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Treating pain in patients with dementia and
the possible concomitant relief of symptoms
of agitation
Joseph V Pergolizzi1, Robert B Raffa2, Antonella Paladini3, Giustino Varrasi4&JoAnn
LeQuang*,1
1NEMA Research, Inc., Naples, FL 34108, USA
2University of Arizona, Department of Pharmacy, Tucson, AZ 85721, USA
3Department of MESVA, University of L’Aquila, L’Aquila 67100, Italy
4Paolo Procacci Foundation, Roma, Italy
*Author for correspondence: joannlequang@gmail.com
Practice points
•Chronic pain, like cognitive decline, is more prevalent in older than younger patients. When chronic pain and
cognitive decits, such as dementia, exist in one patient, that patient may have difculty communicating his or
her need for pain control. This may lead to frustration, despair, anger, aggression and uncontrolled suffering.
•A variety of instruments are available to help assess pain in dementia patients, many of which rely in whole or in
part of observing the patient. Writhing, restlessness, wandering and vocalizations may indicate the patient is in
pain.
•Pain signals are processed differently in the brain with dementia although there are gaps in our understanding as
to how pain in dementia patient is perceived, processed and felt. There is evidence to suggest that pain may be
felt more acutely in patients with mild to moderate Alzheimer’s disease (AD) but as AD becomes more severe,
pain is lessened.
•People with AD do not have placebo response which is an important (although incompletely understood) aspect
of pharmacological pain control. Dosing adjustments may be required, but the patient’s age and comorbidities
must also be taken into account.
•Treating pain in patients with dementia has, in some studies, reduced agitation, distress, aggression and other
negative behavioral aspects of dementia.
•Patients with dementia have diminished ability to communicate but still can feel pain and distress, perhaps even
severely. They deserve pain control and compassionate care. There are limited clinical trials that explore the use
of analgesic therapy in dementia patients, so clinicians must often individualize care based on their holistic
assessment of the patient.
Dementia is an irreversible, progressive form of cognitive dysfunction that can affect memory, learning
ability, thinking, orientation, comprehension, calculation, linguisticskills and executive function but which
does not impair consciousness. Pain prevalence is high among the elderly who are also at elevated risk
for dementia. Pain control for dementia patients is important but can be challenging for clinicians as
cognitive decits can make it difcult to identify, localize and assess pain. Cerebral changes associated with
dementia may change how people process and experience pain in ways that are not entirely elucidated.
Agitation is a frequent symptom of dementia and may be associated with untreated pain as agitation and
aggression symptoms decrease when pain is effectively addressed.
First draft submitted: 18 June 2019; Accepted for publication: 5 September 2019; Published online:
22 November 2019
Keywords: Alzheimer’s disease •analgesia •dementia •opioids •pain •pain assessment •pain treatment
Dementia is an irreversible, typically progressive cerebral dysfunction that can affect memory, learning ability, the
thought process, orientation, comprehension, calculation, linguistic skills, judgment and executive function but
does not impair consciousness. Dementia has been most frequently associated with Alzheimer’s disease (AD) but
may also be secondary to vascular disorders, frontotemporal lobe dysfunction, Lewy body dementia, trauma or
stroke. Associated with all forms of dementia may be deficits in self-control and emotional constraint, impaired
Pain Manag. (2019) 9(6), 569–582 ISSN 1758-1869 56910.2217/pmt-2019-0024 C
2019 Future Medicine Ltd
Review Pergolizzi, Raffa, Paladini, Varrasi & LeQuang
social interactions, disruptive behaviors and lack of motivation [1]. About 50 million people worldwide have
dementia (roughly the population of Spain), of which the majority (33 million) have AD [1,2]. The prevalence of
dementia is expected to increase markedly with the aging of western populations to encompass about 152 million
worldwide by 2050 [2]. It has been estimated that in the USA, about 50% of all long-term care residents have
dementia or some form of significant cognitive impairment [3].
Pain prevalence likewise increases with advancing age and the populations of elderly dementia patients has
substantial overlap with the population of elderly chronic pain patients. Pain is challenging to assess in certain
dementia patients, but the prevalence of chronic pain in dementia patients has been estimated to range from
34 to 50% [4] or 46 to 56% [5]. There are many barriers to the adequate control of pain in the population of
dementia patients: communication difficulties; polypharmacy; resistance to care; agitated, aggressive or disruptive
behaviors; limited ability of clinicians to assess pain; analgesic side effects and comorbid conditions that can
complicate treatment (such as renal dysfunction, etc.). Yet there may be important benefits to controlling pain in
dementia patients in addition to providing pain relief and comfort to the patients. Adequate analgesia may lessen the
likelihood of agitation, disruptive acts or aggressive behaviors; it may improve the patient’s quality of life and it may
have positive effects on caregivers who can better relate and interact with the patient. There is conflicting evidence
about pain control in this population and it appears to vary by region. One systematic review of 23 studies of
US prescription data found opioid analgesics were largely underutilized in cognitively impaired patients compared
with those who were cognitively intact [6], while a prospective study from Australia of 383 long-term care residents
reported opioid analgesic use was similar between those with and without dementia (79.3 vs 73.4%, respectively,
p = 0.20) [7]. A retrospective survey of 113 nursing home residents in England reported that opioid and nonopioid
analgesia consumption was higher in patients with less cognitive impairment compared with those more cognitively
impaired [8]. In a study of patients in 14 long-term care facilities in Norway from 2000, 2004, 2009 and 2011
(n = 1926, 1163, 850 and 1858, respectively), overall strong opioid use increased significantly from 1.9% of patients
in 2000 to 17.9% in 2011 (p <0.001); however, in all of the first three study years, dementia patients received less
analgesia (both opioid and nonopioid) compared with those without dementia; in 2011, analgesic use was similar
in residents with or without dementia [9]. A survey of 1507 patients ≥65 years undergoing surgery for hip fracture
found 19.6% of this population had dementia and were treated with significantly less opioid analgesics on the first
and second days after surgery than patients without dementia (29.0 vs 34.7 mg; p = 0.001 for day 1 and 27.8 vs
31.2 mg; p = 0.019 for day 2). By the third postoperative day, the difference became insignificant [10].Despitethe
importance of this topic and the large number of patients impacted, this subject has not been thoroughly studied.
The authors of this present review set as their objective the treatment of pain in dementia patients, with particular
emphasis on opioid analgesics and the degree to which such analgesic therapy might modify or improve behavioral
symptoms such as agitation. The authors found relatively little in the literature in terms of high-quality randomized
studies. Therefore, this is a narrative review rather than a systematic review. In general, dementia patients appear to
be under-represented in clinical trials likely owing to cognitive roadblocks to informed consent and full participation
in studies.
Methods
The authors searched peer-reviewed medical literature using the PubMed database for the following keywords:
‘opioid for agitation in dementia’, ‘opioid dementia’ and ‘opioid dementia safety’, obtaining 22, 399 and 24 results,
respectively. The search encompassed all types of literature (case reports, systematic reviews, meta-analyses, narrative
reviews, clinical trials, retrospective studies, commentaries etc.) and although no temporal delimiters were imposed
on the searches, authors were free to exclude literature considered to be outdated, typically >10 years. Articles
were excluded if they were not available in full text or not available in English. Also retrieved was information
from authoritative websites and background information (e.g., epidemiological data). Also reviewed were the
bibliographies of the articles. The broader search terms yielded more results, but these results often overlapped with
narrower searches. Altogether, 75 articles were used.
Our approach was limited by several factors. First, there are few if any randomized clinical trials on this topic
for obvious reasons. As such, we had to rely on literature of substantially different weights: case reports, opinions,
commentaries, editorials, reviews – among others. This made it difficult to grade and analyze results as one might
do in a systematic review, since we had such a range of content. We included the literature on point to our topic
and rejected papers not on our subject (not dealing with dementia and pain) or those that were older than 10 years.
Since studying patients with dementia with respect to symptomology and analgesic effectiveness poses challenges
570 Pain Manag. (2019) 9(6) future science group
Treating pain in dementia patients & possible concomitant relief of agitation symptoms Review
to investigators, it is unlikely that a systematic study comparing the results of multiple randomized clinical trials in
this population can be performed. Our approach is not a quantitative review and is limited by the fact that a variety
of evidence levels have been combined. However, given the nature of the subject and the difficulties studying this
population, the authors view this as a reasonable effort that can provide some insight into the challenges of this
important field.
Results
The results of our research yielded information specific to dementia patients: pain epidemiology, pain processing,
challenges in pain assessment, agitation and other behavioral issues possibly related to pain, effective analgesia,
results from pain control studies and considerations about the use of opioids.
Pain epidemiology in the population with dementia
Chronic pain represents a serious, global public health condition that affects people of all ages. In a cross-sectional
population-based survey conducted in 2014 in Umbria, Italy, it was found that chronic pain affected 28.4% of the
population, in whom about half (51.5%) experienced chronic pain considered to be severe. Prevalence of chronic
pain was significantly higher in females than males (p <0.001) and increased with advancing age (p <0.001) [11].
In a survey of 129 patients seeking help from a pain speciality center, 38% did not seek help from a pain center
until suffering years of chronic pain and two-thirds of respondents had visited multiple clinicians prior to seeking
specific pain treatment [12]. While it is not possible to know why there was a protracted time lag between onset of
painful symptoms and seeking effective treatment, it is possible that for many adults pain was accepted as a natural
part of life and many patiently took a ‘wait-and-see’ approach to see if the pain would resolve on its own. Overall,
compared with younger adults, the elderly have a higher incidence and prevalence of chronic pain, which may in
many cases be inadequately treated [13]. Thus, older individuals are vulnerable to chronic painful conditions and
the presence of dementia in this population may compromise care.
Pain is typically a self-reported symptom, and the cognitive challenges and communications deficits of dementia
patients make self-reporting difficult, unreliable, erratic and even impossible. Barriers to pain self-reporting in
dementia patients include linguistic deficits, personality changes, memory loss, confusion, poor judgment, a
decline in abstract thinking and executive function. This is further confounded by the fact that many pain-related
behaviors may be misinterpreted as dementia symptoms (agitation, aggression, vocalizations etc.) [3].
Pain processing in dementia patients
Dementia appears to dysregulate pain processing and different subtypes of dementia may alter pain processing in
different ways [14]. There are substantial gaps in our understanding of how dementia and other cognitively impaired
patients perceive and process pain. The corruption of cognitive skills associated with dementia impedes even basic
pain descriptions, but the inability of people with dementia to describe pain or ask for pain relief should not be
taken to mean that there is no pain [15]. Deficits in communication may obscure the challenging fact that dementia
patients appear to process and perceive pain differently than people without dementia.
The body processes pain using at least two interconnected neural networks in the brain. The medial network
(amygdala, medial thalamus, hippocampus, anterior cortex cinguli and prefrontal cortex) is thought to process the
cognitive, evaluative, motivational, affective, autonomic and endocrine aspects of pain [16]. The rostral or lateral
network (somato-sensory areas of the brain and lateral thalamic nuclei) helps an individual to localize pain, perceive
its relative intensity and describe its characteristics [16,17]. Recent research has proposed a third interconnected
neural network involved in pain: the limbic network, which processes the behavioral aspects of pain. The limbic
system, for example, might cause a patient in pain to vocalize, writhe or become agitated in response to pain [18].
The neuropathology associated with AD seems to result in neural changes that give patients with AD greater pain
tolerance (changes in the medial neural network) while maintaining the same pain threshold (fewer changes in the
lateral network), a shift that becomes more pronounced as the AD worsens [16].
There is considerable overlap among these three systems (medial, lateral and limbic) with the exception of the
ventral striatum of the brain, which works exclusively in the limbic pathway. The ventral striatum can be severely
affected by AD. In patients with mild-to-moderate AD, the ventral striatum is activated to a greater degree by pain,
but as AD becomes increasingly severe, the ventral striatum is activated less. This may help explain why behavioral
changes due to pain appear to be more pronounced in patients with mild-to-moderate AD and that these behavior
changes become blunted as the AD becomes increasingly severe [18]. This aligns with the observational finding
future science group www.futuremedicine.com 571
Review Pergolizzi, Raffa, Paladini, Varrasi & LeQuang
that pain-related aberrant behaviors are not as prevalent in severe dementia patients compared with those with
mild-to-moderate forms [19]. Of course, the brain’s ability to process pain is complex and relies on the interplay of
multiple pathways to integrate the multiple dimensions of the pain experience: sensory, emotional, cognitive and
contextual. It is not clearly understood how dementia affects these other dimensions of the pain experience.
The neuropathological changes to the brain vary with the subtype of dementia and may be reflected in how the
individual feels pain, for example, compared with control patients, vascular dementia patients seem to have greater
pain intensity while patients with frontotemporal dementia and AD have less pain intensity [20]. More research is
needed to better elucidate these distinctions. It has been proposed that changes in white matter in the brain may
play an important role in pain processing. For example, white matter lesions secondary to a stroke may result in
centralized pain symptoms in patients with or without dementia [21]. White matter changes with advancing age
regardless of whether or not cognition is impaired, and these changes in white matter have been associated with
reduced tolerance for pain [22]. A study of elderly patients without dementia found that white matter was involved
in the affective component of pain processing [20]. White matter is involved in the intracortical and intrasubcortical
connections in the brain and is also involved in connecting cortical to subcortical regions [23].
The prefrontal cortex plays a major role in processing emotion, including the emotional component of the pain
experience [24]. Changes in white matter can be correlated to an individual’s pain affect [20]. Changes in white matter
(as well as functional deficits in the lateral pain pathways) may serve to disinhibit the medial pain system, which is
associated with the development of chronic pain [20]. An intriguing finding is that a cingulotomy (transection of
the anterior cingulate cortex) confers analgesic benefit in the form of relief of the aversive symptoms of pain [25].
This likewise warrants further elucidation.
The AD patients were shown to have blunted autonomic responses but normal pain perception when they are
delivered a mild noxious stimulus, but if the stimulus is stronger and well above the pain threshold, such patients
have near-normal autonomic responses but with blunted pain perception [26]. However, autonomic responses to
painful stimuli may be attenuated in all older individuals, regardless of whether or not they have any form of
dementia [27]. Functional MRI studies in AD patients suggest that pain reflexes and facial expressions related to
pain remain the same as in patients without AD or may even be somewhat enhanced [28].
To date, the limited and relatively small studies on pain perception in dementia patients have produced conflicting
and even contradictory findings, reporting that pain processing is increased, decreased or unchanged in dementia
patients. These mixed results may be due to any number of factors, including that different types of dementia were
studied, different types of pain assessments were used and patients may respond differently based on the severity of
dementia. Clinical trials involving patients with dementia can be challenging to conduct and evaluate. In a study
of 35 patients with dementia and 46 age-matched, healthy control patients, subjects were administered noxious
electrical stimuli and assessed by subjective findings (pain rating scale), facial responses, the nociceptive flexion
reflex (NFR) also known as the motor reflex, and autonomic response to pain (heart rate and sympathetic skin
response) [29]. The intensity of the stimuli was calibrated to the pain thresholds of each individual (based on motor
reflex). In terms of verbally rating pain, patients with and without dementia reported similar scores for the stimuli
although some patients with dementia struggled more with the rating process than healthy controls. Patients with
dementia differed from healthy controls in that they had significantly more pronounced facial responses to pain. On
the other hand, the NFR threshold and autonomic responses decreased in patients with dementia versus controls.
This study suggests that patients with dementia, like their matched controls, experience pain but process it in
different ways [29]. Further evidence for this is provided by new research into the placebo effect in pain control.
The placebo effect in pain control is an active area for neuroscientific research as it involves the complex interplay
among various brain functions from expectation, anxiety, and reward, to learning, conditioning and cognition.
A placebo in this setting is more than an ineffective substance, but rather serves as a complex contextual clue,
triggering certain cerebral functions in similar fashion to an active agent. Genetics has been implicated in the degree
to which placebos may affect an individual. Recent research frames the placebo effect as a psychosocial response that
may be affected by the context in which the placebo is administered, along with the accompanying words, rituals,
social stimuli, behaviors and other clues. The mechanisms behind the placebo effect are the same ones triggered by
the drug. Thus, a placebo might provide a set of psychosocial cues that mimic those when meaningful therapy is
being delivered. That placebos work on neural pathways is evident in that dementia patients with AD exhibit little
to no placebo response; these patients have impaired prefrontal executive function, crucial to the placebo effect [30].
In other words, individuals with dementia have an impaired ability to notice and respond to the psychosocial cues
offered with the placebo and thus derive no benefit from a ‘placebo effect’. Since the placebo component of a
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Treating pain in dementia patients & possible concomitant relief of agitation symptoms Review
pain reliever is an important contribution to a drug’s analgesic benefit, the lack of placebo effect suggests that the
effectiveness of various pain relievers may be diminished in patients with prefrontal dysfunction, which would in
turn necessitate a dose increase [30,31]. Of course, there is not just one ‘placebo effect’, but rather there is a range of
effects and responses based on various conditions and activation of different neural systems [30]. These effects may
involve either a reduction in anxiety (the idea that beneficial treatment has been given and analgesia is imminent)
or the triggering of the brain’s reward system (pain relief is perceived as a reward). Placebo administration has been
shown to activate various areas of the brain and extend to the spinal cord [32]. It is interesting to note that opioid
antagonists block placebo analgesia, which suggests that the placebo effect involves opioidergic mechanisms [33].
The loss of the placebo effect in dementia patients underscores that pain is processed differently in patients with
dementia.
Challenges in pain assessment in dementia patients
In a survey of general practitioners in Ireland (n = 157), about two-thirds of responding clinicians had patients
in nursing homes but only 10% were aware of any pain assessment tools appropriate for dementia patients [34].
Several such metrics exist. A mobilization-observation-behavior-intensity-dementia pain scale has been developed
to facilitate pain assessment in individuals with dementia. Mobilization-observation-behavior-intensity-dementia
uses video recordings of the patient for analysis of pain-related behaviors (facial expressions, vocalizations and
guarding behaviors), and it has been validated in a study of 77 patients with severe dementia [35].Basedonthis
study, pain prevalence (any pain) among individuals with severe dementia is 81% with most pain related to the
musculoskeletal system [35]. Other pain assessment metrics for the dementia population exist and a systematic review
found the PACSLAC and DOLOPLUS2 offered particular value in terms of sensitivity and clinical utility [3].
A stepwise protocol from Holland for treating pain in dementia patients, STA OP (Stapsgewijs Onbegrepen
gedrag en Pijn bij dementia de Bass) was evaluated in a randomized control trial of 21 clusters from 12 nursing homes
(n = 288). Pain prevalence in this study ranged from 30.7 to 54.1%. The protocol ‘observed pain’ (measured by
objective observation of the patient) but not estimated pain (measured by the MDS–RAI scale) [36] and investigators
suggest that assessment of behavioral clues might further improve results [37].
Tools for measuring pain exist but must be deployed in these populations. See Table 1. Thus, greater education
in pain management is needed for clinicians, and in particular for clinicians who treat patients with dementia.
The residential situation in which many dementia patients find themselves may contribute to their pain in that
it may instill feelings of isolation, separation, loneliness or confusion (not knowing where they are). Clinicians
may find patients with dementia struggling emotionally with their current living conditions or life status, and this
may masquerade as pain or exacerbate existing pain. Polypharmacy poses a great challenge to the pharmacological
treatment of pain in this population, and education may be necessary to avoid potential pharmacokinetic drug–drug
interactions.
Agitation & behavioral issues possibly related to pain in dementia patients
Agitation may be defined as disinhibition, irritability, restlessness, wandering and aberrant motor behaviors,
which include pacing, hyperkinesia and repetitive sorting behaviors. In some studies, aggression and agitation
are considered together, but agitation may be viewed as a distinct symptom. Aggression would include such
things as verbal attacks, physical assaults and self-injury, the latter of which has rarely been studied in this
population [46]. Agitation in dementia patients can add substantial amounts to the care of such patients, who
may require pharmacological treatment (including antipsychotics), institutionalized care, very close supervision
and frequent medical attention [46]. Among the neuropsychiatric symptoms that can accompany dementia (such
as psychosis, mood disorders, depression, anxiety and apathy), aggression and/or agitation are among the most
frequently reported [46]. It should be noted that the descent into dementia is not always a linear, step-wise
progression and that there can be considerable individual variations in symptomology. Interventions to treat pain in
dementia patients with challenging behaviors, including agitation, were found to be effective in reducing behavioral
symptoms [47].
Pain has been positively correlated to certain disruptive behaviors such as agitation and aggression, but not to
such behaviors as wandering [48]. Untreated pain may also disrupt sleep patterns, reduce quality of life and be
emotionally distressing to the patient, all of which may further cause behavioral issues. A dementia patient suffering
from unrecognized pain may act agitated in an effort to communicate his malaise and be prescribed antipsychotic
medications rather than analgesics, which do not address the pain and may, in fact, confer risks to the patient [49].
future science group www.futuremedicine.com 573
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Table 1. A variety of pain assessment tools may be helpful for evaluating pain in elderly patients with
cognitive impairment and/or dementia, many of which rely on a caregiver observing and then assessing the
patient.
Pain scale Description Appropriateness for dementia
patients
Comments Ref.
Numeric Rating Scale Rate pain from 0 (no pain) to 10 (worst
pain imaginable)
May be used in patients with
mild-to-moderate dementia
Familiar, easy to administer [38]
Visual Analog Scale Select a point on a 10-cm line to dene
pain (from no pain on left to worst pain
imaginable on right)
Requires motor skills and good
vision
Has higher failure rate than
numeric rating scale
[38]
Face Pain Scale Series of faces with increasing degrees
of suffering and distress
Appropriate for patients with
mild-to-moderate cognitive
impairment
May also be used in patients with
low literacy, dyslexia or limited
education. May also be
appropriate for patients who do
not speak the main language of
the caregivers
[38]
Verbal Descriptor Scale Series of phrases that describe pain such
as ‘no pain’, ‘mild pain’, ‘moderate
pain’, ‘a lot of pain’ etc.
Appropriate for use in the elderly
but may not be as appropriate
for those with cognitive
impairment
Phrases should be consistent [38]
Abbey Pain Scale Caregiver assesses six domains and
scores each 0 (no pain) to 3 (most pain)
and adds scores together
Developed for patients with
moderate-to-severe cognitive
impairment and late-stage
dementia
Six domains are vocalization,
facial expression, behavioral
change, change in body
language, physiological change
and physical change. Takes about
1 min to administer
[41]
Doloplus-2 Caregiver assesses ten domains (somatic,
psychomotor and psychosocial) on a
scale of 0 to 3 and then adds together
Designed for use in older
patients and can be used in
patients with severe dementia
Domains are somatic complaints,
protective body posture at rest,
protection or guarding of sore
areas, facial expression, sleep
patterns, washing and/or
dressing, mobility,
communication, social life,
behavior problems. Takes 6–12
min to administer
[42]
PAINAD scale Caregiver assigns a score of 0–2 to ve
dimensions
Designed for ease of use in
patients with severe dementia
Dimension are breathing,
negative vocalization, facial
expression, body language and
consolability. Patient should be
observed for 2–5 min before
proceeding with evaluation
[43]
PACSLAC scale Caregiver assesses 60 items as present
(1) or absent (0) for a total score
ranging from 0 to 60
Designed for the elderly with
limited ability to communicate
Areas assessed include facial
expression, movements,
personality changes, eating,
sleeping and so on. Can be
administered in about 5 min
[45]
CNPI Caregiver observes patient and then
scores 1 if behavior is observed and 0 if
not; six items added together
Designed for those with no or
limited ability to speak or those
with severe cognitive impairment
Domains cover facial expressions,
vocalizations and body language
[38]
PADE Three-part caregiver assessment with 24
total items including physical, global,
and functional assessments
Designed for use in patients with
severe dementia
More complicated scoring system
(different domains score in
different ways), test requires
5–10 min to administer
[44]
CPAT Caregiver-administered test of ve
items scored 0 (no pain) or 1 covering
facial expression, behavior, mood, body
language and activity level
Designed for use in cognitive
impaired patients
[38]
Some of these tools are used in a range of patients with and without cognitive impairment while others were specically developed for use in patients with cognitive
decits or other conditions, such as limited ability to communicate [3, 38-45].
CNPI: Checklist for nonverbal pain indicators; CPAT: Certied nursing assistant pain assessment tool; PACSLAC:Pain assessment checklist for seniors with limited ability
to communicate; PADE: Pain assessment for dementing elderly scale; PAINAD: Pain assessment in advanced dementia scale.
It is difficult to know how many dementia patients experience agitation, as the symptom is diffuse, transient, and
may not be properly identified by informal caregivers or documented by clinicians. About 48–82% of people with
dementia in long-term residential care are thought to suffer agitation and/or aggression at some point [46]. Agitation
can be extremely distressing to the patient but can be equally upsetting to caregivers; patients with agitation may
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be institutionalized or live in restricted settings because of this symptom. Even in a skilled nursing facility, agitated
dementia patients can disrupt workflow, upset other residents, place undue stress on aides and staff, and contribute
to caregiver burnout. Aggressive dementia patients may even pose a physical threat to other residents and staff.
Such patients may need to restrained or exposed to high doses of psychiatric medications with their attendant
side effects [46]. In a study from the UK (n = 967), pain in dementia patients was significantly associated with
prescriptions for antipsychotics [50]. There has been a concerted effort on the part of Centers for Medicaid and
Medicare Services in the form of its National Partnership to Improve Dementia Care in Nursing Homes to decrease
the use of antipsychotics in long-stay nursing home residents [51]. According to a study of 341 nursing home
residents with moderate to severe degrees of cognitive impairment, 63% received at least one antipsychotic agent
while 9% were prescribed opioid analgesics [52]. In a multicentre US study of 89 nursing home residents (mean age
= 85.9 years) with dementia, agitation levels correlated with declining cognitive function and uncontrolled pain
made it difficult to reduce agitation levels [53].
A large number of drugs list agitation as a potential side effect and antipsychotic drugs, in particular, may result
in agitation or aggression [54]. Thus, polypharmacy may be the basis of certain symptoms or it may exacerbate a
tendency toward agitated behaviors. It may also cause a vicious cycle where a patient with dementia in pain exhibits
agitation and is prescribed an antipsychotic, which exacerbates the agitation and necessitates an increased dose,
while the pain goes untreated.
Agitation may be addressed holistically, which involves exploration of the patient’s drug regimen (many drugs
cause agitation as a side effect), potentially untreated pain and untended physical or emotional needs. In some
cases, agitation in dementia patients may be caused by untreated pain and the agitation may be exacerbated by
frustration when the patient cannot communicate his or her analgesic needs to the caregivers [55].
In a study of 2822 cognitively impaired nursing home residents (mean age = 84.1 ±9.1 years), 19.1% of
patients (n = 538) were evaluated as having pain and pain could be statistically significantly associated with socially
inappropriate behaviors (odds ratio [OR]: 1.37; 95% CI: 1.04–1.80), resisting care (OR: 1.48; 95% CI: 1.08–1.83)
and abnormal thought processes (OR: 1.48; 95% CI: 1.16–1.90) [56]. In a secondary analysis of the Minimum
DataSet from a study of 56,577 long-term care residents with dementia ≥65 years in calendar year 2009, residents
with more severe pain were statistically significantly more likely to exhibit aggression and/or agitation than patients
with dementia without pain (OR: 1.04 for aggression and 1.17 for agitation; 95% CI for both ranges 1.01–1.08
and 1.13–1.20, respectively) [48].
A secondary analysis from cluster-randomized controlled trials (n = 352 advanced dementia patients with
agitation) from 18 nursing homes in Europe could associate pain with disinhibition (adjusted OR: 1.21; 95% CI:
1.10–1.34) and irritability (OR: 1.10; 95% CI: 1.01–1.21) [57]. Analgesia decreased agitation and aberrant motor
behaviors significantly (p <0.001 and p = 0.017, respectively), which suggests pain control may be a way to address
agitation in some dementia patients. In this study, the use of opioid analgesics did not result in increased psychotic
symptoms [57].
Effective analgesia for patients with dementia
Cognitive deficits were reported as a major barrier to adequate analgesia in a systematic review about postsurgical
pain control in patients with dementia; dementia patients did not get as much opioid analgesia following surgery
compared with patients without dementia [58]. In a study of 97 patients treated surgically for hip fracture, cognitively
impaired patients received about a third the analgesia that cognitively intact patients received [55]. This problem
may have more widespread application than first appears; one in three patients with hip fracture has concomitant
cognitive impairment [59]. The decrease in the placebo mechanism in dementia patients, which may involve
decreased connectivity between the frontal lobes and the rest of the brain, may mean that dementia patients require
higher doses of analgesia to achieve effective pain control [31]. This contradicts the prevailing concept that suggest
the elderly should have reduced doses of most medications owing to their slowed ability to metabolize drugs. As
with any pharmacological treatment, risks of adverse events must be weighed against benefits.
There is relatively little study of how and to what extent the blood–brain barrier (BBB) is impacted by AD or
other forms of dementia; the deterioration of this barrier may have as yet undefined impacts on how centrally acting
analgesics would affect a dementia patient [60]. The BBB is a complex system of brain capillary endothelial cells,
which regulate the molecular exchange between blood flow and the brain parenchyma. The function of the BBB
is to prevent neurotoxic substances and pathogens from entering the brain; signs of BBB deterioration have been
noted in individuals prior to the onset of AD, suggesting that the breakdown of the BBB may be the cause or at
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Review Pergolizzi, Raffa, Paladini, Varrasi & LeQuang
least a gating event for dementia [61]. The BBB is known to be disrupted by many neurological disorders, including
AD. BBB dysfunction has been implicated as a potential contributor to the pathogenesis of AD [62]. It is not clear
how the BBB in dementia patients might affect analgesia.
Results from pain control studies in dementia patients
Dementia patients are not well represented in clinical trials in general and clinicians caring for patients with dementia
often must rely more on their own experience than clinical evidence or guidance from professional societies, which
is limited. In an analysis of 72 clinical trials for hip fractures, 28% of these studies specifically excluded cognitively
impaired patients, 26% specifically included them, and the balance did not report on this patient characteristic [59].
A cross-sectional analysis of 115 community-dwelling dementia patients plus their caregivers (n = 115) reported
that 54% of patients had some form of noncancer pain ‘on an average day’ and that inadequate treatment of pain
was 1.07-times as likely for each additional year of age, 2.5-times as likely with impaired activities of daily living
and 3.0-times as likely with advanced dementia. Of the patient cohort, 46% received insufficient analgesia for their
pain [63].
While chronic noncancer pain is prevalent in the geriatric population overall, a national register-based study from
Finland from 2005 to 2011 found significantly more community-dwelling seniors without AD took prescribed
opioids than patients with AD (8.7 vs 7.2%, respectively; p <0.0001) [64]. This registry study excluded patients in
active oncological treatment. However, for long-term opioid use (≥180 days), significantly more AD patients took
opioids than those without AD (34.2 vs 32.3%, respectively; p = 0.0004). In particular, patients with AD were
more likely to use transdermal opioids (13.2 vs 5.5%). Long-term opioid use could be associated with advanced
age (≥80 years), female sex, rheumatoid arthritis, osteoporosis, lower socioeconomic status, history of substance
use disorder and long-term benzodiazepine use [64]. In contrast, a study of half of citizens over the age of 85 and all
citizens ≥90 years in three cities in Sweden and Finland (n = 546) found that dementia was diagnosed in 45.2%
and that more patients with dementia than without used acetaminophen (paracetamol; 50.6 vs 21.4%; p <0.001),
antipsychotics (22.3 vs 2.7%; p <0.001), antidepressants (33.6 vs 11.4%; p <0.001), and anxiolytics (19.0 vs
8.0%; p <0.001) but rates of use for opioids, hypnotics and anticonvulsants were similar [65]. The use of opioids
in institutionalized seniors has doubled in the past decade in Finland from 11.8% in 2003 to 22.9% in 2011
(p <0.001) and likely this is a global trend in response to improved identification of pain and willingness to
treat it [66]. Opioid therapy is indicated in carefully selected patients, even the aged [67].InastudyfromDenmark
(n = 35,455 elderly patients), opioid use was higher in seniors who lived in nursing homes (41%) compared with
elderly living at home with dementia (27.5%) and those living at home without dementia (16.9%) [68].
In a cluster randomized clinical trial (60 clusters in 18 nursing homes), 352 residents with moderate-to-severe
dementia and clinically significant behavioral disturbances were randomized to receive usual treatment or care or
greater pain therapy (ranging from acetaminophen to extended-release oral morphine, transdermal buprenorphine
or pregabalin, based on prior therapy) for 8 weeks. At the conclusion of the study, the most significantly reduced
behavior was verbal agitation defined by the study as complaining, negativity, repetitious speech patterns, persistent
repetitive questioning, constant requests for attention, cursing and verbal aggression (p <0.001 vs control). Physical
behaviors that were not aggressive (pacing and restlessness) also decreased significantly (p = 0.008) as did aggressive
actions (p = 0.037) [69].
Considerations about the use of opioids in patients with dementia
There are relatively few high-quality studies about opioid use in dementia patients [70]. A double-blind, placebo-
controlled multicentre study of 106 nursing home residents with dementia and depression were evaluated for
sleep after a pain-control regimen was introduced. Patients randomized to the active arm received acetaminophen
(if they were previously not taking any analgesic) or a 7-day transdermal buprenorphine patch 10 μg/h(ifthey
previously were taking pain medication); these active-treatment patients showed significantly improved sleep at 14
days compared with the placebo patients [71]. However, the same investigators reported that long-term analgesia
did not improve sleep versus placebo and thus did not advocate pain control as a method for improving sleep in
depressed dementia patients [72].
In a survey of general practitioners (n = 157), 51.6% reported that they believed opioids could be safely prescribed
to dementia patients [34]. A retrospective study of medication use in Finnish patients with advanced AD (3327
patients and 3325 matched cohort) reported that opioid initiation was associated with a reduction in the use of
antipsychotics, benzodiazepines and related drugs [73]. Further, the neuroprotective properties of opioids were shown
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Treating pain in dementia patients & possible concomitant relief of agitation symptoms Review
in a murine study in which tramadol ameliorated many of the changes (including behavioral changes) associated
with AD [74]. In a nursing home study in Norway (n = 327 patients with advanced dementia and neuropsychiatric
symptoms), 19.3% of residents were prescribed opioids although 62.1% had moderate-to-severe pain [75].
The role of opioid analgesics in managing moderate to severe pain, particularly near end of life, is well described
but the role of opioids in managing symptoms of agitation is less clear. Further study is needed to better understand
the potential role of opioid therapy to ameliorate general distress and anxiety in patients with dementia and
agitation/aggression [76]. In this context, the balance between risk of side effects and therapeutic benefits must be
met. While it seems intuitively understandable that opioid therapy would decrease agitation in a dementia patient
whose agitation was the result of untreated pain, it is not known if opioids might mitigate agitation/aggression in
a patient without pain. While there may be a reticence to even consider opioids in the latter (unproven) scenario,
agitated/aggressive dementia patients are routinely administered powerful antipsychotics which pose their own
safety risks.
There can be a general resistance to treating agitation and/or pain in dementia patients pharmacologically, in
that drug metabolism in the elderly may limit the type and amounts of drugs they may safely take, in addition
to the fact that they may be taking numerous other drugs to treat potentially life-threatening chronic medical
conditions (hypertension, heart disease, diabetes etc.) with which further drugs could potentially interact. The
role of low-dose opioids as a treatment specifically of dementia-related agitation is currently under discussion
but has understandably met with resistance in part because of limited high-caliber scientific evidence of efficacy,
concerns for patient safety, fears about diversion and the ‘unwarranted’ use of opioid analgesics, and concerns about
opioid-associated morbidity and mortality, for example, opioid overdose. It is interesting that agitation in dementia
patients may be routinely treated with anxiolytics, such as benzodiazepines, which are also associated with addiction
and misuse [77]. In a two-phase, placebo-controlled study of 47 patients with advanced dementia and agitation, the
use of a long-acting opioid was associated with decreased agitation in patients over the age of 85 years but not in
younger patients [78]. While there is a lack of evidence to support the general use of opioids to treat agitation in and
of itself, the relationship between agitation and untreated pain deserves further consideration.
On the other hand, the long-term use of opioids in cognitively intact individuals may be associated with an
increased risk of cognitive decline and/or dementia. In a study of 3434 senior adults (≥65 years) without dementia,
subjects took the Cognitive Abilities Screening Instrument every 2 years and scores below a certain cutoff triggered
a more detailed evaluation and possible diagnosis of dementia. Over a mean follow-up of 7.3 years, 23% of subjects
(n = 797) developed dementia and 19% (n = 637) had probable or possible AD. Individuals with higher opioid use
or higher use of nonsteroidal anti-inflammatory drugs (NSAIDs) had a slightly higher risk of dementia compared
with those subjects who took neither opioids nor NSAIDs [79]. Actually, other frequently prescribed drugs have
been associated with dementia. For example, the use of benzodiazepines, in particular long-acting formulations, is
associated with an elevated risk of dementia [80]. It is not understood how these drugs would affect patients who
already have dementia.
Pain is prevalent among the elderly and a multicentre study in nursing homes (n = 327) found 62.1% of
residents with advanced dementia and neuropsychiatric symptoms had moderate-to-severe chronic pain [75].Itis
not professionally compassionate or caring to let these individuals suffer untreated pain unnecessarily even if they
lack the mental skills to ask for pain relief. Of this subset of residents, 19.3% were taking prescribed opioids but
79.4% of them still suffered pain although about two-thirds of those treated for pain were administered a strong
opioid in the form of a transdermal fentanyl (12 μg/h) or buprenorphine (5 or 10 μg/h) patch [75]. Thus, clinicians
must be aware of untreated pain in dementia patients, be willing to treat it, and to assess it to make sure the
analgesic regimen prescribed is adequate.
Discussion
The under-representation of dementia patients in clinical trials, although understandable in turn has led to a lack
of evidence-based recommendations for pain management in this population [81]. There are clearly challenges in
managing pain in patients with dementia. These patients may be unable to articulate their need for pain control
and even when analgesia is considered important, they may be unable to describe their pain in meaningful ways
to guide treatment. Compliance in this population may be poor. Dementia patients may be unable to identify and
articulate adverse events to the prescriber. Few clinical studies on pain relief in the elderly have been conducted and
even fewer specifically in dementia patients with the result that there is little guidance in the literature to inform
future science group www.futuremedicine.com 577
Review Pergolizzi, Raffa, Paladini, Varrasi & LeQuang
decisions [82,83]. Since there is not a great deal of clinical guidance in terms of how to treat pain in dementia patients,
when treatment occurs, clinicians must be guided by their own observations and experiences more than evidence.
Patients in long-term residential care and those with cognitive impairment in any setting must be recognized
as vulnerable populations, deserving of special protections in clinical research. For instance, it is unclear if such
patients can provide adequate informed consent for participation in a clinical study, which is particularly relevant if
the study involves some sort of clinical intervention such as opioid therapy. In some cases, patients with dementia
may have legally authorized agents who might be able to provide informed consent on behalf of the patient, but
such steps are extreme for clinical research and, furthermore, many nursing home residents have few or no family
members. Thus, there are ethical challenges to studying these populations as well as more logistical, practical
impediments. This is an important point worthy of further discussion as opioid or other pain therapy in such
populations may improve quality of life for these patients. There is a real and urgent need for this evidence.
It appears that untreated pain or inadequate analgesia may result in disruptive behaviors in patients with dementia
and that agitation in some cases may be an attempt to ask for pain relief in a patient with limited linguistic skills
and impaired ability to reason. In some cases, agitation appears to be addressed indirectly, that is, an agitated
patient is offered analgesia rather than antipsychotic medications and the behavioral symptoms subside. This may
be beneficial to the patient, for antipsychotic medications have numerous adverse effects and many carry black-box
warnings for use in the geriatric population. Opioids and nonopioid analgesics also confer their own attendant
risks and benefits and clinicians must make an informed and individualized decision about the use of such pain
relievers in this population.
Conclusion
Pain is prevalent in the population of older individuals with cognitive impairment, as are symptoms of agitation
and aggression. These disruptive behaviors may be the attempt of a person with dementia to express feelings of pain
and suffering which, if properly noted, could be alleviated. It is known that dementia alters not just cognition and
communication, but it changes how pain is perceived and processed with the result that patients with dementia
may feel pain but not express these feelings in the same way as a cognitively intact person. Few studies have been
done in terms of how to treat pain in cognitively impaired patients, but some clinical studies suggest that behavioral
symptoms can subside when pain is treated.
Future perspective
As the population of the industrialized world ages, the prevalence of chronic pain and dementia will increase and
many patients will have both conditions. The care of geriatric patients with dementia is challenging, particularly
when patients exhibit aggressive, confrontational, disturbed, or distressing behaviors or even just restlessness,
fidgeting, verbal outbursts, or wandering. As clinicians we must reasonably wonder if these symptoms are caused by
untreated and unrecognized pain that the patient feels but is hopeless to communicate. A more aggressive approach
to identifying pain in patients with dementia may be helpful, that is, pain should be suspected in older dementia
patients particularly when behavioral issues are concomitantly observed. Clinicians, who care for elderly patients,
may benefit from learning how to assess pain in this population and how to treat it. Pain treatment is always a
challenge and it is more challenging in the elderly – but even with those obstacles, clinicians must reach out in
compassion to help mitigate the pain and suffering that may be felt by vulnerable populations with dementia who
cannot communicate their very real need for pain control.
Financial & competing interests disclosure
The authors have no relevant afliations or nancial involvement with any organization or entity with a nancial interest in or nan-
cial conict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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582 Pain Manag. (2019) 9(6) future science group
