Pain in the Neurodegenerating Brain

Insights Into Pharmacotherapy for Alzheimer Disease and Parkinson Disease

Timothy Lawn; Yahyah Aman; Katarina Rukavina; George Sideris-Lampretsas; Matthew Howard; Clive Ballard; Kallol Ray Chaudhuri; Marzia Malcangio


Pain. 2021;162(4):999-1006. 

In This Article

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.

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.

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.