1. Introduction
The effects of neurodegeneration on the experience of pain remain poorly understood,
despite the risk of suffering from both pain and neurodegenerative diseases rising
concurrently with age.
63,75
Given the anticipated increase in magnitude and median age of the global population,
76,152
the interaction of these 2 clinically unmet needs will become an increasingly pressing
challenge. In particular, a significant proportion of patients with Alzheimer disease
(AD) and Parkinson disease (PD), the 2 most prevalent neurodegenerative diseases,
suffer chronic pain of variable origin (Box 1). As such, they have been the most extensively
studied and, for brevity, will be the focus of this review. Persistent pain in AD
and PD is partially attributable to various concomitant disease manifestations and
comorbidities (Fig. 1).
43,117
In addition, disease-specific neurodegenerative changes may affect a multitude of
regions implicated in the perceptual and cognitive processes underlying pain. Despite
this, the precise perceptual sequelae of neurodegenerative pathophysiology in these
2 diseases remain equivocal, and whether this may result in differential responses
to analgesic treatment remains largely unexplored.
Figure 1.
Conceptual framework relating the respective neurodegenerative pathophysiology within
AD and PD to pain processing and treatment. AD, Alzheimer disease; PD, Parkinson disease.
Box 1.
Definitions
Neurodegenerative disease: a heterogeneous group of disorders that are characterized
by the progressive degeneration of the structure and function of the central nervous
system or peripheral nervous system.
Dementia: a syndrome that involves severe loss of cognitive abilities as a result
of disease or injury. Dementia caused by traumatic brain injury is often static, whereas
dementia caused by neurodegenerative disorders, such as AD, is usually progressive
and can eventually be fatal.
Alzheimer disease: a progressive neurodegenerative disease that impairs memory and
cognitive judgment and is often accompanied by mood swings, disorientation, and eventually
delirium. The most common cause of dementia.
Parkinson disease: a progressive neurodegenerative disorder, characterized by motor
symptoms, such as tremor, rigidity, slowness of movement, and problems with gait.
Motor symptoms are often accompanied with fatigue, depression, pain, and cognitive
problems.
Three key principles lay conceptual foundations for the investigation of the effects
of neurodegenerative pathophysiology on treatment mechanisms: (1) a given intensity
of stimulus produces heterogeneous levels of reported pain and unpleasantness,
30,60,110,109,111,154
(2) genetic and environmental factors predispose some to chronic pain,
1,47,48,87
and (3) diversity of pain physiology and pathophysiology results in heterogeneous
responses to pharmacotherapy
46,100,134,153
. Collectively, these support the notion that heterogeneous physiology and pathophysiology
can give rise to divergent treatment responses. Within this framework, neurodegeneration
and its effects on the central nervous system can be considered as one such external
factor contributing to heterogeneity, resulting in putative perturbation of pain processing
(1 and 2) and responses to analgesic treatments (3) (Fig. 1).
Chronic pain in AD and PD not only impacts patients' quality of life but also presents
a formidable healthcare and socioeconomic challenge. Drugs available for treatment
of chronic pain are associated with high numbers needed to treat and may have serious
side effects.
145
Moreover, poorly managed pain is associated with depression,
33
anxiety,
139
and functional loss.
38
Given the high prevalence of pain and frailty in these patient groups, clear scientific
rationale is imperative to ensure safe and effective clinical management (Fig. 2).
In this article, we discuss pain processing and perception in AD and PD as well as
its emerging relevance to pharmacological treatment.
Figure 2.
Importance of mechanistic research for evidence-based pain medicine.
2.
Alzheimer disease
Alzheimer disease is the most common form of dementia affecting more than 45 million
people worldwide
119
and is clinically characterised by progressive cognitive deterioration.
25,43,77
The prevalence of chronic pain in dementia is between 30% and 80%.
43
However, patients with AD do not report pain as often and are prescribed analgesics
less frequently, compared with healthy age-matched individuals.
34,129
Pain is a key trigger for behavioural and psychological symptoms of dementia such
as agitation and mood disorders, which are a major treatment challenge and can result
in overprescribing of harmful antipsychotic medications.
10,52,123
Pathologically, the basal forebrain and medial temporal lobe are amongst the first
regions affected before progression to neocortical regions.
18,108
Notably, the sensory cortices remain relatively unaffected until terminal stages.
The significance of this is multifaceted: (1) the regions affected partially overlap
with regions implicated in the processing of pain, (2) the regions affected are believed
to be involved more in emotional-affective rather than sensory-discriminative dimensions,
and (3) the cognitive deficits within memory, attention, and communication render
self-report of pain increasingly unreliable with disease severity. Specifically, a
reduced capacity to comprehend and complete standardised pain assessments as well
as an overall reduction in reporting of pain.
2,78,84,113
Therefore, altered pain processing (1 and 2) is challenging to disentangle from a
diminished capacity to accurately provide self-report (3), highlighting the need for
investigation at a mechanistic level.
2.1. Pain processing is altered in Alzheimer disease
Many psychophysical studies investigating noxious stimuli have demonstrated altered
pain processing in AD compared with healthy controls. However, the directionality
of these changes remain equivocal. Thresholds have been reported to be increased
15,35,66,106
or similar to cognitively intact controls.
15,81,79,82,93
Similarly, pain tolerance has been reported to be reduced,
11,35,79,82
equal,
35,66,81,89,88
and increased.
122
In addition, behavioural responses to pain have been shown to be augmented in AD,
72,89,88
with enhanced facial responses throughout the spectrum of disease severity.
12
Patients with AD have also shown a reduced threshold in the nociceptive flexion reflex
(NFR), possibly indicating differences in pain processing further down the neuroaxis.
89
Overall, disparities are likely due to differences in pathophysiological mechanisms,
disease progression, modalities of evoked pain used, and, crucially, outcome measures
used. Collectively, these findings allude to patients with AD potentially suffering
more despite reporting pain less.
Neuroimaging studies have suggested that neural activity in patients with AD may be
augmented in response to noxious stimulation, despite relative preservation of sensory-discriminative
facets of pain. Patients show greater amplitude and duration of blood oxygenation
level dependent (BOLD) signals (an indirect index of brain activity relating to neurovascular
coupling) during noxious pressure stimulation within sensory, affective, and cognitive
regions, including the dorsolateral prefrontal cortex (dlPFC).
35
Consistent with altered cognition being functionally related to pain processing, patients
also show enhanced functional connectivity between the dlPFC and anterior midcingulate,
periaqueductal grey (PAG), thalamus, and hypothalamus.
36
Indeed, the dlPFC plays a central role in both general cognitive function
70
as well as pain modulation.
95,130,149
Furthermore, diffusion tensor imaging has evidenced anatomical connectivity between
the right dlPFC, hypothalamus, and PAG,
71
in which activity has been associated with pain-related escape responses in rodents.
86,98
This may reflect a failure to adequately contextualise and appraise painful experiences
resulting in uncertainty and a higher threat value ascribed to noxious stimulation.
Furthermore, a lack of contextualising features within scanning environments may compound
this.
36
Delineation of the impact of context and setting warrants further investigation. Collectively,
neuroimaging studies indicate greater emotional reactivity and pain processing, despite
equal or mildly diminished thresholds.
The implication of regions including the dlPFC, PAG, and hypothalamus overlaps with
the neural substrates of placebo analgesia through which context and expectation can
profoundly alter treatment responses.
36,118,150
Patients with AD with reduced frontal lobe function exhibited diminished placebo responses
in an open-hidden paradigm, requiring escalation of analgesic dose.
16
Furthermore, executive function is the domain of cognition that best predicts variance
in facial responsiveness to noxious electrical stimulation and the NFR.
90
Thus, patients with milder disease severity may benefit more from analgesics because
of relative preservation of placebo mechanisms. The placebo response is engaged in
the administration of all pharmacotherapy to some extent and accounts for a large
portion of the reduction in pain produced, over and above pharmacological efficacy.
14,17,37,148
Therefore, patients with attenuated placebo responses should require larger doses
to produce the same level of analgesia as controls. Worryingly, as AD and age progress,
patients become increasingly frail, hence dose escalation may be a major concern given
that age is a significant predictor of opioid-related harm.
28,57,85
Placebo analgesia and opioid analgesia partially share neuroanatomical substrates;
covariation has been observed between the activity in the rostral anterior cingulate
cortex (ACC) and the brainstem during both placebo and opioid analgesia, but not during
pain alone.
114,135
Postmortem AD brains also show reduced μ-/δ-opioid receptor binding.
104
Patients with AD may thus present alterations in centrally mediated opioid analgesia.
Further application of open-hidden paradigms alongside pharmacoimaging may offer insights
into how the combined magnitude of pharmacological and placebo analgesia can be maximised
clinically.
2.2. Pharmacotherapy of pain in Alzheimer disease
Overall, patients with AD seem to be prescribed fewer analgesics than healthy individuals.
10,73,128
Conversely, recent studies from Scandinavia have reported an opposite trend.
80,96,126
Paracetamol/acetaminophen remain the principal treatment for mild-to-moderate pain
in AD with additional use of nonsteroidal anti-inflammatory drugs and opioids.
3
However, studies providing mechanistic insight remain scarce.
3,53
For example, of the 3 randomised control trials (RCTs) investigating opioids, 2 were
underpowered and in one investigating the buprenorphine transdermal system, 23 of
the 44 patients withdrew treatment because of adverse events.
52,97,101
No trials have investigated antidepressants and antiepileptics.
3,77
Further RCTs will be necessary to not only produce evidence-based treatment guidelines
but also to provide insights into the putative perturbation of neurotransmitter systems.
3. Parkinson disease
Pain is a prevalent nonmotor symptom in people with PD (PwP), acknowledged by James
Parkinson in 1817,
112
affecting 68% to 85% of patients.
13,23,103,116,127
Despite this, it remains underdiagnosed and undertreated.
6,31,41,58,83,156
Pain in PwP is multifaceted and may result from comorbidities, be caused or amplified
by motor symptoms, and is subject to abnormal nociceptive processing, as PD-specific
neurodegeneration affects peripheral, spinal, and cerebral pain pathways.
42,125
Attempts have been made to synthesize a clear picture of heterogeneous pain in PD
(Table 1)
6,58,151
; however, to date, our basic understanding of the relationship between PD pathophysiology
and pain remains underdeveloped. Identifying well-defined subtypes, and elucidating
their concomitant underlying mechanisms, should facilitate the development of personalised
treatment of pain in PwP.
24,143
Table 1
Overview of the classification systems to date for pain in people with Parkinson disease.
Quinn et al.
121
A) Pain preceding diagnosis of Parkinson diseaseB) Off-period pain (without dystonia)
in patients with a fluctuating response to levodopa 1. Morning pain 2. Wearing-off
pain 3. Beginning-of-dose pain 4. End-of-dose painC) Painful dystonic spasms 1. Early
morning dystonia 2. Off-period dystonia 3. Beginning-of-dose dystonia 4. End-of-dose
dystoniaD) Peak-dose pain
Ford
61
1. Musculoskeletal (aching, cramping, arthralgic, and myalgic sensations in joints
and muscles)2. Radicular/neuropathic (pain in a root or nerve territory)3. Dystonia
(associated with sustained twisting movements and postures)4. Central or primary pain
(burning, tingling, formication, and “neuropathic” sensations, often relentless and
bizarre in quality)5. Akathisia (subjective sense of restlessness, often accompanied
by an urge to move)
Wasner and deuschl
151
A) Pain related to Parkinson disease:
1. Nociceptive: Musculoskeletal (joint pain, pain linked to motor fluctuations—dystonic
or nondystonic, back pain, and pain linked to autonomic failure), visceral (abdominal
pain, gastrointestinal discomfort, constipation, and involuntary dystonic contraction
of anal sphincter), and cutaneous (pressure sores)
2. Neuropathic: Peripheral (radicular) or central Parkinson pain
3. Miscellaneous: pain preceding Parkinson disease, pain linked to restless leg syndrome
and akathisia, and pain linked to depression.B) Pain unrelated to Parkinson disease
—different pain syndromes.
Chaudhuri et al.
32
1. Musculoskeletal pain (pain around joints)2. Chronic pain (a generalised constant,
dull, aching pain or pain related to an internal organ)3. Fluctuation-related pain
(dyskinetic pain, “off”-period dystonia, and generalised “off”-period pain)4. Nocturnal
pain (pain related to periodic limb movement and restless leg syndrome or pain related
to difficulties turning around in bed)5. Oro-facial pain (pain when chewing, pain
due to grinding the teeth, and burning mouth syndrome)6. Discolouration/oedema and
swelling (burning pain in limbs and generalised lower abdominal pain)7. Radicular
pain (a shooting pain/pins and needles down the limbs)
Mylius et al.
107
A) Non–Parkinson disease-related painB) Parkinson disease-related pain: 1. Musculoskeletal
pain 2. Psychomotor restlessness pain 3. Neuropathic pain
3.1. Pain processing is altered in Parkinson disease
Studies have largely reported reduced pain thresholds (greater sensitivity to pain)
and lower pain tolerance in PwP (for meta-analysis, see Ref. 141). Interestingly,
no relationship between pain sensitivity and disease duration was reported across
26 studies.
141
Moreover, significant heterogeneity is seen within and across studies suggesting considerable
interindividual differences with multiple contributory factors. Surveys have found
intensity and frequency of pain to be higher in patients with more advanced PD; however,
this likely reflects an increased incidence of musculoskeletal pain.
141
A study using quantitative sensory testing failed to find a difference between drug-naive
pain-free patients and controls suggesting that abnormalities may arise later in the
disease duration, relate to dopaminergic therapy, or be associated with the development
of chronic pain.
62
In the absence of longitudinal investigation, the effects of disease progression are
impossible to delineate but the power advantages of meta-analysis add credence to
the possibility that enhanced pain sensitivity is engaged at a certain point during
pathogenesis with a strong ceiling effect. Early pathophysiology within the midbrain
and brainstem regions may therefore be important for elevated psychophysical pain
sensitivity and reduced pain thresholds. Conversely, conditioned pain modulation paradigms,
which assess the functionality of descending modulatory mechanisms, have been found
to be comparable in controls and patients with PD in both ON and OFF states.
68,69
However, trend significant differences were seen between PD subtypes (akinetic rigid,
tremor dominant, and mixed). Given the low power of the study, this supports the heterogeneity
of pain processing in PwP and emphasises the need for large studies that allow for
adequately powered substratification.
Functional magnetic resonance imaging has revealed maladaptation of pain networks
present even at early disease stages in pain-free PwP compared with healthy controls.
Increased pain-related BOLD activation was observed in the somatosensory cortex, cerebellum,
and caudal pons.
138
Furthermore, activity in descending pain modulatory regions, such as the dlPFC, dorsal
ACC, and subgenual ACC, is lower in PwP than in healthy individuals, and connectivity
between dorsal ACC and dlPFC during anticipation of pain is reduced.
138
The bilateral activation of the nucleus accumbens (NA) in PwP is also lower than that
in healthy controls, suggesting altered processing of cognitive and evaluative facets
of pain.
120,140
A network-based analysis has shown dysfunction in reward pathways in PwP suffering
from persistent pain, but not those without, with disconnection of the right NA and
left hippocampus.
118
The NA has been implicated in the transition from acute to chronic pain across a variety
of human and animal studies.
8,29,51,56,155
The direction of causality remains unclear, but dysfunction of reward and modulatory
networks may predispose PwP to develop chronic pain and offer therapeutic targets.
3.2. Pharmacotherapy of pain in Parkinson disease
Pain in PwP remains neglected and poorly understood, with only a minority of patients
receiving adequate treatment.
13
People with PD are more likely to be prescribed analgesics, such as opiates, acetaminophen,
antiepileptics, and antidepressants, as well as receive chronic prescriptions, risking
polypharmacy or burdensome side effects.
22
Dopaminergic replacement therapy might lead to pain relief in some PwP.
92,142
For example, a 2-fold improvement in the King's Parkinson Disease Pain Scale domain
“fluctuation-related pain” was observed with rotigotine vs placebo.
124
l-Dopa administration reversed the reduction of pain threshold seen in PwP during
the off-state
64
and normalised abnormally increased pain-related activation within sensory-discriminative
(insula) and cognitive-affective (prefrontal cortex and ACC) regions in a positron
emission tomography study.
21
Interestingly, pain reduction from l-dopa administration or deep brain stimulation
[for review, see; Refs. 39,45,91] does not correlate with motor improvement suggesting
it may act directly on pain circuitry.
40,92,102,142
l-Dopa is not only converted exclusively into dopamine but also into noradrenaline
and may act as a false neurotransmitter within serotonergic terminals.
50
As both monoamines play a role in descending pain modulation and are affected by PD-specific
neurodegenerative changes at prodromal stages, the pain modifying effect of l-dopa
may be partially mediated through nondopaminergic systems.
9,19,20,44,74
Accordingly, duloxetine led to some degree of pain relief in an open-label study.
49
Cannabis has shown an ability to markedly reduce both sensory and affective facets
of pain in PwP.
132
Interestingly, an oxycodone RCT failed to reach significance for the primary end point
of reducing 24 hour pain scores.
144
There was a trend reduction in pain, and the dosage may have been inadequate. However,
opioidergic circuitry is known to be perturbed by PD pathophysiology, and this may
affect the efficacy of opioid analgesia.
54,115,136,140
Safinamide, with actions on dopamine through monoamine oxidase-B inhibition as well
as modulating abnormal glutamate release, has also shown a benefit in PwP.
26,27,65
Rotigotine, a purely dopaminergic agonist, produces limited benefit for overall pain
in PwP suggesting that safinamide may well impart a benefit through glutamatergic
actions and this warrants future investigation.
124
However, there remains a paucity of robust studies with the Movement Disorder Society
non-motor symptoms treatment recommendation identifying only 2 as sufficiently high
quality to include.
131
The multiplicity of neurotransmitter systems through which these drugs act eludes
to the complexity of pain in PD. Future research should use refined populations, or
those large enough for substratification, to further elucidate how these interventions
differentially interact with PD subtypes.
3.3. Utility of animal models
Animal models offer a unique opportunity to probe mechanisms of pain and pharmacotherapy.
This has been well reviewed for PD,
55,147
but remains understudied in AD. Mirroring clinical populations most studies report
altered pain thresholds compared with controls.
7,59,67,94,99,105,133,137
A chemically induced model of osteoarthritis through an intra-articular injection
of monosodium iodoacetate within transgenic TASTPM AD mice has provided insights into
interactions between clinically relevant pain, neurodegenerative pathophysiology,
and opioid analgesia.
4,5
TASTPM mice demonstrate an age-dependent reduction in thermal nociception that coincides
with amyloid pathology in pain-related brain regions.
4
Naloxone, an opioid antagonist, restored thermal nociceptive thresholds to that of
wild-type controls. Mice modelling with combined AD and osteoarthritis exhibited impaired
mechanical hypersensitivity and a lack of weight asymmetry. Subsequent administration
of morphine not only produced an antinociceptive effect but also increased the noxious
threshold significantly greater than that seen in wild-type animals.
5
Conversely, gabapentin showed no efficacy. Thus, altered processing within opioidergic
circuitry may partially mediate altered pain processing as well as influence both
efficacy and centrally mediated side effects of opioidergic pharmacotherapy. Additional
preclinical investigation may yield similar avenues for translational investigation.
4. Conclusion
Pain processing is altered in both AD and PD, but research to date has been focussed
on evoked pain. During chronic pain, structural and functional reorganisation that
takes place can be conceptualised as normal pain processing by the nervous system
interacting with a given aetiology to produce a novel chronic pain brain state.
146
These perturbed states further interact with neurodegenerative pathophysiology in
a manner yet to be investigated; whether this produces differential responses to analgesic
pharmacotherapy to those seen in the general population remains unclear. However,
the theoretical basis outlined here is compelling and mechanistic-level investigation
will be crucial to translate our emerging understanding of dysfunctional pain processing
to inform safe and effective clinical management. Although our focus here has been
on AD and PD, these constructs likely extend to other neurodegenerative diseases that
require similar mechanism-based investigation to facilitate therapeutic development.
Conflict of interest statement
C. Ballard reports grants and personal fees from Acadia pharmaceutical company, grants
and personal fees from Lundbeck, personal fees from Roche, personal fees from Otsuka,
personal fees from Biogen, personal fees from Eli Lilly, personal fees from Novo Nordisk,
personal fees from AARP, grants and personal fees from Synexus, and personal fees
from Exciva, all outside the submitted work. The remaining authors have no conflicts
of interest to declare.