Alzheimer's Pain Study Finds Increased Sensitivity

PAIN & AGING SECTION
Original Research Article
Autonomic, Behavioral, and Subjective Pain
Responses in Alzheimer’s Disease
Paul A. Beach, PhD,*
,†
Jonathan T. Huck, BS,
†
Melodie M. Miranda, MD,‡
and Andrea C. Bozoki, MD
†,§
*Michigan State University College of Osteopathic
Medicine, DO/PhD Training Program, East Lansing,
Michigan, USA;
†
Michigan State University Neuro-
science Program, East Lansing, Michigan, USA;
‡
Michigan State University College of Human Medi-
cine, East Lansing, Michigan, USA;
§

Michigan State
University Department of Neurology and Ophthalmol-
ogy, East Lansing, Michigan, USA
Reprint requests to: Paul A. Beach, PhD, Michigan
State University Department of Neurology and Oph-
thalmology, B-444 Clinical Center, 788 Service Road,
East Lansing, MI 48824, USA. Tel: 517-432-9277;
Fax: 517-432-9414; E-mail: [email protected]
Conflict of interest: The authors declare no conflicts of
interest.
Abstract
Objective. To compare autonomic, behavioral, and
subjective pain responses of patients with Alzhei-
mer’s disease (AD) to those of healthy seniors (HS).
As few studies have examined patients with severe
Alzheimer’s disease (sAD), we emphasized inclusion
of these patients together with mild/moderate Alzhei-
mer’s disease (mAD) patients to characterize pain
responses potentially affected by disease severity.
Design. A controlled cross-sectional study involv-
ing repeated measures behavioral pain testing.
Setting. An outpatient clinical setting and local
nursing facilities.

Subjects. Community dwelling HS controls (N 5 33)
and individuals with chart-confirmed diagnoses of
AD (N 5 38, Diagnostic and Statistical Manual-IV
criteria).
Methods. HS and AD groups were compared in their
responses to repeated applications of five pressure
intensities (1–5 kg) on the distal forearm. Auto-
nomic responses (heart rate [HR]), pain behaviors
(vocal, facial, and bodily as scored by the Pain
Assessment in Advanced Dementia [PAINAD]
scale), and subjective pain ratings (Faces Pain
Scale-Revised) were measured.
Results. HR responses to pressure stimuli were dif-
ferentially affected based on AD severity: sAD
patients had generally decreased HR reactivity com-
pared with other groups (P < 0.01). In contrast, pain
behaviors were increased in AD regardless of sever-
ity (P < 0.001), compared with HS, for all but the low-
est pressure intensity. Increased behaviors
occurred in all measured domains of the PAINAD
(P < 0.005). While sAD were unreliable subjective
reporters, mAD patients (N 5 17) rated low level
pressures as more painful than HS (P < 0.01).
Conclusion. These findings provide behavioral and
subjective-report evidence of increased acute pain
sensitivity in AD, which should be taken into con-
sideration with respect to pain management across
the spectrum of AD severity.
Key Words. Alzheimer’s Disease; Dementia;
Elderly; Behavior; Acute Pain
Introduction

Reliable detection and treatment of pain in elderly per-
sons with Alzheimer’s disease (AD) is an important
means of improving quality of life and reducing behav-
ioral and psychological symptoms of dementia [1–6].
Although recent prevalence estimates of pain in
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Pain Medicine 2015; 16: 1930–1942
Wiley Periodicals, Inc.
demented patients are near 50% [7–9] there are many
reports of under-treatment of pain in AD/dementia
patients [10–15]. Under-treatment of pain may be due,
in part, to limited knowledge about pain in dementia by
caregivers and health care professionals [16–18] and
the use of subjective evaluations of pain rather than vali-
dated clinical scales [19]. AD patients are often impaired
in their ability to provide reliable subjective pain ratings
[20,21], particularly as the disease progresses, and they
report pain less frequently and at a lower intensity in
clinical settings than healthy seniors (HS). These find-
ings, coupled with recognition that AD pathology affects
many pain processing brain regions [22] have prompted
examination of whether AD alters pain perception.
Results of studies testing pain threshold and tolerance
in AD patients, which requires subjective pain ratings,
are mixed. A consistent result has been a lack of
change in acute pain threshold of AD patients [23–25],
indicating AD leaves sensory aspects (intensity/localiza-
tion) of pain intact. Pain tolerance or unpleasantness
findings, thought to reflect pain affect [26], have been

inconsistent. For example, Benedetti et al. [23] found
increased tolerance to electric and ischemic pain; how-
ever, Jensen-Dahm et al. and Cole et al. [27] found
decreased tolerance and increased unpleasantness,
respectively, to pressure pain. It has been proposed
that these mixed results are in part due to impairments
in pain self-report and comprehension of self-report
scales [25].
Different pain indicators may be affected by AD in differ-
ent ways [20]. Indeed, recent reviews highlight the
necessity of observational pain assessment in conjunc-
tion with self-report to improve detection, particularly
those with severe Alzheimer’s disease (sAD). Further
characterization of two such non-verbal indicators, auto-
nomic and behavioral responses, would be helpful in
guiding clinical assessment recommendations and deci-
sion making. Prior studies indicate that, while pain-
related autonomic responses tend to decline as AD pro-
gresses [28,29], pain behaviors, such as facial expres-
sions and guarding [20,21,30,31], are generally
increased in mild/moderate (mAD) patients relative to
HS. How sAD affects pain is unclear as few experimen-
tal studies have included sAD subjects, likely owing to
their inability to provide subjective pain ratings, as well
as ethical issues pertaining to their inclusion in experi-
mental studies [32]. Reduced affect, behavior, and sen-
sation in sAD has been hypothesized [33]. However,
there is clinical evidence of comparable degrees of pain
behavior between sAD and less advanced patients [34]
and experimental evidence of intact pain processing in
late disease stages [24]. Because studies have shown
under-detection and under-treatment of pain in sAD
[11,14] and little is known about pain processing in
advanced stages of AD, further examination of these
patients in an experimental setting is merited.

AD progressively affects brain structures associated with
different aspects of pain (e.g., affective, cognitive, and
sensory) [22]. Limbic structures are affected early by
AD, likely causing changes in pain affect and memory
[22]. Functional brain networks associated with pain
affect/motivation and cognition, such as the salience
and default mode networks, become increasingly dys-
functional as AD progresses [35,36]. Finally, sensory
cortices, associated with processing pain’s intensity and
localization aspects [37], are affected at late stages of
AD [38]. Progressive impairment of brain structural and
functional integrity supports the premise that clinical
indicators of pain may vary based on disease severity
[39]. However, experimental studies further characteriz-
ing pain indicators in sAD and the modulating effects of
disease severity are limited.
In addressing these gaps in the literature, the primary
aim of this study was to examine multiple acute pain
responses (autonomic, pain behaviors, and potential
self-report) in mAD and sAD patients during repeated
application of multiple forearm pressure intensities.
Mechanical pressure algometry was the applied modal-
ity as it has been utilized in multiple studies of pain in
the elderly with and without dementia [20,25,31,40]. In
conjunction with testing for differences between AD
patients and HS, a secondary aim was to determine if
any pain responses varied according to AD severity.
Considering past findings with respect to autonomic
responses [28,29], we predicted that advancing AD
would lead to blunted heart rate (HR) responses. In con-
trast, we predicted that sAD patients would show fewer
pain behaviors than both mAD and HS subjects owing
to advanced brain structural and functional deterioration

as discussed above.
Methods
Subjects
Thirty-eight patients with chart-confirmed Diagnostic
and Statistical Manual IV [41] diagnoses of probable AD
(28 $) and thirty-three HS controls (21 $) participated.
General subject demographics, including percentage of
subjects using of cholinesterase and selective serotonin
reuptake inhibitor medications, are found in Table 1.
Ages of HS subjects were 74.4 6 6.6 (mean 6 SD) years
while AD patients were 79.5 6 8.9 years. Clinical
Dementia Rating (CDR) [42] and Mini-Mental State
Examination (MMSE) scores [43] separated groups,
cognitively (HS: MMSE 26-30, CDR 0; AD: MMSE�23,
CDR 0.5–3). Cutoffs points for designating patients as
mAD were MMSE 18-23 and CDR 0.5-2. Patients were
defined as sAD if they scored MMSE�10 and CDR 3.
HS subjects were required to have no history of subjec-
tive memory complaints. Mean HS MMSE was 29 6 1.1.
Mean AD MMSE was 11 6 9.1.
HS were recruited via ads in newsletters and local AD
support groups. AD patients were recruited through
local nursing facilities and the Michigan State University
Department of Neurology and Ophthalmology’s Cogni-
tive and Geriatric Neurology Clinic. Study sample
Pain Responses in Alzheimer’s Disease
1931

assembly procedures are outlined in Figure 1. A total of
nine AD subjects in the study (all sAD) were nursing
home residents. Subjects were required to abstain from
all standing order analgesic medication for 24 hours
prior to testing. However, individuals were included only
if deemed unlikely to have baseline pain from analgesic
abstinence (determined via chart review and/or caregiver
discussion). No subjects with subjective complaints of
current pain were included. Subjects receiving beta-
blocker medications were allowed if their primary physi-
cian agreed to temporarily discontinue drug treatment
for a period equal to three half-lives prior to study. Fur-
ther exclusions included history of: Type II diabetes,
major depression, history of stroke or transient ischemic
attack, central or peripheral neuropathy, diagnosis of
neurological or psychiatric disorders other than AD, cur-
rent opioid analgesic use, history of chronic pain condi-
tions such as rheumatoid arthritis, fibromyalgia, low
back, and shoulder pain. We also excluded those with
current osteoarthritic pain, those with osteoarthritis in
the stimulus application region (distal forearms), and
those requiring daily analgesics to reduced osteoarthritic
Table 1 Average subject demographics (1/2) standard deviation
Healthy Seniors (n 5 33) Alzheimer’s Disease (n 5 38)
Age (years) 74.4 (1/2) 6.6 79.5 (1/2) 9.9
Sex (F | M) 21 | 12 28 | 10
Mini Mental State Examination (MMSE)* 29 (1/2) 1.1 12.4
(1/2) 9.0
Clinical Dementia Rating (CDR)* 0.0 (1/2) 0.0 2.1 (1/2) 1.1

AD Severity Distribution (mAD | sAD) - - - 17 | 21
Cornell Scale for Depression in Dementia (CSDD)* (1/2) 1.2
7.3 (1/2) 4.5
Neuropsychiatric Inventory Questionnaire (NPI-Q)* 0.0 (1/2)
0.0 7.2 (1/2 0.92
Cholinesterase Inhibitor Medication (% and “n”) - - - mAD:
88.2% (n 5 15)
sAD: 38.1% (n 5 8)
SSRI Medication (% and “n”)* 9.1% (n 5 3) mAD: 52.9% (n 5
9)
sAD: 47.6% (n 5 10)
MMSE ranges: healthy seniors 26-30; AD:�23. CDR healthy
seniors: 0. CSDD normal range: 0–12. mAD 5 mild/moderate
Alzheimer’s disease; mAD range: MMSE 11–23, CDR 0.5–2;
sAD 5 severe Alzheimer’s disease; sAD range: MMSE�10,
CDR 5 3; SSRI 5 Selective serotonin reuptake inhibitor.
* P < 0.001; P < 0.01 considered significant between HS and
AD after Bonferroni correction for multiple comparisons.
Figure 1 Flow chart describing procedures for study sample
assembly. MMSE: Mini-Mental State Exam-
ination; CSDD: Cornell Scale for Depression in Dementia.
* Denotes that abstinence from pain medication or beta-blocker
usage was contraindicated for pain or

cardiovascular health reasons.
Beach et al.
1932
pain. All pain-based exlusions were determined via chart
review and/or caregiver/subject discussion. Care was
taken to exclude patients with probable mixed dementia
through chart review of prior brain imaging and/or clini-
cal evidence of vascular, frontotemporal, or Lewy body
dementia.
This study was conducted in accordance with the Dec-
laration of Helsinki and approved by the Michigan State
University institutional review board. Written informed
consent was obtained for all HS as well as for AD sub-
jects via named health care proxies identified as a
power of attorney for health care or guardian. We
obtained assent from all participants (verbal or non-
verbal) before beginning testing. Testing was discontin-
ued if any subjects became inconsolably agitated or ver-
bally stated that they wished to end participation. This
occurred with one AD subject, who was excluded from
analysis.
Power Analysis
To find differences among HS, mAD, and sAD with
respect to all pain measurements an a priori power
analysis with conservative estimate of correlation
between repeated measures (R 5 0.3), a “small” effect
size (d 5 0.3), estimation for three groups yielded a total
sample size of 45 (N 5 15/group) to achieve 95% power

at alpha 5 0.05. We recruited more than 15 subjects
per group to obtain adequate sampling and for a con-
current neuroimaging study.
Materials and Procedure
Study design was controlled and cross-sectional with
repeated measures testing of behavioral, subjective, and
autonomic responses to mechanical pressure stimuli.
Testing occurred between 1 p.m. and 5:00 p.m. and
lasted 1–1.5 hours. Testing sessions took place within
quiet rooms within long-term care facilities or clinical
research suites at Michigan State University. The proto-
col began with MMSE/CDR testing and completion of
the Cornell Scale for Depression in Dementia (CSDD)
[44]. Any individuals with CSDD >12, indicative of prob-
able depression [44], were excluded. Behavioral and
psychological symptoms were further probed via the
Neuropsychiatric Inventory Questionnaire (NPI-Q) [45].
For AD patients, we obtained CSDD and NPI-Q scores
via proxy, specifically through a family member or pri-
mary caregiver. CSDD and NPI-Q scores were used as
nuisance covariates in statistical analyses. Pressure test-
ing occurred last.
Pressure Stimuli
Pressure stimuli were applied using a Force Dial FDK 20
Force Gauge (Wagner Instruments, Greenwich, CT),
which allows accurate recording of pressure (kg/cm2).
Here, integer pressures shall be referred to in units of
“kg” as per device scaling. The instrument is fitted with
a 1 cm wide rubber disk to prevent skin abrasion. Pres-
sures were applied to the lateral volar surface of the dis-
tal forearm, 2–5 cm from the wrist. Subjects were

seated, upright, during testing and without arm restraint.
Because standardization of pain levels is not feasible in
sAD subjects, pressure application was adapted from a
previous dementia-related pain study [31]. Twenty stim-
uli of 1–5 kg of pressure intensity were applied to left
and right forearms (four stimuli per intensity). Stimulus
order was determined once for use in all subjects
through creation of a randomization algorithm in MAT-
LAB software. The algorithm produced the stimulus
order according to the following rules: each stimulus
must occur four times with application occurring on
both the right and left arms; no intensity could occur
more than twice, sequentially; no stimulus intensity
could be repeated on the same arm twice in sequence.
Subjects were first familiarized to the stimuli via single
application of each intensity to the thigh. Pressure appli-
cation occurred at a rate of approximately 1 kg/s to
peak intensity, which was held for 5 seconds. Intersti-
mulus intervals were approximately 50 seconds. Two
trained investigators performed all cognitive and behav-
ioral testing in a standardized manner (PAB, MM). Video
recording allowed for scoring of behavioral responses
and HR changes after testing procedures were
completed.
Pain Behavior Measures
Behavioral acute pain responses were scored only for
the 5 seconds stimulus application period. The intersti-
mulus interval allowed for a return to resting behavior.
Subjects who did not return to baseline shortly after
stimulus application ceased were considered too agi-
tated to continue (this occurred for one subject, as
mentioned above). Acute pain behaviors were scored
using portions of the Pain Assessment in Advanced
Dementia (PAINAD) scale, a validated observational

scale for assessing pain in demented patients in both
long term care [46–48] and acute care settings [49–52].
The full version of the PAINAD assesses breathing, neg-
ative vocalization, facial expression, body language, and
consolability. Each domain is scored 0–2 for a maximum
score of 10 points. A recent panel review of studies
examining the validity and reliability of the PAINAD found
that breathing had low internal consistency [53] and
construct validity [54]. In the same review, consolability
was considered more likely to reflect an intervention
than a measure of pain [55]. Consolability was also con-
sidered a poor indicator of pain [54] and was not rated
higher in nursing residents with vs without pain [56].
Furthermore, pilot work with patients and controls
yielded rater impressions that application of the consola-
tion portion of the PAINAD was biased toward patients
due to perceived vulnerability, which would have artifi-
cially inflated patient PAINAD scores. Thus, for purposes
of this experimental study, breathing and consolability
were not incorporated, yielding a maximum modified
PAINAD (mPAINAD) score of 6. Scoring was aided for
all raters through use of identical descriptors provided
as part of the PAINAD and PAINAD-related resources
1933
[55]. All raters underwent identical training procedures
via an online resource meant to aid in training nursing
staff on use of the PAINAD [57]. Two trained PAINAD
raters (PAB, MMM) initially scored half of the sessions.
However, as they were not blinded to stimulus order or
group designation a third rater (JTH) was added who

was blinded to both group designation and stimulus
order. This rater rescored all original sessions, blinded
to the original rater scores, as well as all remaining ses-
sions. Final mPAINAD ratings for doubly-scored subjects
were determined through a modified Delphi-type con-
sensus procedure between the blinded rater and the
relevant original rater. The original ratings of doubly-
scored subjects were used as part of rater reliability
testing.
Subjective Pain Measures
Shortly after stimulus completion (�5 seconds after),
after the period in which behavioral responses were
measured, subjects provided subjective pain ratings
with the Faces Pain Scale-Revised (FPS-R) [58]. The
FPS-R consists of six faces corresponding to feeling no
pain to “very much pain.” Each face after the initial
“zero” face represents a two-point stepwise increase,
creating a 0–10 numerical match-up. The FPS-R has
been shown to be reliable in assessing pain in cogni-
tively impaired patients, including those with MMSE
scores < 11 [59,60]. However, AD subjects had to pass
a three-question quiz as part of the FPS-R to be
deemed a reliable informant [61].
Autonomic Measures
Autonomic responses were monitored by way of HR. A
portable infrared monitor (ePulse2TM–Impact Sports
Technologies) displayed HR throughout testing. A
response was determined by subtracting the HR at
stimulus onset (baseline) from the maximum response
within 30 seconds after offset, resulting in an overall
positive or negative response. Interstimulus intervals
allowed for return to resting HR.

Statistical Analysis
Each measured response (mPAINAD, FPS-R, and HR
change) pertaining to repeated pressure applications
were scored separately and entered into statistical anal-
yses discussed below. However, because mPAINAD
and FPS-R data distributions were non-normal each
score was first recoded for purposes of statistical mod-
eling. mPAINAD scores were recoded by clustering
scores: “0,” “1–2,” “3–4,” and “5–6.” FPS-R scores
were recoded by clustering scores: “0,” “1–3,” “4–6,”
“7–9,” and “10.”
Rater reliability testing of mPAINAD scores was deter-
mined through three methods. First, average absolute
agreement intraclass correlation coefficients (ICC) were
calculated for those subjects whose data were scored
by two raters (N 5 36) to determine inter-rater reliability.
ICC was calculated for overall mPAINAD as well as indi-
vidual domains and the overall average ICC was calcu-
lated from those scores. Second, for subjects scored by
a single rater (N 5 35), a randomly selected 15% were
rescored by the single rater who was blinded to stimu-
lus order, group designation, and original scores prior to
calculation of ICC as above. Third, internal consistency
of all subject scores over repeated applications of each
intensity was determined by calculating Crohnbach’s
Alpha. This latter measure was also used to determine
test-retest reliability of repeated pressure applications.
Generalized linear mixed modeling (GLMM) in SPSS TM
(Version 22.0, Armonk, NY: IBM Corp) determined
impact of level-two effects (subject group—HS and AD)

on level-one effects (mPAINAD/FPS-R scores and HR
changes), with subject and stimulus intensity as predic-
tors. GLMM accounts for repeated measures (trials) and
nuisance covariates (age, gender, CSDD, NPI-Q severity
score, stimulus applicant). Significant “group” or
“group*stimulus intensity” interaction effects (P < 0.05)
were followed by post hoc nonparametric Kruskal–Wallis
testing between groups under each stimulus intensity
for mPAINAD and FPS-R scores. To control for family-
wise error, post hoc results were considered significant
if they met a Bonferroni correction threshold of
P < 0.01. HR data were normally distributed, allowing
GLMM procedures to perform post hoc analysis with
Bonferroni correction.
Previous studies of pain in AD indicated increased pain-
specific facial expressions, compared with controls
[20,21]. We attempted to extend this finding by examin-
ing whether groups differentially utilized mPAINAD
domains (verbal, facial, and body) to behaviorally
express pain. Individual mPAINAD scores were dis-
sected for domain-specific points summed across
repeated trials of stimulus intensities. GLMM and subse-
quent post hoc testing, described above, were then
utilized.
To probe potential AD severity-dependent effects, a
secondary analysis was performed whereby AD patients
were split into subgroups: mAD (CDR 0.5-2; MMSE 11-
23; 17 subjects) and sAD (CDR 3; MMSE�10; 21 sub-
jects). A GLMM, incorporating level-one effects and nui-
sance covariates described above, was performed to
distinguish mAD and sAD subgroups (level two effects)
as well as HS. Significant effects were further investi-
gated with appropriate post hoc testing, described
above. Family-wise error was controlled for as described

above.
Results
Study Results
General subject demographics are found in Table 1. Per
independent samples testing, AD subjects were some-
what older, on average, than HS, although this failed to
meet corrected significance threshold (t 5 22.5,
Beach et al.
1934
P 5 0.02). AD subjects scored higher on the NPI-Q and
CSDD (t 5 27.2 and 27.4, respectively, P < 0.01 for
both). However, no subjects had CSDD scores indicat-
ing clinical depression (>12). Community-dwelling AD
subjects and those recruited from nursing homes were
marginally more likely to use cholinesterase inhibitors
and SSRIs (Chi-Sq 5 3.64, P 5 0.06 for both), but were
not different with respect to gender (Chi-Sq 5 1.41,
P 5 0.24); those recruited from nursing homes were
older, had fewer symptoms of depression (lower CSDD
scores), and fewer neuropsychiatric symptoms (NPI-Q
scores; t 5 23.4, 2.4, and 2.1, respectively; P < 0.05 for
all).
ICC for inter-rater reliability testing scored, on average,
0.93 (1/2 0.04, SD, P < 0.005) for overall mPAINAD
and each behavioral domain, suggesting strong agree-
ment between raters. Intra-rater ICC calculation
between original and a rescored subjects’ mPAINAD

scores was 0.86 (SD: 0.08, P < 0.005), indicative of
strong intra-rater reliability. Both inter- and intra-rater
ICC results are consistent with prior studies of PAINAD
consistency [55]. Crohnbach’s Alpha testing yielded an
overall average score of 0.84 (1/2 0.08, SD) indicating
a high level of internal consistency for subject mPAINAD
scores over repeated trials.
There were no significant main effects comparing HR
responses of HS and AD, (group: F 5 0.21, P 5 0.64 |
group 3 stimulus intensity: F 5 1.74, P 5 0.093). Figure
2 shows a plot of average HR responses for HS, AD,
and AD subgroups (mAD/sAD) for each stimulus inten-
sity. Secondary GLMM testing confirmed a severity-
dependent effect for HR: sAD responses were, in gen-
eral, diminished compared with HS and mAD (F 5 4.7,
P 5 0.009). No post hoc comparisons met Bonferroni
correction threshold of P < 0.01. However, sAD subjects
tended to have reduced responses compared with mAD
at 3 kg (t 5 22.6, P 5 0.016) and HS at 3 kg (t 5 22.8,
P 5 0.016). No significant differences between mAD and
HS were found (t 5 1.1, P > 0.2).
GLMM testing of mPAINAD data yielded significant
effects of group and group 3 stimulus intensity
(F 5 34.4, P < 0.001; F 5 270.6, P < 0.001, respectively).
Figure 3 shows average mPAINAD scores (nonrecoded)
for HS and AD. Kruskal–Wallis post hoc testing showed
significantly greater mPAINAD scores for AD subjects at
stimulus intensities 2–5 kg (Chi-Sq all > 12; P < 0.001).
Secondary GLMM found no significant effects (F 5 0.10,
P 5 0.75) indicating no AD subgroup differences for
mPAINAD scores—thus subgroups are not plotted in
Figure 3.

Significant effects of group and group 3 stimulus inten-
sity were found for each mPAINAD domain (vocal:
group–F 5 261.9, P < 0.001–interaction–F 5 3.131.8,
P < 0.001 | facial: group–35.2, P < 0.001–interaction–
F 5 286.5, P < 0.001 | body: group–F 5 67.5,
P < 0.001–interaction–F 5 2.083, P < 0.001). These
results suggest that each domain contributed to the
overall increase in mPAINAD scores for AD subjects.
Average summed domain responses for HS and AD are
plotted in Figure 4a–c. Post hoc Kruskal–Wallis testing
of each domain yielded significant increases for AD sub-
jects in: vocalization for 2–5 kg (Chi-Sq 5 8.8, 18.7,
23.9, 29.4, respectively, P < 0.003); facial expression at
2–5 kg (Chi-Sq 5 7.7, 13.3, 12.3, 7.9, respectively,
P < 0.005); and bodily response at 2–5 kg (Chi-
Sq 5 8.8, 10.8, 13.9, 15.9, respectively, P < 0.003).
Secondary GLMM testing found no severity-dependent
effects for individual domains (vocal: F 5 0.23, P 5 0.63 |
facial: F 5 0.002, P < 0.97 | body: F 5 0.242, P 5 0.62),
thus subgroup responses are not plotted in Figure 4.
AD patients with high levels of cognitive impairment
(MMSE�10/CDR 5 3, sAD subgroup) were unable to
pass FPS-R reliability testing. FPS-R results therefore
Figure 2 Average HR changes from baseline (beats per minute,
bpm) across stimulus intensities (kilo-
grams, kg). Error bars represent standard error of the mean
(SEM). P < 0.01 considered significant after
Bonferroni correction for multiple comparisons.
1935

represent differences between the mAD subgroup and
HS. Here, GLMM testing found a non-significant group
effect (F 5 1.48, P 5 0.22) but a significant group 3
stimulus intensity interaction (F 5 14.1, P < 0.001). Fig-
ure 5 shows average (non-recoded) FSP-R scores for
HS and AD. Kruskal–Wallis testing showed FPS-R rat-
ings were higher in AD patients for lower level stimuli 1
and 2 kg (Chi-Sq 5 8.7, P 5 0.003; Chi-Sq 5 8.0,
P 5 0.005, respectively). Ratings for 3 and 4 kg inten-
sities were slightly higher in AD subjects, but did not
reach Bonferroni correction threshold (Chi-Sq 5 3.6,
P 5 0.057; Chi-Sq 5 3.5, P 5 0.067). Ratings at 5 kg
were very similar (Chi-Sq 5 0.32, P 5 0.57) between
groups.
Discussion
Although recent studies have reported behavioral and
neuroimaging evidence of increased pain sensitivity in
AD, few studies have included severe patients
(MMSE�10/CDR 5 3). We, therefore, examined acute
pain responses (autonomic, pain behaviors, and poten-
tial self-report) in mAD and sAD patients, as well as HS,
during repeated application of multiple forearm pressure
intensities. A secondary analysis probed for severity-
dependent differences for mAD and sAD subgroups.
There was no overall difference in HR response
between HS and AD subjects as a whole. However,
consistent with our prediction, secondary analyses
found that sAD patients had diminished responses com-
pared with both HS and mAD. A tendency for AD
patients to show blunted autonomic responses to mild

pain is a consistent finding in the literature
[20,21,28,29]. In studies including patients with MMSE
as low as 8, increasing cognitive impairment was asso-
ciated with autonomic blunting [21,28,29], with higher
levels of noxious stimulation required for “quasi-normal”
autonomic responses. Our findings extend these prior
results to patients with MMSE as low as 0. Blunted
autonomic responses have been interpreted by some
authors as evidence of reduced pain affect in AD
[28,29]. However, it is equally likely that central auto-
nomic dysfunction is responsible. Altered autonomic
function has been described in AD [62,63], and cortical
and subcortical autonomic regulators are affected by
AD pathology [22]. The result may be a disconnect
between pain-related autonomic and affective-
behavioral responses that worsens with AD progression.
Considering our pain behavioral findings, it would
appear that autonomic responses are not a reliable pre-
dictor of pain in AD.
AD subjects had higher mPAINAD scores than HS for
all but the lowest pressure intensity indicating greater
overall behavioral responsiveness. In contrast with our
initial predictions regarding pain behaviors in sAD, no
severity-dependent differences in mPAINAD scores
were found. Prior studies also reported increased
behavioral expression of pain in AD and other dementia
patients. Multiple studies have found increased pain-
related facial expressions in AD/dementia patients, rela-
tive to HS [20,21,30,31]. Greater degrees of body-
based pain responses, namely stiffness, guarding, and
nociceptive flexion, were also found in prior studies of
cognitively impaired patients [20,30]. Using portions of
the PAINAD, which scores behaviors such as facial
expressions on a more approximate level, we also found

increases in pain-related facial responsiveness, bodily
responses, and negative vocalizations contributed rela-
tively equally to overall increased pain behaviors in AD
patients, regardless of severity.
The level of cognitive impairment played a role in
whether subjects could self-report, as no sAD subjects
could reliability rate pain with the FPS-R. However, mAD
subjects, all reliable reporters, rated low-level stimuli,
and to a lesser degree mid-level stimuli, as more painful
than HS. Our findings here imply greater subjective pain
in AD patients. However, some caution is merited as
our primary group differences occurred at low levels of
pressure, becoming more equivalent at higher pres-
sures. Thus, an alternative explanation of our FPS-R
findings could be an exaggerated patient response to
Figure 3 Average mPAINAD scores across each stimulus
intensity (kg). Error bars represent SEM.
P < 0.01 considered significant after Bonferroni correction for
multiple comparisons.
Beach et al.
1936
innocuous pressures or weak pain by patients. The lat-
ter could have occurred, despite all mAD patients pass-
ing reliability testing, perhaps through misunderstanding
of the context or the clinical scale utilized. However,
greater degrees of pain behaviors in patients vs con-
trols, via mPAINAD scores, at the same low pressure
levels makes it equally likely that pain sensitivity is

increased in AD. Indeed, our findings are in accordance
with recent studies that showed increased unpleasant-
ness to low level pain and reduced pain tolerance in
mAD patients experiencing mechanical pressure [25,27].
These results contradict early findings of increased pain
tolerance in AD patients [23,28,29], which included
some advanced patients (MMSE 8-10). Early studies uti-
lized electrical and ischemic pain modalities, which may
account for some differences in results. It should be
noted that increased cognitive deterioration was associ-
ated with impaired subjective pain report here and in
other studies [20,31]. In healthy adults, pain memories
deteriorate on the order or seconds [64]; this effect is
likely far worse AD patients. Indeed, reduced pain-
related semantic memory in AD was associated with
reduced self-report of pain in one study [65], suggesting
patients may under-report pain due to cognitive
impairment.
A neural mechanism for increased subjective and
behavioral acute pain responses in AD is currently not
known. One fMRI study of healthy subjects found that
facially expressive individuals had greater activation in
pain processing and motor regions, with less activity in
prefrontal and striatal regions compared with “stoic”
subjects [66]. While expressive subjects had a higher
sensory/affective experience, stoic individuals, investiga-
tors concluded, were better able to maintain self-reflec-
tive/introspective states and suppress motor responses
in accordance to learned display rules. AD affects the
function of networks and structures associated with
Figure 4 Average summed total mPAINAD points in each
domain across repeated trials of each stimu-

lus intensity (kg) for Healthy Seniors and Alzheimer’s disease
subjects. (a) mPAINAD vocal domain; (b)
mPAINAD facial domain; (c) mPAINAD bodily domain. Error
bars represent SEM. P < 0.01 considered
significant after Bonferroni correction for multiple
comparisons.
1937
cognitive control, introspection/self-reflection, and pain/
salience processing [22,35,36]. In advanced stages,
even sensory cortices are affected [38]. AD may thus
increase acute pain sensitivity and pain behavior
through its effects on cognitive control, salience, and
self-reflective neural processing. Indeed, fibromyalgia
and chronic back pain patients have altered connectivity
between self-reflective and salience processing struc-
tures [67–69]. Pain-processing/salience structures may
also become sensitized, leading to greater activity dur-
ing acute pain. Supporting this notion, Cole et al.
[27,70] found moderate pressure pain induced greater
activation and functional connectivity among pain-
processing regions in mAD vs HS. Nevertheless, a
reduction in cognitive control mechanisms cannot be
ruled out as a driver of increased pain behaviors, and
perhaps pain ratings, in patients. For example, milder
pain in AD patients may be subjected to less top–down
cortical influence compared with more moderate/severe
pain. This could then lead to increased pain behaviors
and ratings seen in this study and others [20,31] more

so at lower stimulus levels. As late AD pathology does
affect somatosensory cortex [22,38], altered sensory
pain may also have contributed to behavioral findings in
patients. Further examination of AD-related brain func-
tion in the context of acute pain would be advantageous
to further test these hypotheses.
A strength of this study is its inclusion of a relatively large
number of sAD subjects. However, this precluded a more
detailed examination of pain threshold and tolerance. Our
subject population was majority Caucasian (�90%),
which limits the ethnic generalizability of our findings. We
also only tested pain responses using one stimulus
modality, pressure, and only in one session. It is possible
that different results may have been obtained through use
of electric and/or ischemic modalities, such as those by
Benedetti et al [23]. However, increased behavioral pain
responses and similar pain ratings in AD compared with
HS have also been found using electrical, laser, and nee-
dle stick modalities [20,21,24]. It would be interesting for
future studies to investigate pain behaviors across multi-
ple acute pain modalities to examine whether AD patients
exhibit varied sensitivities in that regard. Pain behaviors
measured in AD patients could be related to psychosocial
distress, a proposed confounder of PAINAD scoring [71].
However, both subjective and behavioral pain responses
increased to a greater degree with advancing stimulus
levels in patients, compared with controls, suggesting
that discomfort/pain was in fact measured. Although sub-
jective pain ratings and pain behaviors were increased in
patients, compared with controls, the two were not
increased concurrently. While subjective ratings of
patients were higher than controls primarily at low-level
pressures, pain behaviors were consistently higher across
most pressure levels. This discrepancy has occurred in

multiple studies [20,27,31] and may relate to differences
in the effects of AD on the neural processes differentially
responsible for subjective pain and pain behaviors.
Impairment of pain memories and use of pain scales may
also be involved. Future work could investigate the speci-
ficity of global pain behavioral measures such as the
Figure 5 Subjective pain ratings results. Top: Faces Pain Scale-
Revised [FPS-R (58)] with appropriate
matching numerical and affective descriptors added for clarity
(affective descriptors not part of the FPS-
R; The FPS-R has been reproduced with permission of the
International Association for the Study of
Pain
VR
; the figure may not be reproduced for any other purpose
without permission); Bottom: Average
subjective pain-report scores for each stimulus intensity (kg).
Scores of AD patients represent those who
passed reliability testing for the FPS-R. Error bars represent
SEM. P < 0.01 considered significant after
Bonferroni correction for multiple comparisons.
Beach et al.
1938

PAINAD by correlating scores with experimental tools
such as the Facial Action Coding System, which may
more precisely measure pain-specific facial expressions.
Finally, because we focused our efforts on acute pain
responses, we cannot speak to whether our results
extend to chronic (clinical) pain states. Some prior studies
examined clinical/chronic pain in demented/cognitively
impaired elderly by measuring responses during proce-
dural modalities (e.g., physiotherapy maneuvers) [30,72].
Future study could, therefore, involve replicative work
strictly related to AD patients.
This study examined various biobehavioral pain indicators
including autonomic responses, behavioral, and subjective
pain ratings in mild, moderate, and severe AD patients. We
found that while sAD patients had overall blunted auto-
nomic pain responses, both sAD and mAD patients
showed greater degrees of pain behaviors, compared with
HS. Mild/moderate Alzheimer’s disease patients also rated
low-level stimuli as more painful than HS. Further inclusion
of sAD patients in experimental study is necessary to fur-
ther validate findings here. However, our data support the
notion that acute pain may be exacerbated in AD, regard-
less of severity or ability to self-report. Our findings thus
have a number of translational consequences. First, auto-
nomic responses lose utility as a measure of pain as AD
advances; we cannot endorse their use in a clinical con-
text. In contrast, assessment of non-verbal pain behaviors
was rather sensitive to pain in patients of all severities.
Importantly, we found that the behavioral components of
the PAINAD were able to measure gradations in pain inten-
sity, rather than simply the presence or absence of pain.
The PAINAD thus could be used to determine effective-
ness of analgesic interventions of patients. Mild and severe
patients alike showed increased sensitivity to pressure
pain, compared with controls. Thus, it should not be

assumed that reductions in self-report represents and
absence of pain, particularly in advanced AD. Indeed, all
AD patients should receive frequent behavioral assess-
ments to increase comfort and reduce behavioral and psy-
chological symptoms of dementia [3,5,73]. Finally, our
finding of pain behaviors out of proportion to subjective rat-
ings in mAD patients suggests that pain may be under-
reported by patients, even those deemed “reliable” self-
reporters. We would thus recommend that clinicians and
caregivers integrate frequent proxy and self-report meas-
ures of pain in AD patients as part of an overall assessment
strategy to improve clinical pain management and patient
quality of life.
Acknowledgments
We thank: participating nursing facilities, patients and
families, and control volunteers; undergraduate
research assistants Katie Swanic and Rose Delaney;
Drs. Laura Symonds and Kevin Foley for experimental
design and manuscript advice; MSU Center for Statisti-
cal Training and Consulting (CSTAT). We also thank
funding sources: the MSU Dept. of Family Medicine
Pearl Aldrich Graduate Student Fellowship (Grant:
RT083166-F5015) and the Blue Cross Blue Shield of
Michigan Foundation (Grant:1981.SAP).
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1942
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