REVIEW

Chronic Pain in the Elderly with Cognitive Decline:A Narrative Review

Luca Cravello . Simona Di Santo . Giustino Varrassi . Dario Benincasa .

Paolo Marchettini . Marina de Tommaso . Jacob Shofany .

Francesca Assogna . Daniele Perotta . Katie Palmer . Antonella Paladini .

Fulvia di Iulio . Carlo Caltagirone

Received: September 27, 2018 / Published online: January 21, 2019� The Author(s) 2019

ABSTRACT

The presence of pain in elderly persons withcognitive decline is often neglected, under-re-ported, underestimated, misdiagnosed and notadequately treated, with consequences thathave a strong impact on health, independencein activities of daily living and quality of life.There is no empirical evidence that people withdementia experience less pain; therefore, in

patients with severe cognitive impairment theprogression of cognitive decline dramaticallyaffects the ability to verbalize the presence ofpain. Self-assessment scales are considered the‘‘gold standard’’ for pain assessment, but thepresence of cognitive impairment is likely toreduce the reliability of these measures. Treat-ment of pain in elderly with cognitive declineor dementia is based on non-pharmacologicaland pharmacological strategies. Pharmacologi-cal treatment should consider physiologicalchanges, high comorbidity and drug interac-tions that occur frequently in the elderly. Thisnarrative review aims to describe currentknowledge, methods of detection and treat-ment approaches for chronic pain in elderlypersons with cognitive deficits.

Enhanced Digital Features To view enhanced digitalfeatures go to: https://doi.org/10.6084/m9.figshare.7306751.

L. Cravello (&) � D. PerottaCentro Regionale Alzheimer ASST Rhodense,Passirana di Rho Hospital, Milan, Italye-mail: lcravello@asst-rhodense.it

S. Di Santo � J. Shofany � F. di Iulio � C. CaltagironeIRCCS Fondazione Santa Lucia, Rome, Italy

S. Di SantoDipartimento di Medicina dei Sistemi, UniversitaTor Vergata, Rome, Italy

G. VarrassiPaolo Procacci Foundation, Rome, Italy

G. VarrassiWorld Institute of Pain, Winston-Salem, USA

D. BenincasaIstituto Regina Elena IFO-Neurologia, Rome, Italy

P. MarchettiniIstituto Scientifico Ospedale S. Raffaele, Milan, Italy

M. de TommasoNeurophysiology and Pain Unit, University of BariAldo Moro, Bari, Italy

F. AssognaLaboratory of Neuropsychiatry, Department ofClinical and Behavioral Neurology, IRCCS SantaLucia Foundation, Rome, Italy

K. PalmerFondazione Ospedale San Camillo IRCCS, Venezia,Italia

A. PaladiniDepartment of MESVA, University of L’Aquila,L’Aquila, Italy

Pain Ther (2019) 8:53–65

https://doi.org/10.1007/s40122-019-0111-7

Keywords: Aging; Alzheimer’s disease; Chronicpain; Dementia; Elderly; Frailty

INTRODUCTION

Chronic pain is defined as persistent andrecurrent pain that is perceived over a pre-de-fined period of time, commonly 3 or 6 monthsafter onset or, according to a broader definitioninvolving no arbitrarily fixed duration, painthat extends beyond the expected healing per-iod [1].

The worldwide prevalence of chronic pain isestimated to be between 25% and 50% inelderly people living in the community [2] andup to 83% in those living in nursing homes [3].The prevalence of chronic pain increases withage, reaching a plateau at around 70–75 years[4].

The presence of pain in the elderly is oftenignored, underestimated, underreported andthus improperly treated, with important con-sequences on health, the ability to perform theactivities of daily living and quality of life. Sleepdisorders, musculoskeletal problems, lowerdegree of mobility, falls, malnutrition, cognitiveimpairment, increased use of drugs, depressedmood depression and reduced social participa-tion are usual manifestations of symptomaticpain in elderly patients [5].

Although chronic pain affects cognitiveabilities, the inverse relationship is unclear.Neurodegenerative diseases, which lead to cog-nitive impairment, can influence the perceptionof pain. Given the progressive increase in theaging population and the high prevalence ofdementia in the elderly, the topic of chronicpain, its detection and quantification in peoplewith cognitive impairment and the identifica-tion of useful therapeutic approaches is of highinterest and importance.

This narrative review aims to describe cur-rent knowledge, methods of detection andtreatment approaches for chronic pain inelderly persons with cognitive deficits.

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

PAIN IN ALZHEIMER’S DISEASEAND OTHER DEMENTIAS

Pain is a complex perceptual and subjectiveexperience that has sensory, affective and cog-nitive dimensions. In vegetative and minimalstates of consciousness there is a residual corti-cal response to nociceptive experimental stim-uli [6], thus the perception of pain seemsessential for survival and deserves evaluation inthe absence of valid subjective reports, such asin people with severe cognitive impairment.

Neuropathological changes that occur inpeople with dementia are considered responsi-ble for alterations in pain perception [7].Although these alterations could be common indifferent types of dementia, the vast majority ofclinical and experimental studies investigatingpain assessment or treatment in dementia arefocused on patients with Alzheimer’s disease(AD).

The neuropathological changes that occur inAD selectively affect important areas involvedin the medial pathway of pain, especially themedial nuclei of the thalamus, hypothalamus,cingulus and insula, whereas the brain areasinvolved in the lateral pathway of pain are rel-atively well preserved [8]. Thus, according to awidely accepted theory, typical degeneration ofAD involves the affective-motivational compo-nent of pain (medial pathway) more than thesensory-discriminative dimension (lateral path-way) [9]. Furthermore, the typical cognitiveimpairment of AD, which is characterized bymemory deficits and reasoning, could affect theindividual assessment of a painful experienceand the ability to describe it. According to thisclinical theoretical construct, an unchangedpain threshold and a higher tolerance of painfulstimuli should be observed in AD patients.Indeed, some authors found a higher tolerancefor intense pain in AD patients than in controls[10] and some others suggested that in AD theperception of acute pain is preserved and thatthe experience of chronic pain may be altered[11]; a reduction in the autonomic response as aresult of impending pain has also been reported[12].

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Conversely, other studies have provided dif-ferent results [13]. For example, after nocicep-tive stimuli administration a functional brainneuroimaging study did not show more reducedactivity of specific brain areas involved in themedial pain pathway in AD patients than inhealthy controls [14]. This indicates that theemotional aspects of the experience and emo-tional pain are not selectively reduced in thesepatients [14]. These data are still consistent withthe results of previous works indicating thatsensory-discriminative pain is preserved even inthe advanced stages of AD [12], whereas paintolerance is enhanced with increasing severityof the disease [10].

Another key point related to the neu-ropathological changes that occur in the pre-frontal lobe of patients with AD is alteration ofthe response to analgesic drugs. An experimen-tal study showed that the placebo mechanism,which is an important aspect of pain manage-ment, is reduced in patients with AD. This effectis particularly noticeable when the connectionsbetween the prefrontal lobes and the rest of thebrain are extensively damaged [15]. It is, there-fore, likely that patients with AD require ahigher dosage of pain medication to obtain theanalgesic effect that is normally reached incognitively healthy persons. In addition, it isstill unclear whether the changes in theblood–brain barrier that occur during thedementia process influence the effect of cen-trally acting pain medications, such as opioids[16].

Neuropathological changes differ, at leastpartially, between dementia syndromes. It hasbeen, therefore, suggested that the prevalenceof pain differs among different types ofdementia. However, evidence from studiesenrolling patients with dementia types otherthan AD is scarce.

Pain perception in vascular dementia (VaD)may increase because of white matter lesions ofpathways ascending to the thalamus, such asthe spinothalamic tract [17]. As far as we areaware, there are only a few studies on chronicpain in patients with VaD, observing that thelevel of pain reported by patients with VaD issignificantly higher than that reported by per-sons without dementia [18–20]. Moreover, in a

recent study of Binnekade et al., patients withmild to moderate AD and mixed AD and VaDare less likely to report pain than patients withsubjective cognitive impairment in an outpa-tient memory clinic setting [21].

There is overlap between AD and fronto-temporal dementia (FTD) in affected pain-re-lated areas. However, compared with AD, thedegeneration of the cingulate cortex and theinsula is higher in FTD, while atrophy of theamygdala and hippocampus appears milder[22]. It, therefore, might be argued that theevaluative and motivational-affective aspects, aswell as the autonomic responses and memoryfor pain, should be particularly affected in FTDpatients. Accordingly, in one study, the per-ception of pain and ability to withdraw fromnociceptive stimuli in FTD was found to besignificantly lower than in AD and VaD [23].Nevertheless, no study was found to report theprevalence of pain specifically in patients withFTD.

Also, pain perception in dementia with Lewybodies (LBD) may be altered due to brain atro-phy and damage caused by Lewy bodies. How-ever, studies reporting the prevalence of pain inpeople with LBD are scarce. Since LBD neu-ropathology may be a key feature of Parkinson’sdisease (PD), a specific reason for the lack ofstudies in LBD could be that these patientsmight be included within trials assessing pain inPD, in which prevalence of pain is estimated tobe of 59.7% [24].

A recent review investigated pain prevalencein AD, VaD, FTD and LBD. The sample-weightedprevalence of pain could only be calculated forAD, VaD and mixed dementia: pain was esti-mated to affect 45.8% (95% CI 33.4–58.5%) ADpatients, 56.2% (95% CI 47.7–64.4%) personswith VaD and 53.9% (95% CI 37.4–70.1%) withmixed dementia [7].

According to three studies found, the preva-lence of pain in patients with LBD rangesbetween 50% and 70% [25–27]. In a recentreview and meta-analysis on pain in atypicalParkinsonism, patients with LBD had a pooledpain prevalence of 38% with a multi-localizedcharacterization [28].

Pain Ther (2019) 8:53–65 55

ASSESSMENT OF PAIN IN ELDERLYWITH COGNITIVE DECLINE

Self-assessment scales are considered the ‘goldstandard’ for assessing pain, but the presence ofcognitive impairment decreases their reliability.In 2002, the American Geriatrics Society estab-lished guidelines for the assessment of behav-ioral indicators of pain [29]. More recently, theAmerican Society for Pain Management, withthe Nursing Task Force on the assessment ofpain in patients unable to verbally communi-cate, recommended a comprehensive hierar-chical approach, incorporating measures of self-evaluation and the observation of behaviorsrelated to pain [30]. On the basis of these rec-ommendations, the assessment of pain inelderly patients affected by cognitive impair-ment should be carried out as follows:1. An attempt should be made to obtain a self-

rating by the patient; the severity of cogni-tive impairment is important for choosingthe strategy and the evaluation tools. Self-assessment of pain is often possible inpatients with mild to moderate cognitiveimpairment, but its accuracy decreases withthe progression of dementia. The use ofvalidated and standardized assessmentscales is widely recommended to allowmore accurate monitoring of patients, withthe possibility of comparing the course ofpain over time and more effective commu-nication between the different operators. Ahigh percentage (61%) of patients withsevere dementia can understand at least asimple scale of pain self-assessment (e.g.Visual Analogical Scale, Verbal Rating Scale,Faces Scale). Observational scales for painshould not be administered routinely inpatients with severe dementia if they arestill able to provide pain self-assessmentmeasures [31]. Communicative skill could,however, be compromised by the presenceof delirium, an altered level of conscious-ness, medical devices such as endotrachealtubes, sedation or the effect of pharmaco-logical treatments.

2. Researching possible causes of pain. Com-mon etiological factors should always be

investigated in elderly persons: pathologicalconditions (musculoskeletal or neurologicalproblems), treatment procedures or othercauses (infections, fecal retention, falls,entrapment, etc.) are common etiologiesof chronic pain.

3. Observing and describing the patient’sbehavior, also using specific scales. Whenverbal expression is severely impaired (as insome forms of dementia or in severe stagesof illness), behavior remains the primarysource of communication. Modification ofbehavior can be an important sign of pain[32]. Behaviors that should be observed inpatients with dementia include: facialexpressions, verbalizations/vocalizations,body movements, changes in interpersonalinteractions, changes in daily life, changesin cognitive status [29].Although several studies have been con-ducted on this topic, the behaviors mostoften associated with pain in persons withdementia have not yet been unequivocallyidentified [33]. The observation should takeplace preferably while the patient is partic-ipating in an activity, since the pain may beminimal or absent at rest. Changes in vitalparameters do not represent reliable painindicators. Behavioral modifications can bedescribed and quantified using validatedscales appropriate to the patient’s settingand clinical condition.

4. Obtaining information from a caregiver.Sufficiently reliable information can beobtained from formal and informal care-givers (family members, nurses, care per-sonnel in nursing home/hospital) who haveadequate knowledge of the patient’s historyand past and current behavior and may beadequately trained to assess pain. Painassessment should be included in the train-ing of all staff members involved in clinicalcare. There are discrepancies betweenpatient self-assessment and that of familymembers and clinical staff, who tend tooverestimate and underestimate the painexperienced by the individual [34].

5. Trying an analgesic treatment. It is impor-tant to try pain reduction by administeringan analgesic; this should be done following

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procedures and doses appropriate for thedisease and after estimating intensity ofpain and the patient’s comorbidities [35].

Several tools have been developed to assess painin elderly persons with cognitive impairment.Reviews in the literature [36, 37] concluded thatthe existing instruments need further imple-mentation and psychometric validation beforethey can be commonly used in clinical practice.All scales designed to assess pain in elderlypatients with dementia have significant limita-tions in terms of usability, construct validity,reliability and inter-rater and test–retest relia-bility [38]. In particular, observational scalesshould be validated versus the gold standard ofself-rating assessment in people without cogni-tive impairment. Moreover, almost all researchin the literature has focused exclusively onpatients with moderate to severe dementia. Todate only two studies have compared measuresof self-evaluation and observational scales inpeople with and without cognitive impairment,i.e., a study on acute pain associated withphysical therapy in patients with post-operativerehabilitation and research comparing patientswith mild to moderate dementia with cogni-tively intact elderly persons [39]. There is,however, sufficient consensus that measures ofself-assessment cannot represent the gold stan-dard in patients who are unable to understandthe scale instructions/requests and provideeffective and uniquely interpretable verbalresponses.

Direct assessment relies generally on simpleanalogue scales or on more complex instru-ments, which are, however, difficult to use inthe presence of cognitive impairment. Indirectassessment is carried out with scales aimed atdetecting and recording behaviors or attitudesindicative of pain, such as difficulty in breath-ing, restlessness, facial expressions, vocaliza-tions and agitation.

TREATMENT OF CHRONIC PAININ THE ELDERLY WITH COGNITIVEDECLINE

Pain therapy in the elderly is different than inyounger people. Clinical manifestations of

chronic pain are often complex and multifac-torial. Moreover, pain in elderly persons withcognitive disorders may be under-reported orunderestimated. The presence of comorbidityand polypharmacy must always be taken intoconsideration when choosing the painkillertreatment as it increases the risk of complica-tions and adverse events. Current evidencefrom clinical trials on pain treatment cannotprovide adequate indication in many situationscommonly encountered in clinical practice:most of the evidence, in fact, is based on specificconditions and trials conducted in populationsof young adults while few studies have beenconducted on patients aged over 75 years andthose on elderly people with cognitive declineare poor [40]. Age-related differences in efficacy,sensitivity, toxicity and in the pharmacokineticand pharmacodynamic properties of drugscannot be ignored in the formulation of anadequate therapeutic program.

The efficacy of pain-relieving treatments inpatients with dementia could be influenced bythe level of cognitive impairment, with areduction of the awareness of the disease and ofcommunication and relational skills. Moreover,behavioral symptoms such as agitation, aggres-sion and delirium could be the only manifes-tation of pain [31]. Often, this type of patientreceives a sedative treatment and the prescrip-tion of antipsychotic drugs, that have dubiousefficacy on painful symptoms and expose thepatient to potential even serious side effects,such as increased mortality, cardio- and cere-brovascular events and falls [41]. Referring thento the treatment of pain in elderly patients withcognitive impairment, the first consideration isto use appropriate pain assessment methodsand to correctly set the diagnosis in order tochoose the most appropriate drug therapy andavoid the use of inappropriate, potentiallyharmful drugs.

Given the lack of clinical evidence that canbe extrapolated from clinical trials, the indica-tions of interventions provided by the mainguidelines for the treatment of pain are basicallybased on clinical experience.

The probability of obtaining adequateantalgic efficacy can be maximized by carefultraining of caregivers, analyzing the patient’s

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risk factors and comorbidities, and carefullymonitoring the patient over time. Althoughrealistic expectations about the possible benefitsmust be met and provided, especially in somepersistent pain conditions, the goal in elderlypatients, and even more so in those with cog-nitive impairment, is not to completely elimi-nate pain, but to reduce the intensity, durationand frequency of pain episodes, so as to maxi-mize both independence in activities of dailyliving and quality of life, and to minimize therisk of side effects, often severe, that are asso-ciated with treatments [42].

Pain therapy can utilize non-pharmacologi-cal treatments, as well as pharmacologicaltreatments. Among the non-pharmacologicaltreatments, the following may be useful: phys-ical therapy (physical exercises, TENS, vibratorytherapy, massages, exposure to heat or coldsources) [43, 44], alternative therapies(acupuncture, acupressure, aromatherapy).There are also other types of non-pharmaco-logical antalgic therapies used in elderly personswithout cognitive impairment, such as educa-tional programs, music therapy and psycho-logical methods, which are difficult to apply indementia patients, since cognitive impairmentreduces treatment compliance.

Until now, the most recent guidelines forpharmacological treatment published by theBritish Geriatric Society [45] suggest that thechoice of treatment should be dictated by theseverity of the pain symptomatology and con-ducted gradually. The categories of pain medi-cation to be used include non-opioid analgesics,opioids and adjuvant drugs. The first line drugsto be used are non-opioid analgesics and, ifnecessary, opioid analgesics can be added. Inthe case of severe pain, it is preferable to startwith opioids by following the criterion of painintensity.

Clinical practice requires a gradual increasein the dosage of drugs, in order to allow a betteradaptation and tolerance to the therapy andavoid possible side effects of drugs. As thegradual titration of pain medication is reques-ted at the beginning of the treatment, when thepain symptoms disappear, it is recommended togradually reduce the dosages of drugs until theend of antalgic therapy.

Pain control through the use of psychoactivedrugs (e.g. neuroleptics and benzodiazepines),often improperly used in elderly patients withdementia, should be avoided as these drugs canworsen the overall clinical condition. In addi-tion, drugs that are indicated for the treatmentof neuropathic pain in adults (e.g. gabapenti-noids) should be used with caution in theelderly due to the increased risk of side effects.Other drugs, such as serotonin and nore-pinephrine reuptake inhibitors, may be a goodalternative to non-steroidal anti-inflammatorydrugs and opioids due to their ability to raisethe pain threshold and the lower risk of sideeffects.

NON-PHARMACOLOGICAL PAINMANAGEMENT IN THE ELDERLYWITH COGNITIVE DECLINE

Recent theories support the concept that psy-chological factors may influence the way inwhich people interpret, respond to and copewith pain. Although pharmacological therapycan be helpful in managing pain, it may not becompletely effective and older people may beparticularly susceptible to side effects and druginteractions [46]. In addition, non-pharmaco-logical interventions may be helpful, not justwhen pharmacological therapy is ineffective,but as an adjunct to medication or as a first-linetherapy [47]. Gagliese et al. proposed that painin older people with dementia is the result of anintricate network of interactions betweenbiopsychosocial phenomena; moreover,dementia and pain may have a reciprocal rela-tionship [48]. Based on this model, pain in olderpeople with dementia can be conceptualized asthe final result of the interaction of threeheterogeneous phenomena—pain, aging anddementia—which are created and influenced bythe interactions of predisposing, lifelong, andcurrent biopsychosocial factors [48]. Thus,interventions on biopsychological factors suchas affective and social dimension can be effec-tive on pain relief. For example, it has beenfound that treatment of depression in olderpeople with osteoarthritis may have a signifi-cant impact on function and pain [47, 49];

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moreover, there is some evidence that psycho-logical interventions such as cognitive beha-vioural therapy may be effective in decreasingchronic pain in adults and improving disabilityand mood [47]. Cipher et al. applied a multi-modal cognitive behavioural therapy interven-tion consisting of comprehensive initial evalu-ation of several domains, including level ofdementia, emotional distress and pain; thetherapists worked collaboratively with nursinghome residents, their families and othersinvolved in their care and used structured andindividualized treatment plans incorporatingthese to encourage behavioral change [50]. Atthe end of the program the 44 elderly partici-pants showed a significant decrease in pain [50].In another study, the authors examined theeffects of mindfulness meditation on 27 olderadults with chronic back pain and concludedthat the patients experienced ‘‘numerous bene-fits’’ after intervention, including less pain,better sleep and improved quality of life [51].

Physical activity is important in the man-agement of persistent pain in older people.Indeed, physical inactivity is common in elderlypeople and it can have impact on quality of life,with reduced level of functioning, leading toincreased disability and pain. To date, studiesexclusively focused on exercise and physicalactivity in people over 65 years with chronicpain are scarce and no randomized clinical trialsare available on elderly persons with chronicpain and dementia. Data consistent with evi-dence from reviews of randomized clinical trialson populations with chronic pain that include,but are not exclusive to, people over 65 years[52, 53] support the use of programs that com-prise strengthening, flexibility and enduranceactivities to increase physical activity andreduce chronic pain. Ellis et al. conducted astudy on 95 participants at five residential agedcare facilities in Australia [54]. The authorsapplied a pain management program usingnon-pharmacological approaches. The painmanagement program involved a physiothera-pist implementing four sessions per week oftreatments (massage therapy, TENS, exercisesand stretching, or combinations of these).Resulting data showed a small but statisticallysignificant decrease in the number of as

required medications, and a decrease in averagepain ratings from ‘‘some to moderate pain’’ to ‘‘alittle pain’’. Notably, residents with dementiareceived lower pain ratings than those without.The authors concluded that non-pharmacolog-ical interventions may be effective in reducingpain and reliance on required medications inresidential care settings, especially when two ormore are used [54].

There is also evidence of the use of sometypes of complementary therapies (e.g.osteopathy, acupuncture, herbal medicine,homeopathy, aromatherapy, Ayurvedic medi-cine) for the management of painful conditionsin older people [47]. However, no data fromrandomized clinical trials are available aboutthe efficacy of complementary therapies onchronic pain in patients with dementia. Somestudies highlighted that specific effects of aro-matherapy on brain pathways, implicated inboth emotional response and cognitive perfor-mance, might have a secondary effect on neu-ropsychiatric symptoms that can be anexpression of pain in patients with dementia[55].

PHARMACOLOGICAL TREATMENTOF CHRONIC PAIN IN THE ELDERLYWITH COGNITIVE DECLINE

Below, we describe drugs that are indicated inthe main guidelines for the treatment ofchronic pain in elderly persons that can also beused for treatment of patients with dementia.1. Non-opioid analgesics

They constitute a heterogeneous category ofcompounds (salicylic acid and its deriva-tives, Paracetamol, non-steroidal anti-in-flammatory drugs—NSAIDs), which sharesome therapeutic actions and side effects.They represent the most commonly pre-scribed class of analgesics and are particu-larly useful especially for somatic pain,particularly if caused by inflammatory pro-cesses or tissue injury. Recent reviews of theliterature [56], in agreement with currentpain guidelines [29, 42, 45, 47] indicateparacetamol as the first-line approach forthe management of pain also in patients

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with dementia. The use of NSAIDs inpatients with dementia differs significantlyfrom elderly persons without dementia; aScandinavian study reported the use ofparacetamol in 46% of people withdementia compared to 25% of cognitivelyhealthy elderly [57].The greatest limitation of the use of NSAIDsis related to their ‘‘roof effect’’, a phe-nomenon whereby increasing the doseabove a certain level does not correspond tobetter analgesia, but only an increase in sideeffects, which may include potentially life-threatening gastrointestinal and cardiovas-cular disorders [45, 58–61]. NSAIDs shouldbe carefully used, especially in the case ofpatients particularly at risk, such as theelderly, those with peptic ulcer disease,coagulation disorders, renal insufficiencyand those under corticosteroid treatment.An NSAIDs treatment should be co-pre-scribed with a gastroprotection (i.e. protonpump inhibitor). It should also be takeninto account that even paracetamol,although considered a drug without majorside effects, can be hepatotoxic in excessiveor long-term treatments [62].

2. OpioidsThey include morphine and any othersubstance able to produce Morphine-likeeffects that can be blocked by specificantagonists, such as naloxone. Several neu-ropeptides and synthetic analogues are partof the opioid family. Evidence from ran-domized clinical trials (RCTs) indicates thatdifferent opioids are effective in the treat-ment of neuropathic pain and chronic painrelated to musculoskeletal disorders. OneRCT conducted on 25 subjects found thatopioid treatment is effective in reducing theagitation of patients with advanced demen-tia [63]. However, evidence of efficacy forlong-term treatment is poor and clinicaltrials in elderly patients are lacking.The main side effects of opioids includetolerance, dependence, sedation, delirium,disorders of the gastrointestinal tract, inter-action with the absorption of other drugsand respiratory depression which, althoughinfrequent, constitutes the most dangerous

adverse event. The possibility of adverseevents increases with increasing age, thenumber of comorbid diseases and existingpharmacological treatments. Interactionsbetween opioids and psychotropic drugsare very frequent and some studies haveshown that the combination opioids withpsychotropic drugs increases the risk offalling and hip fractures four times [64, 65].

3. AdjuvantsThe term ‘‘adjuvants’’ refers to drugs formu-lated for other therapeutic indications thathave, however, shown an analgesic efficacy.Some adjuvants are particularly effective inneuropathic pain, such as tricyclic antide-pressants and antiepileptics [47]. Tricyclicantidepressants are not recommended forthe treatment of pain in the elderly as theyareassociatedwithanticholinergiceffects andimportant side effects (urinary incontinence,hypotension, sedation, glaucoma, cardiacarrhythmia), which, besides increasing therisk of falls, are dangerous for this type ofpatient. Anti-depressant serotonin and nora-drenaline reuptake inhibitors (SNRIs), such asduloxetine, are generally more effective andbetter tolerated. The evidence on otherantidepressants, such as serotonin reuptakeinhibitors (SSRIs), is insufficient and theguidelines advise against their use as painkil-lers [45]. Antiepileptic drugs, such as carba-mazepine, sodium valproate and phenytoin,have been widely used in the treatment ofneuropathic pain. However, their use in theelderly is not without problems due to centraladverse effects, the need for regular monitor-ing of blood parameters and their potentialinteractions with other drugs. Otherantiepileptic drugs, such as gabapentin andpregabalin, have become widely used in neu-ropathic pain and many studies have shownanalgesic efficacy and fewer side effects thanprevious-generation antiepileptics [66]. How-ever, there are currently no studies investi-gating the use of anti-epileptics for thetreatment of pain in patients with dementia.

4. Other treatmentsNew approaches to pain control are aimedat multiple therapeutic interventions andthey act at both neuronal and non-neuronal

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levels. The most recent literature shows thatthis is possible by using active ingredientsthat can normally be found in foods inaddition to drugs.In recent years, increasing evidence has high-lighted the functional significance of theinteraction between immune and nervoussystems in the mechanisms of pain [67]. Morespecifically, the role of mast cells has beenrecognized in peripheral sensitization mech-anisms related to neurogenic inflammationand neurogenic pain and of microglia in themechanisms of central sensitization, which isgreatly involved in neuroinflammation andneuropathic pain [68]. The endogenouspalmitoylethanolamide (PEA), a natural lipi-dic substance of the N-acyletanolamidicstructure, which is contained in many foodswidely used by humans and in particular invegetable oils, is able to reduce neuroinflam-mation by means of inhibitory antagonistcontrol on non-neuronal cells involved in theprocesses of peripheral sensitization and cen-tral pain; these include mast cells and micro-glia [69, 70]. When administered orally, PEAhas been shown to be effective in treatingpainful peripheral neuropathies of variousorigins aswell aspainsymptomatology linkedto carpal tunnel syndrome in diabetics and inpersons without any other neuropathies [71].Significant effects were also obtained in sen-sory and motor neuropathies induced bychemotherapy. When associated with certainpolyphenols with antioxidant activity, PEAhas also proven effective in treating chronicpelvic pain. From a clinical point of view, theadministration of PEA to treat painful symp-toms isof particular interestgiventhe absenceof severe side effects even after prolongedperiods of use in frail elderly individuals.Therefore, the preclinical and clinical effec-tiveness of PEA against chronic pain has beenwidely documented [72, 73].

CONCLUSION

We performed a narrative review on the topic ofchronic pain in the elderly with cognitive

decline and the key points here discussed aresummarized in Table 1.

Despite its high prevalence the diagnosis andtreatment of chronic pain in cognitivelyimpaired elderly people is still a challenge forclinicians. Neuropathological changes occur-ring in patients with AD and the loss of com-munication abilities could lead to under-assessment and under-treatment of pain inthese patients. Self-report scales may represent

Table 1 Chronic pain in elderly with cognitive decline:key points

1. Make a correct diagnosis of pain in patients with

cognitive impairment

2. Use validated and standardized tools for pain

assessment

3. Self-assessment pain scales are indicated for patients

with mild to moderate cognitive impairment and

observational scales for those unable to understand

the scale instructions

4. Consider non-pharmacological interventions for the

treatment of chronic pain in elderly with cognitive

decline

5. Avoid using inappropriate and potentially dangerous

drugs to treat pain in frail elderly people

6. In choosing analgesic drugs, take into account clinical

variables and comorbidity of elderly patient with

cognitive decline

7. According to severity of pain, start therapy with non-

opioids and, if necessary, consider opioids later

8. Make a gradual titration of pharmacological

treatment for pain (start low, go slow)

9. Avoid using neuroleptics and benzodiazepines as pain

killers

10. Use antiepileptic drugs with care

11. Consider SNRI as adjuvants and/or an alternative

to NSAIDs and opioids

12. Consider using natural compounds able to

modulate the pain threshold

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valid tools for the assessment of pain in peoplewith mild to moderate cognitive decline. How-ever, in severe stages of dementia nonverbalpain behaviors are useful in assessing painsymptoms. The complexity of patients withdementia makes it difficult not only to make acorrect diagnosis of pain but also to start ade-quate treatment. Indeed, pharmacologicaltreatment should take into account physiolog-ical changes, high comorbidity and drug inter-actions that occur frequently in the elderly.

Novel pharmacological approaches able toincrease pain thresholds and with lower sideeffects may represent a valid alternative for thetreatment of chronic pain in elderly personswith cognitive decline.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Luca Cravello, Simona DiSanto, Giustino Varrassi, Dario Benincasa, PaoloMarchettini, Marina de Tommaso, Jacob Sho-fany, Francesca Assogna, Daniele Perotta, KatiePalmer, Antonella Paladini, Fulvia di Iulio andCarlo Caltagirone have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any

noncommercial use, distribution, and repro-duction in any medium, provided you giveappropriate credit to the original author(s) andthe source, provide a link to the CreativeCommons license, and indicate if changes weremade.

REFERENCES

1. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI,Benoliel R, et al. A classification of chronic pain forICD-11. Pain. 2015;156(6):1003–7.

2. International Pain Summit Of The InternationalAssociation For The Study Of Pain. Declaration ofMontreal: declaration that access to pain manage-ment is a fundamental human right. J Pain PalliatCare Pharmacother. 2011;25(1):29–31.

3. Won AB, Lapane KL, Vallow S, Schein J, Morris JN,Lipsitz LA. Persistent nonmalignant pain and anal-gesic prescribing patterns in elderly nursing homeresidents. J Am Geriatr Soc. 2004;52(6):867–74.

4. Gibson MC, Schroder C. The many faces of pain forolder, dying adults. Am J Hosp Palliat Care.2001;18(1):19–25.

5. Gallagher RM, Verma S, Mossey J. Chronic pain.Sources of late-life pain and risk factors for disabil-ity. Geriatrics. 2000;55(9):40–4.

6. de Tommaso M, Navarro J, Ricci K, Lorenzo M,Lanzillotti C, Colonna F, et al. Pain in prolongeddisorders of consciousness: laser evoked potentialsfindings in patients with vegetative and minimallyconscious states. Brain Inj. 2013;27(7–8):962–72.

7. van Kooten J, Binnekade TT, van der Wouden JC,Stek ML, Scherder EJ, Husebo BS, et al. A review ofpain prevalence in Alzheimer’s, vascular, fron-totemporal and Lewy body dementias. DementGeriatr Cogn Disord. 2016;41(3–4):220–32.

8. Braak H, Braak E. Staging of Alzheimer-related cor-tical destruction. Int Psychogeriatr. 1997;9(Suppl1):257–61 (discussion 69–72).

9. Scherder EJ, Bouma A. Is decreased use of analgesicsin Alzheimer disease due to a change in the affec-tive component of pain? Alzheimer Dis Assoc Dis-ord. 1997;11(3):171–4.

10. Benedetti F, Vighetti S, Ricco C, Lagna E, Bergam-asco B, Pinessi L, et al. Pain threshold and tolerancein Alzheimer’s disease. Pain. 1999;80(1–2):377–82.

62 Pain Ther (2019) 8:53–65

11. Pickering G, Jourdan D, Dubray C. Acute versuschronic pain treatment in Alzheimer’s disease. Eur JPain. 2006;10(4):379–84.

12. Benedetti F, Arduino C, Vighetti S, Asteggiano G,Tarenzi L, Rainero I. Pain reactivity in Alzheimerpatients with different degrees of cognitiveimpairment and brain electrical activity deteriora-tion. Pain. 2004;111(1–2):22–9.

13. Gibson SJ, Voukelatos X, Ames D, Flicker L, HelmeRD. An examination of pain perception and cere-bral event-related potentials following carbondioxide laser stimulation in patients with Alzhei-mer’s disease and age-matched control volunteers.Pain Res Manag. 2001;6(3):126–32.

14. Cole LJ, Farrell MJ, Duff EP, Barber JB, Egan GF,Gibson SJ. Pain sensitivity and fMRI pain-relatedbrain activity in Alzheimer’s disease. Brain.2006;129(Pt 11):2957–65.

15. Benedetti F, Arduino C, Costa S, Vighetti S, TarenziL, Rainero I, et al. Loss of expectation-relatedmechanisms in Alzheimer’s disease makes analgesictherapies less effective. Pain. 2006;121(1–2):133–44.

16. Banks WA. Drug delivery to the brain in Alzhei-mer’s disease: consideration of the blood-brainbarrier. Adv Drug Deliv Rev. 2012;64(7):629–39.

17. Jellinger KA. The pathology of ‘‘vascular dementia’’:a critical update. J Alzheimers Dis. 2008;14(1):107–23.

18. Scherder EJ, Plooij B, Achterberg WP, Pieper M,Wiegersma M, Lobbezoo F, et al. Chronic pain in‘‘probable’’ vascular dementia: preliminary findings.Pain Med. 2015;16(3):442–50.

19. Scherder EJ, Slaets J, Deijen JB, Gorter Y, Ooms ME,Ribbe M, et al. Pain assessment in patients withpossible vascular dementia. Psychiatry. 2003;66(2):133–45.

20. van Kooten J, Smalbrugge M, van der Wouden JC,Stek ML, Hertogh C. Prevalence of pain in nursinghome residents: the role of dementia stage anddementia subtypes. J Am Med Dir Assoc.2017;18(6):522–7.

21. Binnekade TT, Scherder EJA, Maier AB, Lobbezoo F,Overdorp EJ, Rhebergen D, et al. Pain in patientswith different dementia subtypes, mild cognitiveimpairment, and subjective cognitive impairment.Pain Med. 2018;19(5):920–7.

22. Scherder EJ, Sergeant JA, Swaab DF. Pain processingin dementia and its relation to neuropathology.Lancet Neurol. 2003;2(11):677–86.

23. Bathgate D, Snowden JS, Varma A, Blackshaw A,Neary D. Behaviour in frontotemporal dementia,Alzheimer’s disease and vascular dementia. ActaNeurol Scand. 2001;103(6):367–78.

24. Rana AQ, Kabir A, Jesudasan M, Siddiqui I,Khondker S. Pain in Parkinson’s disease: analysisand literature review. Clin Neurol Neurosurg.2013;115(11):2313–7.

25. Bostrom F, Jonsson L, Minthon L, Londos E.Patients with dementia with Lewy bodies havemore impaired quality of life than patients withAlzheimer disease. Alzheimer Dis Assoc Disord.2007;21(2):150–4.

26. Colosimo C, Morgante L, Antonini A, Barone P,Avarello TP, Bottacchi E, et al. Non-motor symp-toms in atypical and secondary parkinsonism: thePRIAMO study. J Neurol. 2010;257(1):5–14.

27. Hendriks SA, Smalbrugge M, Galindo-Garre F, Her-togh CM, van der Steen JT. From admission todeath: prevalence and course of pain, agitation, andshortness of breath, and treatment of these symp-toms in nursing home residents with dementia.J Am Med Dir Assoc. 2015;16(6):475–81.

28. Rana AQ, Qureshi AR, Siddiqui O, Sarfraz Z, Rana R,Shtilbans A. Prevalence of pain in atypical parkin-sonism: a systematic review and meta-analysis.J Neurol. 2018. https://doi.org/10.1007/s00415-018-9049-7.

29. AGS Panel on Persistent Pain in Older Persons. Themanagement of persistent pain in older persons.J Am Geriatr Soc. 2002;50(6 Suppl):S205–24.

30. Herr K, Coyne PJ, McCaffery M, Manworren R,Merkel S. Pain assessment in the patient unable toself-report: position statement with clinical practicerecommendations. Pain Manag Nurs. 2011;12(4):230–50.

31. Pautex S, Michon A, Guedira M, Emond H, Le LousP, Samaras D, et al. Pain in severe dementia: self-assessment or observational scales? J Am GeriatrSoc. 2006;54(7):1040–5.

32. Herr K, Coyne PJ, Key T, Manworren R, McCafferyM, Merkel S, et al. Pain assessment in the nonverbalpatient: position statement with clinical practicerecommendations. Pain Manag Nurs. 2006;7(2):44–52.

33. Chapman CR. Progress in pain assessment: thecognitively compromised patient. Curr OpinAnaesthesiol. 2008;21(5):610–5.

34. Kappesser J, Williams AC, Prkachin KM. Testing twoaccounts of pain underestimation. Pain. 2006;124(1–2):109–16.

Pain Ther (2019) 8:53–65 63

35. Kovach CR, Logan BR, Noonan PE, Schlidt AM,Smerz J, Simpson M, et al. Effects of the Serial TrialIntervention on discomfort and behavior of nursinghome residents with dementia. Am J Alzheimers DisOther Demen. 2006;21(3):147–55.

36. Herr K, Bjoro K, Decker S. Tools for assessment ofpain in nonverbal older adults with dementia: astate-of-the-science review. J Pain Symp Manag.2006;31(2):170–92.

37. Stolee P, Hillier LM, Esbaugh J, Bol N, McKellar L,Gauthier N. Instruments for the assessment of painin older persons with cognitive impairment. J AmGeriatr Soc. 2005;53(2):319–26.

38. Hadjistavropoulos T, Herr K, Turk DC, Fine PG,Dworkin RH, Helme R, et al. An interdisciplinaryexpert consensus statement on assessment of painin older persons. Clin J Pain. 2007;23(1Suppl):S1–43.

39. Horgas AL, Elliott AF, Marsiske M. Pain assessmentin persons with dementia: relationship betweenself-report and behavioral observation. J Am GeriatrSoc. 2009;57(1):126–32.

40. McLachlan AJ, Bath S, Naganathan V, Hilmer SN, LeCouteur DG, Gibson SJ, et al. Clinical pharmacol-ogy of analgesic medicines in older people: impactof frailty and cognitive impairment. Br J ClinPharmacol. 2011;71(3):351–64.

41. Ballard C, Smith J, Husebo B, Aarsland D, Corbett A.The role of pain treatment in managing the beha-vioural and psychological symptoms of dementia(BPSD). Int J Palliat Nurs. 2011;17(9):420.

42. American Geriatrics Society. Pharmacologicalmanagement of persistent pain in older persons.J Am Geriatr Soc. 2009;57(8):1331–46.

43. Ferrell BA. Pain evaluation and management in thenursing home. Ann Intern Med. 1995;123(9):681–7.

44. Gloth FM 3rd. Pharmacological management ofpersistent pain in older persons: focus on opioidsand nonopioids. J Pain. 2011;12(3 Suppl 1):S14–20.

45. Abdulla A, Bone M, Adams N, Elliott AM, Jones D,Knaggs R, et al. Evidence-based clinical practiceguidelines on management of pain in older people.Age Ageing. 2013;42(2):151–3.

46. Palmer K, Villani ER, Vetrano DL, Cherubini A,Cruz-Jentoft AJ, Curtin D, et al. Association ofpolypharmacy and hyperpolypharmacy with frailtystates: a systematic review and meta-analysis. EurGeriatr Med. 2018. (In Press).

47. Abdulla A, Adams N, Bone M, Elliott AM, Gaffin J,Jones D, et al. Guidance on the management of

pain in older people. Age Ageing. 2013;42(Suppl1):i1–57. https://doi.org/10.1093/ageing/afs200.

48. Gagliese L, Gauthier LR, Narain N, Freedman T.Pain, aging and dementia: towards a biopsychoso-cial model. Prog Neuropsychopharmacol Biol Psy-chiatry. 2018;87:207–15.

49. Lin EH, Katon W, Von Korff M, Tang L, Williams JWJr, Kroenke K, et al. Effect of improving depressioncare on pain and functional outcomes among olderadults with arthritis: a randomized controlled trial.JAMA. 2003;290(18):2428–9.

50. Cipher DJ, Clifford PA, Roper KD. The effectivenessof geropsychological treatment in improving pain,depression, behavioral disturbances, functionaldisability, and health care utilization in long-termcare. Clin Gerontol. 2007;30(3):23–40.

51. Green SM, Hadjistavropoulos T, Sharpe D. Clientpersonality characteristics predict satisfaction withcognitive behavior therapy. J Clin Psychol.2008;64(1):40–51.

52. Jamtvedt G, Dahm KT, Christie A, Moe RH,Haavardsholm E, Holm I, et al. Physical therapyinterventions for patients with osteoarthritis of theknee: an overview of systematic reviews. Phys Ther.2008;88(1):123–36.

53. Walsh NE, Mitchell HL, Reeves BC, Hurley MV.Integrated exercise and self-management pro-grammes in osteoarthritis of the hip and knee: asystematic review of effectiveness. Phys Ther Rev.2006;11(4):289–97.

54. Ellis JM, Wells Y, Ong JSM. Non-pharmacologicalapproaches to pain management in residential agedcare: a pre-post-test study. Clin Gerontol.2017;1–11.

55. Cravello L, Caltagirone C. Aromatherapy for thetreatment of neuropsychiatric symptoms ofdementia. In: Bagetta G, Cosentino M, Sakurada T,editors. Aromatherapy basic mechanisms and evi-dence-based clinical use. Clinical pharmacognosyseries. Boca Raton: Taylor & Francis Group, LLC;2016. p. 327–31.

56. Corbett A, Husebo BS, Achterberg WP, Aarsland D,Erdal A, Flo E. The importance of pain managementin older people with dementia. Br Med Bull.2014;111(1):139–48.

57. Haasum Y, Fastbom J, Fratiglioni L, Kareholt I,Johnell K. Pain treatment in elderly persons withand without dementia: a population-based study ofinstitutionalized and home-dwelling elderly. DrugsAging. 2011;28(4):283–93.

64 Pain Ther (2019) 8:53–65

58. Abraham NS, El-Serag HB, Hartman C, RichardsonP, Deswal A. Cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs and the risk ofmyocardial infarction and cerebrovascular acci-dent. Aliment Pharmacol Ther. 2007;25(8):913–24.

59. Chen LC, Ashcroft DM. Risk of myocardial infarc-tion associated with selective COX-2 inhibitors:meta-analysis of randomised controlled trials.Pharmacoepidemiol Drug Saf. 2007;16(7):762–72.

60. Singh G, Wu O, Langhorne P, Madhok R. Risk ofacute myocardial infarction with nonselective non-steroidal anti-inflammatory drugs: a meta-analysis.Arthritis Res Ther. 2006;8(5):R153.

61. White WB, West CR, Borer JS, Gorelick PB, LavangeL, Pan SX, et al. Risk of cardiovascular events inpatients receiving celecoxib: a meta-analysis ofrandomized clinical trials. Am J Cardiol. 2007;99(1):91–8.

62. Shimp LA. Safety issues in the pharmacologicmanagement of chronic pain in the elderly. Phar-macotherapy. 1998;18(6):1313–22.

63. Manfredi PL, Breuer B, Wallenstein S, Stegmann M,Bottomley G, Libow L. Opioid treatment for agita-tion in patients with advanced dementia. Int JGeriatr Psychiatry. 2003;18(8):700–5.

64. Hartikainen S, Mantyselka P, Louhivuori-Laako K,Enlund H, Sulkava R. Concomitant use of analgesicsand psychotropics in home-dwelling elderly peo-ple-Kuopio 75? study. Br J Clin Pharmacol.2005;60(3):306–10.

65. Shorr RI, Griffin MR, Daugherty JR, Ray WA. Opioidanalgesics and the risk of hip fracture in the elderly:codeine and propoxyphene. J Gerontol. 1992;47(4):M111–5.

66. Barber JB, Gibson SJ. Treatment of chronic non-malignant pain in the elderly: safety considera-tions. Drug Saf. 2009;32(6):457–74.

67. Marchand F, Perretti M, McMahon SB. Role of theimmune system in chronic pain. Nat Rev Neurosci.2005;6(7):521–32.

68. Ren K, Dubner R. Interactions between the immuneand nervous systems in pain. Nat Med.2010;16(11):1267–76.

69. Costa B, Comelli F, Bettoni I, Colleoni M, GiagnoniG. The endogenous fatty acid amide, palmi-toylethanolamide, has anti-allodynic and anti-hy-peralgesic effects in a murine model of neuropathicpain: involvement of CB(1), TRPV1 and PPAR-gamma receptors and neurotrophic factors. Pain.2008;139(3):541–50.

70. Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli L,Leon A. Nerve growth factor: from neurotrophin toneurokine. Trends Neurosci. 1996;19(11):514–20.

71. Paladini A, Fusco M, Coaccioli S, Skaper SD, VarrassiG. Chronic pain in the elderly: the case for newtherapeutic strategies. Pain Physician. 2015;18(5):E863–76.

72. Skaper SD, Facci L, Fusco M, Della Valle MF, Zusso M,Costa B, et al. Palmitoylethanolamide, a naturallyoccurring disease-modifying agent in neuropathicpain. Inflammopharmacology. 2014;22(2):79–94.

73. Paladini A, Fusco M, Cenacchi T, Schievano C, Pir-oli A, Varrassi G. Palmitoylethanolamide, a specialfood for medical purposes, in the treatment ofchronic pain: a pooled data meta-analysis. PainPhysician. 2016;19(2):11–24.

Pain Ther (2019) 8:53–65 65