Geriatric Nursing 50 (2023) 7 14

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Geriatric Nursing
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Featured Article

Self-reported pain and fatigue are associated with physical and cognitive
function in middle to older-aged adults
Jessica A. Peterson, PhDa,b, Roland Staud, MDa,c, Pavithra A. Thomas, BSd,e,
Burel R. Goodin, PhDd,e, Roger B. Fillingim, PhDa,b, Yenisel Cruz-Almeida, PhDa,b,f,*
a
College of Dentistry, Pain Research & Intervention Center of Excellence (PRICE), University of Florida, Gainesville, FL, USA
b
College of Dentistry, Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL, USA
c
College of Medicine, Rheumatology, University of Florida, Gainesville, FL, USA
d
College of Arts and Science, Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
e
School of Medicine, Center for Addiction & Pain Prevention & Intervention (CAPPI), University of Alabama at Birmingham, Birmingham, AL, USA
f
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA

A R T I C L E I N F O A B S T R A C T

Article history: Persistent fatigue is often reported in those with chronic musculoskeletal pain. Separately, both chronic pain
Received 1 November 2022 and chronic fatigue contribute to physical and cognitive decline in older adults. Concurrent pain and fatigue
Received in revised form 15 December 2022 symptoms may increase disability and diminish quality of life, though little data exist to show this. The pur-
Accepted 16 December 2022
pose of this study was to examine associations between self-reported pain and fatigue, both independently
Available online 13 January 2023
and combined, with cognitive and physical function in middle-older-aged adults with chronic knee pain.
Using a cross-sectional study design participants (n = 206, age 58.0 § 8.3) completed questionnaires on pain
Keywords:
and fatigue, a physical performance battery to assess physical function, and the Montreal Cognitive Assess-
Pain
Fatigue
ment. Hierarchical regressions and moderation analyses were used to assess the relationship between the
Physical function variables of interest. Pain and fatigue both predicted physical function (b = -0.305, p < 0.001; b = -0.219,
Cognitive function p = 0.003, respectively), however only pain significantly predicted cognitive function (b = -0.295, p <0.001).
Musculoskeletal pain A centered pain*fatigue interaction was a significant predictor of both cognitive function (b = -0.137,
Older adults p = 0.049) and physical function (b = -0.146, p = 0.048). These findings indicate that self-reported fatigue may
contribute primarily to decline in physical function among individuals with chronic pain, and less so to
decline in cognitive function. Future studies should examine the impact of both cognitive and physical func-
tion decline together on overall disability and health.
© 2022 Elsevier Inc. All rights reserved.

Introduction
Chronic fatigue is complex biopsychosocial phenomenon1 that
presents as a primary or secondary symptom of many pathological
ailments, and as a comorbidity of many neurological diseases.2-5
Fatigue is a subjective symptom and is commonly described as
extreme tiredness and inability to function due to lack of energy.4
Fatigue is a prevalent complaint in those with chronic musculoskele-
tal pain, with up to 70% of individuals reporting co-occurring, persis-
tent fatigue (6-8). For those with chronic pain, comorbid fatigue
likely exacerbates disability by impairing activities of daily living and
reducing functional independence,6,7 however this relationship is not
clearly defined or well explored. Existing research demonstrates that
community-dwelling older adults experiencing fatigue, regardless of
*Corresponding author at: Department of Community Dentistry and Behavioral Sci-
ence, University of Florida, Gainesville, FL 32610, USA.
E-mail address: cryeni@ufl.edu (Y. Cruz-Almeida).
pain status, have greater risk of mortality over ten years.8 The magni-
tude of the association between chronic fatigue and mortality in older
adults is similar to that seen in those with heart disease and diabe-
tes.8 Due to the lack of concrete diagnostic criteria (except for chronic
fatigue syndrome) to differentiate fatigue from normal day to day
fluctuations in exhaustion or tiredness, a focus on the initiation
and sustainability of physical and/or cognitive functioning is
recommended.3
Fatigue and pain are subjective experiences with physical and
cognitive components that are related yet distinct.4 Those reporting
musculoskeletal pain often experience fatigue that may lead to diffi-
culty with physical activities and physical function.9,10 Those present-
ing with both fatigue and pain symptoms tend to take more time
with activities of daily living, require more rest, and become easily
exhausted compared to those with musculoskeletal pain symptoms
only. In addition to physical fatigue, those with musculoskeletal pain
report cognitive difficulties, such as mental confusion, memory
decline, issues with psychomotor abilities, or speech difficulties.11-13

https://doi.org/10.1016/j.gerinurse.2022.12.015
0197-4572/$ see front matter © 2022 Elsevier Inc. All rights reserved.
8 J.A. Peterson et al. / Geriatric Nursing 50 (2023) 7 14
These symptoms could be reflective of cognitive fatigue and/or
declining cognitive performance. Cross-sectional research demon-
strates that fatigue, in the absence of pain, is associated with changes
in brain function (e.g. hypo-metabolism, brain atrophy, abnormal
activity of prefrontal cortex and frontal basal ganglia) and compro-
mised cognition; both of which affect daily functioning.3,14-17 These
physical and cognitive limitations often force patients to seek addi-
tional support to meet individual role obligations, including at home
assistance and job modifications from employers.18 However, the
scope of existing research is limited to pain as the primary driver for
reduced cognitive function in chronic pain populations, and very lit-
tle data exist on the impact of fatigue on cognitive function in indi-
viduals with chronic pain.
Fatigue and pain often co-occur, with previous studies demonstrat-
ing strong, positive associations.19,20 The relationship between pain
and fatigue could be synchronous, meaning that presence of concurrent
pain and fatigue may amplify physical and cognitive decline, leading to
increased disability and reduced quality of life. Currently, the indepen-
dent versus combined contributions of pain and fatigue to cognitive
and physical function have not been examined in individuals with
chronic knee pain. Therefore, the primary objective of this study was to
determine if self-reported pain and fatigue were associated indepen-
dently and/or synergistically with cognitive and physical function in
middle-older aged adults with chronic knee pain. We tested the follow-
ing hypotheses: 1) higher levels of self-reported pain and self-reported
fatigue scores are associated with lower cognitive and physical function
independently; and 2) the interaction of fatigue and pain is associated
with lower cognitive and physical function.
Methods
Sample
This study was a part of a larger project that examined race group
differences in physical symptoms, psychosocial functioning, and
pain-related central nervous system structure and functioning in
those with or at risk of developing knee osteoarthritis. Study proce-
dures and sample characteristics from various aspects of the project
have been reported in previous publications.21-25 We used a power
calculation for a multiple regression approach to achieve 95% power
and detect a small effect of change in pain/fatigue (Cohen’s d = 0.15)
which would suggest a participant pool of 150. This assumed an
unconditional (random X’s) model attributable to two independent
variables (i.e., physical, and cognitive function) at a significance level
(alpha) of 0.025 and adjusted for an additional four covariates (age,
study site, race, and gender). Adults between 45-85 years of age
(n = 206, age 58.0 § 8.3) with or without knee pain were recruited
from the local area around the University of Florida and University of
Alabama at Birmingham. Individuals self-identified as non-Hispanic
and “African American/Black” or “White/Caucasian/European” and
were English speaking. Exclusion criteria were 1) significant surgery
to the most painful knee; 2) cardiovascular disease or history of acute
myocardial infarction; 3) uncontrolled hypertension (blood pressure
> 150/95 mmHg); 4) systemic rheumatic diseases; 5) neuropathy; 6)
chronic opioid use; 7) serious psychiatric illness; 8) neurological dis-
ease; 9) if the participant was pregnant; 10) had a significantly
greater pain in a body site other than the knee and 11) failed a tele-
phone interview for cognitive function. All participants provided
written informed consent prior to data collection procedures and
both study sites’ institution review boards approved the study.
Procedures
Telephone screenings were utilized to collect the sociodemo-
graphic (e.g., age, sex, race) and health information (e.g., knee pain
symptoms) required to determine study eligibility. Eligible individu-
als completed an in-person visit to undergo informed consent proce-
dures and a health assessment (including self-reported pain). The
questionnaires, physical tasks, and scales used for this analysis were
obtained during the initial health assessment visit.
Self-reported pain
The Graded Chronic Pain Scale (GCPS) provides characteristic pain
intensity (items 1-3), and pain interference (items 4-6) subscales
relating to pain that the participant has experienced during the past
six months.26 Summed higher scores from each of the subscales indi-
cate more severe pain intensity and more severe pain interference.
Using the GCPS pain severity grades where grade 0 is no pain, grade I
is low disability-low intensity, grade II is low disability-high inten-
sity, grade III is high disability-moderately limiting, and grade IV is
high disability-severely limiting,26 we classified individuals into three
groups reflective of the impact chronic pain had on their life; high
impact pain (grades 3-4), low impact pain (grades 1-2), and a no pain
control group (grade 0). This method is consistent with previous
research27 and uses the recommendations from the Task Force for
the Classification of Chronic Pain consensus for the 11th version of
the International Classification of Diseases (ICD-11) of the World
Health Organization (WHO).28
Self-reported fatigue
The Fatigue Severity Scale (FSS) is a unidimensional, 9 item ques-
tionnaire that examines the impact and severity of fatigue.29 Partici-
pants rate items on a scale from 1 (strongly disagree) to 7 (strongly
agree) based on the past seven days. The overall score is the summed
total of the individual item scores and can range between 9 and 63.
FSS scores of 36 or above are indicative of fatigue and our sample was
dichotomized into fatigue and non-fatigue groups based upon the
suggested cut-off.29,30
Physical function assessment
The Short Physical Performance Battery (SPPB)31,32 is composed of
three tasks that assesses physical function in the lower extremities: a
hierarchical balance task (side-by-side stance, modified tandem
stance, and tandem stance), a chair stand task (rising from a chair
five times), and a gait speed task (fastest walking pace over 4m).
Tasks are scored from 0 (unable to complete) to 4 (highest level of per-
formance) and are summed for total SPPB score that ranges from 0 to
12, with higher scores indicating greater functional ability. We
dichotomized the into those who indicate physical frailty (< 9 total
SBBP), and those who do not (> 8 total SPPB).33
Cognitive assessment
The Montreal Cognitive Assessment (MoCA) is a 30 item, validated
screening tool for mild cognitive impairment, with lower scores indi-
cating worse cognition.34 The MoCA assesses several cognitive
domains, including visuospatial processing, language, executive func-
tion, naming, memory, attention, abstraction, and orientation.35
MoCA scores greater than 25 are considered “normal functioning” in
terms of cognition, thus we dichotomized the sample into low ( 25)
and high (>25) function.
Statistical analysis
All statistical analyses were performed using SPSS 27 (IBM
Armonk, New York). One-way analysis of variance (ANOVA) was
used to compare mean values in continuous/discrete ordinal
 J.A. Peterson et al. / Geriatric Nursing 50 (2023) 7 14 9

variables between pain impact groups, and chi-square was used for
comparison of nominal variables. Assumptions underlying each sta-
tistical test were examined. Given the multidimensional component
of fatigue and pain we performed analyses using both nominal
(i.e. fatigue groups, pain groups) and continuous (i.e. fatigue severity,
pain severity) variables.
As described above, certain continuous variables were dichoto-
mized based upon clinical significance of results i.e., fatigue (fatigue
vs no fatigue), physical function (frail vs non-frail), and cognitive
function (low cognitive function vs high cognitive function). Indepen-
dent measures t-tests were used to compare fatigue, cognitive func-
tion, and frailty group differences in pain severity (Graded Chronic
Pain Scale), pain interference (GCPS), self-reported fatigue (Fatigue
Severity Scale), cognitive function (Montreal Cognitive Assessment),
and physical function (Short Physical Performance Battery).
Spearman’s Rho Correlations were performed using correlation
coefficients between predictor and criterion variables to determine
their zero-order associations in order to verify our hypothesis that pain
and fatigue would be associated with each other and that they would
be associated with physical function and cognitive function. False dis-
covery rate (FDR) p-values were reported when a Benjamini-Hochberg
procedure was conducted to correct for multiple comparisons.
Hierarchical regression analyses using continuous variables were
performed to test whether pain and fatigue made independent (regres-
sion 1; Table 3) and synergistic contributions (regression 2; Table 4) to
the prediction of physical functioning and cognitive function (repre-
sented by SPPB and MoCA, respectively) after controlling for age, sex,
race, and study site. For independent assessment of pain and fatigue,
covariates (age, race, gender, study site) were entered in the first block,
pain severity and pain interference were entered in the second block,
and fatigue severity was entered into the third block. When examining
the synergistic effects of pain and fatigue on physical and cognitive
function, pain severity and fatigue severity predictor variables were
centered before being entered into the model to address multicolli-
nearity. Following this, covariates (age, race, gender, study site) were
entered in the first block, pain severity was entered in the second block,
fatigue severity was entered into the third block, and the interaction
effect of pain severity and fatigue severity was entered into the fourth
block. The beta weights and significance levels of each predictor were
examined to evaluate their associations.
Results
Descriptive characteristics of the three groups are shown in
Table 1. Those with high impact pain had a higher percentage of
Non-Hispanic Black (NHB; 60% vs 41.9% and 38.7%) and weighed
more (p = 0.009; hp2 = 0.046) compared to the other two groups.
Those with high impact pain (HIP) and low impact pain (LIP) reported
greater pain severity (p < 0.001; hp2=0.564), pain interference
(p < 0.001; hp2 = 0.391) than the no pain control group. The HIP
group reported greater levels of fatigue (p < 0.001; hp2 = 0.113) and
were more likely to have meet the criteria for clinically significant
self-reported fatigue (43.9%) compared to the LIP (15.9%) and no pain
control groups (12.9%).
Similarly, with cognitive function, the HIP pain group scored
lower on the MoCA (p = 0.003; hp2 = 0.057) than the other two groups
and 66.7% of the HIP group met the criteria for low cognitive function.
The HIP group had lower balance scores than the LIP group
(p = 0.044; hp2 = 0.031), lower sit to stand scores than both LIP and
pain free controls (p = 0.009; hp2=0.083), lower walking scores than
the pain free controls (p = 0.021; hp2=0.038), and the HIP had a lower
overall total SPPB score than the LIP and pain free controls (p <
0.001; hp2 = 0.123). Additionally, 30.0% of those with HIP met the cri-
teria that may indicate physical frailty compared to 12.9% and 15.9%
in those with no pain and low impact pain respectively.
Fatigue, cognition and physical function group differences
Participants were also grouped based upon whether they met the
defining criteria for clinical fatigue vs no fatigue, low cognitive func-
tion vs high cognitive function, and indications of frail vs not frail.
These group differences in pain severity, pain interference, fatigue
severity, cognitive function and physical function are displayed in
Fig. 1. Furthermore, when controlling for age, sex, and race in our
sample, these group differences did not change.

Table 1
Pain Group Differences in demographic data, pain, cognitive function, and physical function

Measure No Pain Controls Low Impact Pain High Impact Pain P-value Direction

Age 60.1§9.9 58.7§8.1 56.15§7.2 0.052

Sex (Female) 70.9% 66.7% 61.7% 0.651
Race (NHB) 41.9% 38.7% 60.0% 0.026 HIP>CON+LIP
Site (UF) 67.7% 61.3% 60.0% 0.756
Height 165.8§7.8 167.8§9.5 169.6§9.3 0.161
Weight 82.7§16.8 84.3§18.4 92.5§18.2 0.009 HIP>CON+LIP
BMI 30.0§5.4 30.0§6.5 32.2§6.0 0.074
Self Report Pain
Pain severity (GCPS) 0.0§0.0 11.6§6.7 20.7§5.5 <0.001 HIP>LIP>CON
Pain interference 0.3§1.8 5.7§5.8 55.9§53.6 <0.001 HIP>LIP>CON
Self Report Fatigue
FSS score 23.7§13.3 25.1§12.9 33.9§14.7 <0.001 HIP>CON+LIP
FSS group (Fatigue) 12.9% 15.9% 43.9% <0.001 HIP>CON+LIP
Cognitive Function
MoCA score 25.3§3.0 25.1§3.3 23.4§3.5 0.003 HIP<CON+LIP
MoCA group (MCI) 35.5% 37.8% 66.7% <0.001 HIP>CON+LIP
Physical Function
SPPB balance 3.8§0.5 3.9§0.4 3.6§0.8 0.044 HIP<LIP
SPPB sit to stand 2.9§1.1 2.5§1.1 1.9§1.3 <0.001 HIP<CON+LIP
SPPB walking 3.9§0.4 3.8§0.5 3.6§0.7 0.021 HIP<CON
SPPB total 10.7§1.2 10.1§1.4 9.1§1.8 <0.001 HIP<CON+LIP
Frailty group (Indicates frail) 3.2% 10.8% 30.0% <0.001 HIP>CON+LIP
Note: HHB Non-Hispanic Black, UF University of Florida, BMI Body Mass Index, GCPS Graded Chronic Pain Scale. MCI Mild Cognitive Impairment. FSS Fatigue Severity
Scale, MoCA Montreal Cognitive Assessment, SPPB Short Performance Physical Batter, HIP High Impact Pain. LIP Low Impact Pain, CON - Control.
10 J.A. Peterson et al. / Geriatric Nursing 50 (2023) 7 14

Fig. 1. Fatigue (fatigue vs not fatigue), cognition (low vs high), and frailty group (frail vs not frail) differences in A. Pain Severity (Graded Chronic Pain Scale), B. Pain Interference
(Graded Chronic Pain Scale), C. Self-reported fatigue (Fatigue Severity Scale), D. Cognitive Function (Montreal Cognitive Assessment), E. Physical Function. *denotes significant dif-
ference between groups.

Those who had fatigue compared to those who did not have reduced physical function (p < 0.001; d = 0.704). There was no differ-
fatigue (n=48 vs n=151, respectively) reported higher pain severity ence in cognitive function (p = 0.303; d = -0.171).
(p < 0.001; d = -0.678), higher pain interference (p < 0.001; Participants categorized to the low cognitive function group
d = -0.896), higher fatigue severity (p < 0.001; d = -3.558), and (n = 95) reported higher pain severity (p < 0.001; d = -0.781), higher
 J.A. Peterson et al. / Geriatric Nursing 50 (2023) 7 14 11

Table 2
Spearman Rho Correlations among pain, fatigue, cognitive function and physical function variables.

Pain Severity Pain Interference FSS Fatigue MoCA SPPB Balance SPPB Sit to stand SPPB Walk Total SPPB

Pain Severity - 0.68 0.37 -0.46 -0.10 -0.23 -0.13 -0.28

Pain Interference - 0.47 -0.30 -0.11 -0.26 -0.12 -0.31
FSS Fatigue - -0.03 -0.09 -0.23 -0.05 -0.26
MoCA - 0.26 0.14 0.30 0.28
SPPB balance 0.00 0.21 0.33
SPPB sit to stand - 0.12 0.89
SPPB Walk - 0.47
Total SPPB -
FSS Fatigue Severity Scale, MoCA Montreal Cognitive Assessment, SPPB short performance physical battery.
Bolded values indicate significant correlations P<0.001 & FDR<0.05.

pain interference (p = 0.004; d = -0.415), reduced cognitive with cognitive and physical function in middle-older aged adults
(p < 0.001; d = 2.721), and physical function (p < 0.001; d = 0.636) with chronic knee pain. The primary findings of this study were that
compared to those who had high cognitive function (n = 111). There 1) pain and fatigue are independently and synergistically associated
was no difference in fatigue severity (p = 0.129; d = -0.218). with physical function, 2) pain alone is a predictor of cognitive dys-
Lastly, those who demonstrated indications of frailty (n = 33) function however, when concurrent, pain and fatigue predict cogni-
reported higher pain severity (p < 0.001; d = -0.794), higher pain tive function. This study also found that individuals with co-morbid
interference (p = 0.004; d = -0.553), higher fatigue severity indications of frailty and chronic pain report higher levels of pain,
(p < 0.001; d = -0.766), and had both reduced cognitive (p < 0.001; fatigue, and experience reduced physical and cognitive outcomes
d = 0.672), and physical function (p < 0.001; d = 2.952) compared to compared to those who are deemed as not frail. Similarly, those with
those who did not demonstrate indications of frailty (n =173). co-occurring fatigue and pain have more severe pain and fatigue and
reduced physical performance than those with pain alone. Lastly,
Associations between pain, fatigue, cognition and physical function those with lower cognitive function and pain have higher pain levels,
and reduced cognitive and physical performance scores than those
Spearman rho correlations coefficients are displayed in Table 2. who are considered cognitively “normal”.
Regression analysis revealed that when controlling for age, site, In our sample of individuals experiencing knee pain, we found
race, and gender, the final model accounted for 47.9% of the variance that pain and fatigue are related in several ways similar to findings in
in physical function and that pain severity and fatigue severity were previous literature. For example, one study investigated whether
both significant predictors of physical function accounting for 12% changes in pain precede the changes in fatigue, or vice versa, or
and 4% of the variance, respectively (Table 3). Using the same pre- whether pain and fatigue fluctuate together in time in older adults.36
dictors for cognitive function, the final model accounted for 51.9% of The authors found that pain and fatigue showed monthly fluctuations
the variance in cognitive function, with pain severity accounting for that were synchronous rather than showing a temporal relationship
7.3% of the variance. Race was a large predictor of cognitive func- with a time lag.36 In fact, it was recommended that both manifesta-
tion, accounting for 16% of the variance. When examining the inter- tions should be treated together because it cannot be expected that
action effects of pain severity and fatigue severity on physical and an improvement in one is followed by an improvement in the
cognitive function (Table 4), the pain*fatigue interaction was a sig- other.36 Examining both fatigue and pain as collective reported
nificant predictor of both physical function (p = 0.048) and cognitive symptoms in patients with chronic musculoskeletal pain (regardless
function (p = 0.049). of disease type) may improve clinical trials and ultimately, treatment
outcomes. A psychometric tool assessing both symptoms of pain and
Discussion fatigue simultaneously in chronic pain populations is lacking and
would provide clinicians and researchers a more comprehensive
The purpose of this study was to determine if self-reported pain assessment towards understanding “pain-related fatigue”.
and fatigue were associated independently and/or synergistically Our finding that pain and fatigue are independently associated
with physical function is well established.10,12,21,37-42 However, the
Table 3 novelty of our findings lies within the interaction between pain and
Summary of hierarchical regression analysis for cognitive function and physical func-
fatigue, and the role of fatigue as a moderating factor between pain
tion with select covariates, pain severity, pain interference and fatigue as predictors
and physical performance. Musculoskeletal pain is highly prevalent
Variables R DR2 Std b p for b p for Model and associated with decreased physical function and increased dis-
Physical Function
ability in aging individuals,11,41,43 however, the contributors to lower
Study Site 0.152 0.023 0.158 0.017 <0.001 physical function in persons with pain are likely complex and multi-
Age 0.157 0.002 -0.191 0.006 factorial. While peripheral factors have been previously reported in
Gender 0.168 0.003 -0.080 0.222 persons with chronic pain (i.e., structural changes in joint, muscle
Race 0.268 0.044 0.112 0.118
mass, muscle biochemistry, peripheral afferents44-47), other more
Pain Severity 0.435 0.118 -0.305 <0.001
Pain Interference 0.438 0.003 0.006 0.944 systemic contributors remain to be elucidated (i.e., brain, epigenetic
Fatigue Severity 0.479 0.037 -0.219 0.003 mechanisms48-50). Those with chronic pain often demonstrate avoid-
Cognitive Function ance behaviors leading to reduced physical activities contributing to
Study Site 0.111 0.012 -0.065 0.313 <0.001
muscle wasting and functional decline. Furthermore, those
Age 0.135 0.006 -0.046 0.494
Gender 0.165 0.009 0.033 0.606
experiencing fatigue are often too “tired” to perform functional tasks
Race 0.434 0.161 0.297 <0.001 and other physical activities thus contributing to declines in overall
Pain Severity 0.511 0.073 -0.295 <0.001 physical health, further worsening both fatigue and pain symptoms
Pain Interference 0.512 0.001 -0.074 0.340 in a negative feedback loop.51,52 It is possible that changes in fatigue
Fatigue Severity 0.519 0.007 0.094 0.184
and pain may precede or simultaneously occur with declines in
12 J.A. Peterson et al. / Geriatric Nursing 50 (2023) 7 14
Table 4
Summary of hierarchical regression analysis for centered pain and fatigue with dis-
played interaction effects of fatigue severity*pain severity on predicting physical and
cognitive function
Variables R DR2 Std b p for b p for Model
Physical Function
Covariates 0.322 0.104 <0.001
Pain Severity (centered) 0.399 0.055 -0.212 0.021
Fatigue (centered) 0.445 0.039 -0.172 0.036
Fatigue*Pain Interaction (centered) 0.466 0.019 -0.146 0.049
Cognitive Function
Covariates 0.457 0.209 <0.001
Pain Severity (centered) 0.551 0.094 -0.434 <0.001
Fatigue (centered) 0.560 0.010 -0.153 0.043
Fatigue*Pain Interaction (centered) 0.575 0.017 -0.137 0.048
physical function due to changes in both peripheral and systemic
processes.
Our result showing that pain, rather than fatigue, contributes
more to reduced cognitive function may indicate that those
experiencing persistent pain may experience cognitive difficulties
regardless of their fatigue symptoms. Furthermore, when examining
the interaction of pain and fatigue, there seems to be a moderated
association between the two symptoms and cognition. Throughout
the literature, an association is present between chronic pain and
cognitive performance,13,53-59 though a clear mechanistic link
remains to be elucidated. This association appears to parallel that
observed in people experiencing chronic fatigue.36,60-62 To our
knowledge, this study is the first to examine both pain and fatigue
and their roles in cognitive function in those with chronic pain. Dis-
ruption of cognitive processing has been investigated in a variety of
common chronic pain and chronic fatigue syndromes, with studies
focusing on different types of cognitive features. There is consider-
able overlap that exists between the neuroanatomical and neuro-
chemical substrates implicated in both pain and cognition, and
studies demonstrate pain-related alterations at cognitive, behavioral,
morphological, neurochemical and molecular levels.13,63,64 During
the preclinical phase of Alzheimer’s disease and related dementias,
there is a 20 to 30-year span where cognitive deficits are not present,
but pathological changes may already be occurring,65, 66 and it is
important to identify early on, what these changes are. In fact, both
pain and fatigue symptoms (when studied independently) may be
clinical markers of accelerated brain aging,49,67,68 and those
experiencing either of these symptoms may have more brain atrophy
than expected for their age, particularly in brain regions that are
more susceptible to aging and Alzheimer’s disease. Future studies
should examine the combined impact of the two symptoms on global
brain health.
Chronic pain and lasting fatigue are likely to reflect underlying
shared mechanisms, and it has been suggested that pain patients
should be classified based on experienced symptoms, regardless of
the underlying disease due to heterogeneity within specific condi-
tions, (i.e. knee osteoarthritis, low back pain, etc.) as this contributes
to the difficulty in the development of effective management strate-
gies.69 It has been argued that this heterogeneity is a major, if not the
primary cause of so many failed clinical pain trials.70 By grouping our
sample into those who have pain and fatigue, pain and low cognitive
function, and pain and indications of frailty, we were able to provide
preliminary evidence exploring pain with and without potential
comorbidities regarding pain outcomes, fatigue outcomes, physical
function, and cognitive function. Those with both pain and indica-
tions of frailty had worse outcomes on all measures compared to
their pain only counterparts. Those with both pain and fatigue were
similar to the pain-only group in their cognitive function yet showed
worse outcomes in pain severity, pain interference, fatigue, and phys-
ical function, and those with both pain and low cognitive function
demonstrated similar fatigue scores yet showed worse outcomes in
pain severity, pain interference, cognitive, and physical function.
As a cross-sectional study, neither causality nor the temporal
order of the associations can be directly established. Future larger
longitudinal studies may provide fundamental insights into these
important associations, particularly when establishing whether phys-
ical or cognitive decline predates pain and fatigue, and vice versa. Our
data focused on the potential role of concurrent pain and fatigue in
middle to older aged individuals and did not examine these linkages
in younger adults. Future research across the lifespan is needed to
assess critical time points where comorbid fatigue and pain may be
most prevalent, which may elucidate critical ages where possible
interventions may be beneficial to prevent declines in cognitive and
physical performance. Tracking physical activity may have been ben-
eficial as physical activity has been associated with improved out-
comes with both physical and cognitive performance, but also has
been shown to alleviate both fatigue and pain symptoms. This study
was a secondary data analysis using only perceived fatigue, therefore
additional measures directly examining physical fatigue and cogni-
tive fatigue would be beneficial for analysis with those with chronic
pain. Furthermore, the MoCA instrument is used for detecting
patients with dementia and has limitations when used with the gen-
eral population who are cognitively sound and so the lack of finding
between fatigue and cognition may be due to the sensitivity of the
MoCA as such, other measures of cognitive function should be exam-
ined in future studies.
Future studies, including participants with other specific chronic
pain conditions are needed to further elucidate the association
between pain and fatigue impact. While not a limitation per se, we
specifically examined perceived fatigue in this paper, this is distinct
from fatigability that can open additional research avenues to address
this complex phenomenon. Fatigability tends to describe how
fatigued a person gets relative to defined activities which may be
impact physical function further. A simple way of operationalizing
fatigability is the ratio of self-reported fatigue to activity level, where
the latter is described in terms of work performed.71 This distinction
is important as heterogeneity due to the multidimensional experi-
ence of pain and fatigue between individuals could be influenced by
activity level. Since this analysis also provided evidence that fatigue
and pain may play a role in cognitive function and it is well estab-
lished that physical activity plays a role in preventing neurodegener-
ative diseases and optimizing brain health, it is important that future
research should address the influence of physical activity on fatigue
and fatigability.
Conclusions
Despite these limitations, the current study findings implicate
comorbid pain and fatigue as drivers of declining physical function
and cognitive function in individuals experiencing chronic pain.
Given the high prevalence of pain and fatigue in middle to older aged
adults, it is imperative that future research continues to investigate
these two symptoms as sources of physical impairment and cognitive
decline within this population. By doing so, we can begin to alleviate
the physical and emotional suffering faced by individuals with
chronic pain, thereby improving quality of life in those who live with
both chronic pain and persistent fatigue.
Declaration of Competing Interest
The authors have no conflicts of interest to declare.
 J.A. Peterson et al. / Geriatric Nursing 50 (2023) 7 14
Acknowledgements
UPLOAD2 participants and study team; UAB National Center for
Advancing Translational Sciences of the National Institutes of Health
under award UL1TR003096.
Funding sources
This study was funded by the National Institute of Health
[R01AG059809, R01AG067757, R37AG033906].
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