect a complex interplay among multiple interacting factors, including those that are non-modifiable as well as those that are modifiable [3]. Most important among the former is age, with ADRD risk increasing exponentially with rising age [13]. For example, in the U.S., the percentage of adults with AD increases from 3% in those aged 65–74 to 17% in elders 75–84 and 32% in people 85 and older [3]. ADRD risk is also elevated in those with a family history of dementia and rises in a dose-dependent fashion with the presence of one or more APOE ɛ4 alleles [3, 14]. In addition, many studies have documented increased likelihood of ADRD in women and in African American and Hispanic adults, although some investigations suggest these disparities may reflect differences in socioeconomic, health-related, and other modifiable factors [3, 15].

In addition to these predisposing factors, a number of modifiable risk factors have also been linked to the development of CI and ADRD, providing potential opportunities for intervention. These include socioeconomic factors (e.g., low educational attainment [3, 17], unemployment [18, 19], and poverty [3]); lifestyle behaviors (e.g., smoking, physical inactivity, and mid-life obesity [3, 20–29]); and psychosocial factors, including depression [30–34], anxiety [31, 36], post-traumatic stress disorder [37–39], and other distressful states [40, 41], as well as sleep impairment [26, 42] and lack of social engagement [3, 25]. Several physical health conditions have also been linked to subsequent cognitive decline, CI, and ADRD, including: traumatic brain injury (TBI) and other head trauma [3, 43–45]; and history of specific chronic disorders, including hypertension in mid-life [3], diabetes [3, 47], heart disease [48, 49], chronic obstructive pulmonary disease (COPD) [50], and stroke [20, 49], as well as multimorbidity, the presence of multiple chronic conditions [51, 52]. In addition, certain medications have been linked to both increased and reduced risk for ADRD. For example, statin use has been consistently associated with reduced risk for dementia [53, 54]; conversely, benzodiazepines have been associated with elevated dementia risk in some studies [55, 56], although evidence for this association remains more equivocal [56–58]. Recent studies also suggest that polypharmacy may also increase risk for accelerated cognitive decline [59] and the development of dementia [60, 61].

However, while there has been considerable progress in identifying modifiable risk factors for ADRD, major knowledge gaps remain, hampering the development of effective prevention and treatment strategies. Important among these is our still limited understanding regarding the contribution of chronic pain and common chronic pain conditions to the development of CI and ADRD. Like ADRD, chronic pain continues to increase rapidly in prevalence worldwide, and itself poses a looming global public health crisis [62–65].

Chronic pain: Prevalence, burden, and relation to neurocognitive dysfunction

Chronic pain is a common and distressing condition associated with substantial clinical, economic, and societal burden in both developing and developed countries [66–68]. In the U.S., chronic pain affects up to 41% or more of the general population [67, 69–71] and up to 60% or more of older adults [72, 73], with prevalence continuing to increase [71]. Economic and social costs attributable to chronic pain are also high; for example, estimated excess annual healthcare costs in the U.S. range from $261–300 billion [74] and total costs, from $560 to $635 billion in 2010 dollars [75], far exceeding those for diabetes, hypertension, heart disease, cancer, and other common chronic disorders [73, 74]. Chronic pain can also lead to significant declines in productivity, physical function, quality of life, social engagement, and overall health, mood, and well-being [70, 76–78], and is a leading cause of disability both in the U.S. and globally [65, 79]. Moreover, as addressed in more detail in the discussion, many of these relationships are bidirectional, leading to a vicious cycle of increasing pain and social isolation, declining physical and mental health, disrupted sleep, and deterioration in mobility and function.

In addition, chronic pain can have significant effects on neurocognitive function. Because the neural systems involved in memory and cognition are closely linked to those involved in pain processing, these systems may affect one another reciprocally [76, 80] disrupting cognitive processing and contributing to a downward spiral of continuing pain, adverse neurostructural changes, and deteriorating cognitive function. Patients with chronic pain show changes in brain morphology paralleling those implicated in cognitive decline and CI, including grey matter volume reduction in brain regions involved not only in pain processing and emotional regulation, but in attention, memory consolidation, and cognitive processing [76, 80–84]. Chronic pain has also been shown to disrupt the functioning of the default mode network and other brain networks essential to normal cognitive function [82]. These alterations are thought to help explain the deterioration in memory and cognitive performance documented in many populations with chronic pain [76, 85], deterioration which may ultimately presage cognitive decline and the onset of CI and ADRD.

A growing body of evidence from epidemiologic studies suggests that chronic pain may be linked to subsequent cognitive decline, CI, and the development of ADRD. In this systematic review, we critically evaluate available evidence from published case-control and longitudinal studies regarding the association of chronic pain and specific common chronic pain conditions to incident dementia, as well as to adverse changes in cognitive function and new onset CI. We also outline major limitations and gaps in the current literature, provide a preliminary conceptual model illustrating potential pathways by which pain may influence cognitive change, and suggest directions for future research.

Association of chronic pain conditions to incident dementias

Association of chronic pain symptoms to cognitive decline, cognitive impairment, and dementia

We identified five studies using longitudinal data to investigate the relation of chronic pain symptoms to subsequent cognitive decline [99, 101], new onset CI [97], or incident dementia [96, 98]/dementia probability [99]; three were conducted in U.S. populations [97–99], with the remaining two studies based on data from Japanese [96] and British [101] cohorts. While providing support overall for a link between chronic pain and risk for adverse cognitive outcomes, findings differed across studies, likely due in part to discrepancies in study design, population, measures, length of follow-up, attrition, and other factors. For example, a survey study of 10,065 older U.S. adults followed for up to 12 years, indicated a modest association between persistent pain and acceleration in both overall cognitive decline and probability of dementia. Broadly consistent with these findings, pain interference, although not pain intensity, was associated with significantly increased risk for dementia in a retrospective cohort study of 1,114 adults (114 new dementia cases) followed for an average of 4.4 years [98]. Conversely, studies in a representative sample of British adults (N = 6,515) [101] and a small U.S. cohort (N = 441) [97] followed an average of 2.75 [97] to 4 years [101] suggested a link only between high pain severity and deterioration in memory but not in other cognitive domains. A recent investigation of 14,627 elderly Japanese applicants to a national long term care program followed up to 3 years (482 with incident dementia), self-reported knee pain, but not back pain at baseline were associated with significantly increased risk for incident dementia after adjustment for demographics, lifestyle factors, social interaction, and certain physical and mental health conditions (AHR = 1.32, CI 1.06-1.64) [96].

While collectively, these studies suggest that chronic pain may accelerate cognitive decline and increase risk for CI and dementia, findings remain somewhat mixed and several factors limit conclusions. The latter include small sample sizes [97, 98] as well as the lack of adjustment for certain lifestyle characteristics and comorbidities associated with chronic pain and ADRD, potential self-report and/or survival bias, and the relatively short follow-up periods characterizing most studies. Pain was ascertained based on a single question in 3 of the 5 studies identified; in the one study reporting largely negative findings, associations may have been attenuated by adjustment for chronic pain conditions—notably arthritis, the major contributor to pain in this population, as well as by attrition bias and other factors.

Future directions for research and preliminary conceptual model

Research regarding the relation of chronic pain and chronic pain conditions to subsequent cognitive decline and conversion to CI and dementia remains relatively sparse, and that regarding the potential relation of certain chronic pain conditions (i.e., FMS) or specific chronic pain manifestations (e.g., chronic knee or back pain) to any cognitive outcome is currently restricted to single studies. To our knowledge, no investigations have yet examined the potential link between certain common chronic pain manifestations, including neck pain and neuropathic pain, to any adverse cognitive outcome or examined the relation of any pain condition to the entire cognitive trajectory, from cognitive decline to dementia. Moreover, of the 11 studies examining the association of common chronic pain conditions to incident dementia, 7 were conducted in Taiwan using the same data source. Additional rigorous prospective studies in other regions and populations are thus clearly needed to confirm and extend the findings detailed above. These include studies designed to: investigate the independent influence of specific pain conditions and associated chronic pain symptoms on subsequent cognitive decline, new onset CI, and conversion to dementia; assess the effects of pain chronicity, intensity/severity, and overall burden (including sites affected) on these associations; evaluate the potential mediating role of mood impairment, sleep deficits, and other psychosocial factors; assess the possible modifying effects of these and other ADRD risk factors on the relation of chronic pain and chronic pain conditions to adverse cognitive outcomes; identify underlying mechanisms and, and ultimately, explore the potential role of effective chronic pain management approaches in buffering the putative adverse long term effects of chronic pain on cognitive function.

Moreover, given that the development of ADRD is insidious and that both chronic pain and ADRD are influenced by a constellation of interacting factors, large, long term prospective studies that take into account the role of the multiple potentially confounding and mediating factors are clearly needed. Figure 2 provides a preliminary conceptual model to help guide future epidemiologic research, illustrating specific key interacting pathways by which chronic pain and chronic pain conditions may contribute to cognitive decline and the development of CI and dementia and the factors linked to both chronic pain and ADRD risk that warrant consideration in causal models. While other psychosocial factors, including pain catastrophizing, self-efficacy, and coping strategies may also play a mediating role, emphasis in this conceptual model is on those factors for which information is generally available in large clinical, government, insurance, and other existing databases.

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Fig.2

Conceptual Framework: Possible pathways by which chronic pain and chronic pain conditions may contribute to the development of cognitive decline, cognitive impairment, and ADRD. Hx, history; CVD, cardiovascular disease; COPD, chronic obstructive pulmonary disease; ADRD, Alzheimer’s disease and related dementias.

Link between chronic pain and adverse cognitive outcomes: Potential explanatory factors and underlying mechanisms

As illustrated in Fig. 2, chronic pain and chronic pain conditions may influence cognitive outcomes via multiple pathways. As summarized below, these pathways include both non-modifiable and modifiable factors linked to chronic pain and ADRD risk and are complex, interacting, and multidimensional.

Non-modifiable factors include increasing age and female gender, factors strongly and positively linked to risk for both chronic pain [15, 102] and dementia [3], as well as to certain risk factors for these conditions [3, 103–107]. In addition, black adults have been reported to be at elevated risk for ADRD [3] and to experience more frequent, severe, and disabling pain [108] relative to Caucasians, although other studies have found little or no evidence for this association after adjustment for socioeconomic status [15, 102].

Modifiable factors include multiple demographic/socioeconomic, lifestyle, and health-related risk factors. As illustrated in Fig. 2, most of the relationships of these factors to chronic pain and ADRD risk are likely reciprocal. Moreover, many of these risk factors may interact in a synergistic fashion to exacerbate risk for both pain and ADRD, contributing to a vicious cycle of increasing pain and pain-related dysfunction, deteriorating mood and sleep, reduced social engagement and physical activity, declining socioeconomic status and physical health, and increased use of medications, including those with documented adverse effects on cognitive health. Key demographic/socioeconomic factors include low educational level, poverty, unemployment, and social deprivation, which have been associated with significantly increased risk both for ADRD [3] and for chronic pain and specific chronic pain conditions [15, 102].

Lifestyle factors linked to increased risk for chronic pain and/or chronic pain disability include obesity [15, 109], physical inactivity [15, 109], poor diet [109], and social isolation/loneliness [110–112], as well as smoking [109], alcohol misuse [15], and substance abuse [113–115], factors which can contribute directly or indirectly to elevated risk for cognitive decline and the development of dementia [3, 116]. Moreover, most of the relationships between lifestyle factors and chronic pain/chronic pain disability are likely bidirectional [117, 118].

A number of physical and mental health conditions have also been linked to chronic pain and pain-related disability. These include diabetes [119–121], hypertension [122, 123], cardiovascular disease [15], COPD [15], and history of TBI [85] and stroke [124, 125], as well as multimorbidity [15]. As detailed above, these conditions have, in turn, been associated with increased ADRD risk [3, 46–52]. In addition, chronic stress [109], depression [15, 126–128], anxiety [15, 128], and sleep impairment [129, 130] can both result from and exacerbate chronic pain. These factors have also been significantly associated with cognitive decline [33, 132] and incident dementia [35, 132–135], and may in part mediate the observed relationships between chronic pain and the subsequent accelerated deterioration in cognitive function and development of ADRD [83, 94]. Finally, chronic pain often leads to the use of certain medications, including analgesics, benzodiazepines, and specific anti-depressants, factors which have been linked to ADRD risk in some [55, 56], although not all studies [56–58]. Chronic pain has also been associated with polypharmacy [136–138], an emerging risk factor for dementia [61].

Link between chronic pain and adverse cognitive outcomes: Possible underlying mechanisms

As noted above, chronic pain can also have profound effects on neurocognitive function, with potentially significant implications for the development of CI and conversion to ADRD. In a recent review of 53 studies of cognitive performance in chronic pain populations, the authors concluded that chronic pain was related to deficits in several key neurocognitive domains, including memory, attention, and processing speed, and, albeit less consistently, executive functioning [85]. The neural systems involved in memory and cognition are closely linked to those involved in pain processing and likely affect one another reciprocally [76, 80], disrupting cognitive processing and contributing to a vicious cycle of continuing pain, adverse neurostructural changes, and deteriorating cognitive function [83]. Patients with chronic pain show changes in brain morphology paralleling those implicated in cognitive decline and CI, including grey matter volume reduction in the hippocampus, insular cortex, anterior cingulate cortex, thalamus, prefrontal cortex, and other brain regions involved in attention, memory consolidation, and cognitive processing [76, 139]. Chronic pain has also been shown to disrupt specific brain networks critical to normal cognitive performance [82]. As noted above, these alterations are thought to help explain the deterioration in cognitive function documented in many chronic pain populations [76, 85], deterioration which may ultimately contribute to accelerated cognitive decline and the development of CI and ADRD.

Chronic pain and chronic pain conditions may contribute to ADRD pathogenesis via other pathways as well. For example, OA and other chronic pain conditions have been associated with activation of central pain processing pathways [140, 141] and central nervous system hypersensitivity [141, 142], factors linked to disruption of cognitive functioning [76, 143]. Both systemic and peripheral inflammation may also play a role. For example, systemic increases in high-sensitivity C-reactive protein, interleukin-6, and other proinflammatory mediators have been implicated in the development and progression of both specific chronic pain conditions (e.g., OA, FMS) and CI [141, 144]. Likewise, local proinflammatory changes associated with chronic pain conditions have been linked to neuroinflammation [141, 144], cerebrovascular dysfunction [144], and adverse nociceptive and structural changes in the brain [141, 145], alterations that may impair cognitive processing and promote cognitive dysfunction [141, 146]. Chronic pain may also contribute to ADRD risk via adverse effects on cellular aging. For example, OA [147] and other chronic pain conditions [148] have been associated with shortened telomere length, a marker of accelerated cellular aging that has been linked to increased risk for ADRD [149–151].

Strengths and limitations

Our review included only studies that used longitudinal data, reported a minimum of 50 outcome cases, and that adjusted, at a minimum, for age and gender, helping to increase confidence in findings. In the tables provided, we include information on multiple domains of study quality, and take into account design and methodological limitations in our discussion of findings. However, this systematic review also has several potential limitations that warrant consideration. While studies were identified using a comprehensive, multi-pronged search strategy, our review was restricted to investigations published in English, potentially introducing bias. However, we did not identify any research published in non-English languages that met our inclusion criteria, reducing this likelihood. Publication bias may have resulted in disproportionate capture of studies reporting positive findings. However, pain is not yet an established risk factor for cognitive decline or ADRD, rendering this possibility less likely. Studies have, to date, been conducted in only a handful of countries, and the majority (7 of 11) of studies investigating the association of included chronic pain conditions were conducted in Taiwanese nationals using the same primary data source. It thus remains unclear if the findings discussed in the current review are generalizable to other populations, cultures, and/or regions. While overall, the investigations published to date have yielded results supportive of a link between chronic pain and the development of cognitive decline and dementia, the considerable heterogeneity in study populations (notably, those assessing the association of chronic pain symptoms to cognitive outcomes), design, follow-up periods, measures and ascertainment of outcome and explanatory variables, analysis, and other factors render direct comparisons across studies challenging. As detailed above, conclusions are limited by a number of design and/or methodological concerns characterizing the majority of studies, including small sample sizes; relatively short follow-up periods; lack of adjustment for the potential confounding influence of specific demographic, lifestyle, and health-related factors associated with both pain and dementia risk; potential selection, self-report, detection, and/or survival bias; and/or lack of information on pain chronicity, duration, intensity or other indicators of chronic pain burden.

Conclusions

Published case-control and cohort investigations to date suggest chronic pain and certain chronic pain conditions may increase risk for accelerated cognitive decline, new onset CI, and incident ADRD. However, research remains sparse, and interpretation of existing findings is hampered by the methodological and other limitations characterizing most studies. The relation of chronic pain and chronic pain conditions to specific forms of dementia also remains unclear. Additional large prospective investigations that address these concerns are needed to confirm and extend the findings of current studies, to elucidate the contributions of chronic pain and chronic pain conditions on the entire cognitive trajectory, to clarify the relation of chronic pain to specific dementia types, and to explore potential mediating factors and identify underlying mechanisms.