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. Author manuscript; available in PMC: 2022 May 19.
Published in final edited form as: J Am Assoc Nurse Pract. 2021 Mar 12;34(1):18–25. doi: 10.1097/JXX.0000000000000580

Experimentally evoked pain in Alzheimer’s disease

Alison R Anderson 1, W Larkin Iversen 2, Michael A Carter 3, Karen O Moss 2, Ronald L Cowan 4, Todd B Monroe 2
PMCID: PMC9118535  NIHMSID: NIHMS1797780  PMID: 33731557

Abstract

Background:

Pain continues to be underrecognized and undertreated in Alzheimer’s disease (AD) while existing guidance about pain assessment and management in dementia is not widespread. Brain regions involved in pain processing and modulation are damaged during AD, and the pain experience in AD is not well understood. Experimental pain studies using psychophysics can further our understanding of the pain experience in AD, which may lead to improved assessment and management of pain in people living with AD.

Objective:

A systematic review was conducted to explicate the current understanding of experimentally evoked pain in AD from primary research using psychophysical methods.

Data Sources:

Peer-reviewed publications were found via PubMed, CINAHL, and PsycINFO. A total of 18 primary research, peer-reviewed full articles that met inclusion criteria were included, representing 929 total participants.

Conclusions:

Experimentally evoked pain in people with AD demonstrates that despite cognitive impairment and a reduced ability to effectively communicate, individuals with AD experience pain similar to or more unpleasant than cognitively intact older adults. This may mean amplified pain unpleasantness in people with AD.

Implications for practice:

Our current best practices need to be widely disseminated and put into clinical practice. Self-report of pain continues to be the gold standard, but it is ineffective for noncommunicative patients and those unable to understand pain scales or instructions because of memory/cognitive impairment. Instead, pain treatment should be ethically initiated based on patient reports and behaviors, caregiver/surrogate reports, review of the medical record for painful conditions, analgesic trials, and regular reassessments.

Keywords: Alzheimer disease, dementia, pain, psychophysics, review

Background:

Approximately 50% to 75% of people living with Alzheimer disease (AD) and related dementias experience pain regularly (Corbett et al., 2012; de Tommaso et al., 2016). This represents substantial numbers because there are 5.8 million people with AD in the United States (Alzheimer’s Association, 2020) and more than 50 million with dementia worldwide (Alzheimer’s Disease International, 2019). Clinicians have struggled to assess the complex, subjective phenomena that comprise the pain experience in people who are cognitively intact (Denny & Guido, 2012). This struggle becomes increasingly profound as cognition declines (Monroe & Mion, 2012), and pain is underrecognized and undertreated in people with AD (Cravello et al., 2019; Hadjistavropoulos et al., 2014). A recent review found that many nurses were not adequately educated in pain recognition or use of pain assessment tools for people with dementia (May & Scammell, 2020). Also concerning is that existing guidance regarding pain in dementia has not been widely implemented into clinical practice (Jennings et al., 2018) and is not included in annual reports from major AD/dementia and pain organizations (Anderson et al., 2020).

One method of building the knowledge base needed by clinicians to evaluate pain in AD is to conduct studies that use experimental pain induction to measure psychophysical data. Psychophysics involves noxious stimuli with corresponding pain reports, which has a long history of successful use in human pain studies (Rainville et al., 1992). One important advantage of using psychophysics is that the experimental pain stimuli can be tightly controlled, making individual subject comparisons more homogenous (Monroe et al., 2017). Because they provide mechanistic properties of the pain experience (Rainville et al., 1992), experimental pain studies hold high translational relevance and can lead to clinical interventions studies that change practice.

The American Nurses Association (ANA) uses McCaffery pain definition of “whatever the experiencing person says it is, existing whenever he says it does” in their position statement (ANA, 2018, para. 2), and the American Society for Pain Management Nursing (ASPMN) supports this ANA position statement (ASPMN, 2020). Many elements contribute to the pain experience, including culture/race/ethnicity, past experiences, contextual factors, biological sex, gender, genetics, depression, and anxiety (Coghill, 2010; Rahim-Williams et al., 2012). The processes that are memory based are likely altered in people with cognitive decline (Beach et al., 2017).

In the brain, pain processing involves the medial, lateral, and rostral pain networks (Monroe et al., 2012) as well as the descending pain modulatory system (DPMS) that shares many brain structures with these networks (Tracey & Mantyh, 2007). The medial pain network represents emotion, arousal, attention, memory, and unpleasant aspects of pain, encompassing the “affective” components of pain that include “pain unpleasantness.” The lateral pain network is involved in the identification of the location, intensity, and quality of pain, encompassing the “sensory and discriminative” components of pain, including “pain intensity” (Monroe et al., 2012). The rostral pain network overlaps the medial and lateral networks and may be responsible for behavioral expressions of pain (Monroe et al., 2012). The DPMS regulates nociceptive processing of pain to either facilitate or inhibit pain sensations (Tracey & Mantyh, 2007).

The AD trajectory includes damage to many pain-processing brain structures, which may change the pain experience (Monroe et al., 2012). For example, the periaqueductal gray (PAG) is part of the medial and rostral pain networks and the DPMS. The PAG is one of the most important brain structures for pain modulation partly because it releases endogenous opioids and is involved in the pain-relieving effects of exogenous opioid analgesics (Bodnar & Heinricher, 2013). The PAG is damaged in AD (Brilliant et al., 1992; Iseki et al., 1989; Parvizi et al., 2000; Uematsu et al., 2018), which could result in a reduced ability to release or mediate opioids. Possibly exacerbating this damage is that there is general opioid system dysfunction in AD (Cai & Ratka, 2012). Additionally, the rostral and medial pain network regions are damaged earlier in AD, but the lateral regions are not damaged until later in the disease process. These spatial differences in neurodegeneration may mean that the patient with AD can still experience sensory pain in a similar capacity as cognitively intact controls prior to the late stages of the disease (Monroe et al., 2012).

Objective

The objective of this systematic review was to explicate the current understanding of experimentally evoked pain in AD from primary research using psychophysics. This knowledge may aid in better pain assessment and management for this vulnerable population by nurse practitioners (NPs) and other clinicians.

Review methods and data sources

First, PubMed was searched with the following terms individually then in any combination therein: “pain,” “pain neurobiology,” “pain neurophysiology,” and “psychophysics” each with “Alzheimer” and then “dementia.” Then, CINAHL and PsycINFO were searched with “pain neurobiology” then “pain neurophysiology” then “psychophysics” each with “Alzheimer” and then “dementia” as combined with “AND.” Additional sources were found by examining reference lists of published, peer-reviewed articles for applicable articles.

Inclusion criteria included the publication being an English-language, peer-reviewed, original/primary research article and having a full text available, and incorporating psychophysical methods of repeated pain stimuli to experimentally evoke pain in participants with AD/dementia. No date limits were used because older studies are still cited in the current literature and their inclusion makes this review comprehensive. Searching concluded August 2020. Articles were initially screened by title, then abstract, then full text when applicable (Figure 1). The broad search terms used resulted in broad findings that were pared down based on applicable content, and studies were excluded if they did not meet inclusion criteria. Ultimately, 18 relevant articles met inclusion criteria and were included in the review.

Figure 1.

Figure 1.

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PRISMA diagram.

Results

Psychophysical data from experimentally evoked pain

Across the 18 studies, there were 929 total participants, with 487 being individuals with AD or another form of dementia. One study examined sex differences in AD (Cowan et al., 2017), whereas another examined the association of Mini-Mental State Examination (MMSE) scores and pain in participants with AD (Benedetti et al., 2004); therefore, neither had healthy controls (HC). Of the studies with HC, there were 871 participants: 429 with AD (at least 260 women) and 442 controls (at least 257 women). One study (Lints-Martindale et al., 2007) (N = 63) did not report sex demographics; however, it is still evident that there were more female participants than male participants across the 18 studies reviewed. This is not unexpected because AD affects women more than men (Alzheimer’s Association, 2020).

Table 1 includes the primary review results including detailed study and psychophysical data from experientially evoked pain in AD and can be found online as Supplemental Digital Content at http://links.lww.com/JAANP/A114. A summary snapshot is shown in Table 2 of the psychophysical outcomes from studies that included HC. Results from the studies without HC are included in Table 1 (see Supplemental Digital Content 1, http://links.lww.com/JAANP/A114) and within the text but are not included in Table 2.

Table 2.

Summary of psychophysical outcomes of participants with AD compared to HC

Conditions Heat Pressure Electric Shock Ischemia Cold Water Overall Totals
Stimulus detection AD > HC
Gibson et al., 2001
Monroe et al., 2016, 2017
AD = HC
Jensen-Dahm, Werner, Dahl, et al., 2014; Jensen-Dahm et al., 2015, 2016 		AD > HC
Cole et al., 2006, 2011
AD = HC
Lints-Martindale et al., 2007 		AD = HC
Benedetti et al., 1999
Lints-Martindale et al., 2007 		– – AD > HC × 5
AD < HC × 0
AD = HC × 6
Pain threshold AD > HC
Monroe et al., 2016
AD = HC
Gibson et al., 2001
Jensen-Dahm, Werner, Dahl, et al., 2014; Jensen-Dahm et al., 2015, 2016 		AD > HC
Cole et al., 2006
AD = HC
Jensen-Dahm, Werner, Dahl, et al., 2014 		– AD = HC
Benedetti et al., 1999 		AD = HC
Jensen-Dahm, Werner, Dahl, et al., 2014 		AD > HC × 2
AD < HC × 0
AD = HC × 7
Pain tolerance – AD < HC
Jensen-Dahm, Werner, Dahl, et al., 2014 		AD > HC
Benedetti et al., 1999 		AD > HC
Benedetti et al., 1999 		AD < HC
Jensen-Dahm et al., 2015
AD = HC
Jensen-Dahm, Werner, Dahl, et al., 2014 		AD > HC × 2
AD < HC × 2
AD = HC × 1
Pain unpleasantness AD > HC
Jensen-Dahm et al., 2015
AD = HC
Jensen-Dahm et al., 2016
Monroe et al., 2016, 2017 		AD > HC
Cole et al., 2006
Kunz et al., 2007, 2009
Beach et al., 2015, 2016, 2017
AD = HC
Cole et al., 2006, 2011
Lints-Martindale et al., 2007
Kunz et al., 2009 		AD < HC
Rainero et al., 2000
AD = HC
Benedetti et al., 1999
Rainero et al., 2000
Lints-Martindale et al., 2007 		– AD = HC
Jensen-Dahm, Werner, Dahl, et al., 2014 		AD > HC × 7
AD < HC × 1
AD = HC × 11
Pain habituation AD = HD
Jensen-Dahm et al., 2015 		– – – – AD > HC × 0
AD < HC × 0
AD = HC × 1
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Note: AD = participants with Alzheimer’s disease; HC = healthy controls; >, <, and = refer to the participant group result compared with the other group (e.g., AD > HC means that participants with AD had greater responses for that condition than HC; and AD = HC means that there were no differences between participants with AD and HC).

Each journal article was independently scored by two authors (A.R.A. and W.L.I.) based on the widely used method presented by Hawker et al. (2002) to systematically review research even if comparing disparate data. Next, the two scores were averaged to obtain the final score of each article (see Table 1, Supplemental Digital Content 1, http://links.lww.com/JAANP/A114). Although only one study received the maximum possible 36 points, overall, most individual scores fell in the “good” range, demonstrating acceptable rigor. Older studies typically received lower scores because of the lack of details, such as ethics board approval and demographic details.

Studies were conducted in Australia, Denmark, Germany, Italy, and the United States. Each study used a stimulus to induce perceptually matched pain, with various stimulus types being incorporated, including heat, pressure, electric shock, tourniquet-induced ischemia, and cold water on different areas of the arm, hand, or leg (see Table 1, Supplemental Digital Content 1, http://links.lww.com/JAANP/A114). Different pain scales or descriptors were used among the studies, and all participants either verbally reported their pain, were scored by an observational pain scale, or both. Each study, except for the two comparing sex differences (Cowan et al., 2017) and MMSE (Benedetti et al., 2004), were case controlled with healthy older adults who were at least approximately age matched and sex matched. Several studies with HC also included MMSE as a component of their study. Some studies had additional aims, such as neuroimaging findings; however, this review focused on the psychophysical aim.

Of the 11 outcomes on stimulus detection between participants with AD and HC, five demonstrated that participants with AD needed higher intensities when detecting and reporting the stimulus at a variety of stimulus intensities (Cole et al., 2006, 2011; Gibson et al., 2001; Monroe et al., 2016, 2017), whereas six (including two arms of one study) demonstrated no differences between AD and HC (Benedetti et al., 1999; Jensen-Dahm, Werner, Dahl, et al., 2014; Jensen-Dahm et al., 2015, 2016; Lints-Martindale et al., 2007). Mini-Mental State Examination scores did not correlate with electric-shock stimulus detection (Benedetti et al., 2004) but were associated with higher temperatures to detect warmth (Monroe et al., 2016). Sex differences were found in stimulus detection where women with AD detected mild and moderate pain stimuli at lower temperatures than did men with AD (Cowan et al., 2017).

Of the nine outcomes on pain threshold between participants with AD and HC, two demonstrated that higher stimulus intensities were needed to reach threshold in AD (Cole et al., 2006; Monroe et al., 2016), whereas seven demonstrated no differences (including multiple study arms within the same study) (Benedetti et al., 1999; Gibson et al., 2001; Jensen-Dahm, Werner, Dahl, et al., 2014; Jensen-Dahm et al., 2015). Mini-Mental State Examination scores did not correlate with electric-shock pain thresholds in one study (Benedetti et al., 2004).

Of the five outcomes on pain tolerance, tolerance was significantly higher in AD for electric-shock and tourniquet-induced ischemia (Benedetti et al., 1999), but it was lower in AD for two of the outcomes (Jensen-Dahm, Werner, Dahl, et al., 2014; Jensen-Dahm et al., 2015). Pain tolerance was the same in participants with AD and HC in one outcome (Jensen-Dahm, Werner, Dahl, et al., 2014). For cold tolerance, participants with AD only had about half the tolerance of controls (Jensen-Dahm et al., 2015). Mini-Mental State Examination scores in one study were significantly correlated with greater pain tolerance in electric-shock and ischemic pain (Benedetti et al., 1999).

Of the 19 outcomes on pain unpleasantness, pain was more unpleasant for participants with AD compared with HC in seven outcomes (Beach et al., 2015, 2016, 2017; Cole et al., 2006; Jensen-Dahm et al., 2015; Kunz et al., 2007, 2009) and less unpleasant than HC in only one (Rainero et al., 2000). Unpleasantness was the same for AD and HC in 11 outcomes (multiple study arms) (Benedetti et al., 1999; Cole et al., 2006, 2011; Jensen-Dahm et al., 2016; Kunz et al., 2009; Lints-Martindale et al., 2007; Monroe et al., 2016, 2017; Rainero et al., 2000). Mini-Mental State Examination scores were not associated with pain unpleasantness ratings in one study (Monroe et al., 2016). Sex differences were found because men with AD reported greater pain unpleasantness compared with women with AD at mild and moderate pain (Cowan et al., 2017).

No difference in pain habituation was found between participants with AD and HC (Jensen-Dahm et al., 2015). An additional study by the same lead author also found that habituation was the same for AD and HC (Jensen-Dahm, Werner, Ballegaard, et al., 2014), but this study was not included in the official review or tables because it was a poster presentation report.

Overall, the psychophysical results demonstrate that people with AD may need a greater stimulus to report pain; still, more results demonstrate it is the same for AD and HC. Pain threshold, pain tolerance, and habituation also appear to be the same in people with AD and HC. Pain unpleasantness seems to be greater or the same for people with AD compared with HC. This indicates that people with AD continue to experience pain similarly to or more unpleasant than cognitively intact older adults. This is a significant problem because, despite studies from over 10 years ago demonstrating pain in AD, pain continues to be underrecognized and undertreated in AD and pain assessment methods in AD remain inadequate.

Additional findings pertinent to the study of pain in AD include the observation that one of the studies performed repeated psychophysics to also evaluate test–retest results (Jensen-Dahm, Werner, Dahl, et al., 2014). The test–retest findings indicated that participants with mild to moderate AD are able to understand and cooperate with heat pain and pressure pain testing because the results were reproducible and demonstrated performance comparable to control subjects (Jensen-Dahm, Werner, Dahl, et al., 2014). Heat pain produced the best test–retest results (Jensen-Dahm, Werner, Dahl, et al., 2014), indicating that it may be the superior choice for experimental studies of pain in AD.

In two studies, participants with dementia were not able to reliably report their pain, and their ability to give a self-report of pain decreased as their level of cognitive impairment increased (p < .001 for both studies) (Kunz et al., 2007, 2009). In a third study, patients with severe AD also could not reliably self-report their pain (Beach et al., 2015). Also of importance is that no differences were found between mild/moderate AD and severe AD in pain scores given to them by an observer (Beach et al., 2015).

There are limitations of this review. Other influences exist that can affect the experience of pain, such as those mentioned earlier, that is, biology, culture, and contextual factors, and these are not covered in this review. This review kept a focus on experimentally evoked pain studied via psychophysics and did not include observational studies or neuroimaging results. Some of the studies in this review included other forms of AD-related dementia alongside AD (Kunz et al., 2009), and older studies may have included dementias other than AD but were not diagnosed as such. It could be that other forms of dementia affect pain processing differently than the disease process specific to AD. Although some of the studies in this review did include severe AD, there is a lack of inclusion of severe AD in research in general, and people with severe AD may respond differently to pain than those with mild and moderate AD. There is also a general lack of research that includes African American, Hispanic, and Asian participants with AD (Alzheimer’s Association, 2020), and ethnic/cultural differences may affect pain differently. Additionally, the neural mechanisms of pain in AD must be investigated further to better determine the pain experience in AD rather than rely only on psychophysics.

Implications for practice

Despite cognitive impairment and a reduced ability to effectively communicate, individuals with AD experience pain similar to or more unpleasant than cognitively intact older adults. With the prevalence of pain in AD, this is of great concern. There are currently no widespread policies or guidelines that incorporate this knowledge, or existing guidance about pain in AD/dementia (Jennings et al., 2018), into practice even as pain continues to be undertreated in AD (Anderson et al., 2020; Cravello et al., 2019). Not only does untreated pain violate ANA position statements on the ethical treatment of pain (ANA, 2018) but it can also be considered elder abuse (Denny & Guido, 2012). New approaches for disseminating and reinforcing current best clinical practices for managing pain in AD are needed (Anderson et al., 2020).

Self-report of pain continues to be the gold standard, but it is ineffective for noncommunicative patients and those unable to understand the scale or instructions because of memory/cognitive impairment (Beach et al., 2015; Kunz et al., 2007, 2009; Rababa, 2018). Because of cognitive impairment, people with AD and related dementias may not have the ability to provide reliable pain reports even when they can vocalize a report (Beach et al., 2015; Kunz et al., 2007, 2009). Observational pain scales are recommended as a component of pain assessment for patients unable to adequately self-report their pain. Recently, the Pain Assessment in Impaired Cognition scale (PAIC15) was developed in efforts to combine the best of the many existing observational scales into one improved scale (Kunz et al., 2020).

Pain scales like the PAIC15 should be used alongside pain reports from the patient, family, and/or surrogate as well as a review of the medical record for painful conditions (Anderson et al., 2018). Patients with advanced AD will likely not be candidates for cognitive-based adjunct therapies given the damage to brain regions and pain networks, although other complementary therapies may be helpful (Anderson et al., 2017). It may also be helpful to note that a patient with AD may take longer to recognize or report their pain, and women with AD may detect pain sooner than men with AD. However, these are based on mixed and limited results, making it inappropriate to recommend definite rules. The most ethical treatment is to appropriately initiate therapy for any painful condition or sign of pain in all patients with AD and monitor accordingly.

The International Association for the Study of Pain (IASP) recently revised their definition of pain as follows: “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” (Raja et al., 2020, p. 1977). The IASP includes six “key notes” to add context to this definition. One note mentions the inability to communicate (Raja et al., 2020), which supports a recent ASPMN position statement about pain assessment in patients unable to self-report, including those with dementia (Herr et al., 2019). These ASPMN recommendations are useful for all patients with AD and related dementias because of their comprehensive nature and because of the risk of unreliable pain reports in this patient population (Beach et al., 2015; Kunz et al., 2007, 2009). Briefly, their clinical practice recommendations (Herr et al., 2019, p. 403) include:

  1. Use the hierarchy of pain assessment techniques:
    1. Be aware of potential causes of pain including known painful interventions;
    2. attempt self-report;
    3. observe patient behaviors;
    4. solicit reporting of pain and behavior/activity changes;
    5. attempt analgesic trial.

  2. Use behavioral pain assessment tools, as appropriate.

  3. Minimize emphasis on vital signs.

  4. Assess regularly, reassess postintervention, and document.

Conclusion

In summary, experimentally evoked pain in people living with AD confirms that this group continues to experience pain, but this experience may be different from cognitively intact older adults. Pain is reported by participants with AD either in a way that is similar to cognitively intact older adults or in a way that may mean amplified pain unpleasantness. Pain may be recognized or reported slower by individuals with AD, and women with AD may detect pain sooner than men with AD. The multidimensional, subjective, and complex experience of pain is even more challenging when assessing and treating pain in people with AD. The disease process of AD causes damage in many areas of the brain, including those involved in interpreting, processing, and modulating pain. However, when considering pain assessment and treatment in patients with AD, it appears that there is greater risk that the patient has an intact pain experience causing suffering rather than an absent or blunted pain experience. Compassionate care is needed for this vulnerable population, which may mean treating pain even if these individuals cannot adequately report their pain.

Supplementary Material

Supplementary Table

Acknowledgment:

The authors acknowledge Curtis Roby, MA, for his editorial assistance.

Funding:

Support was provided by NIH/NIA grants K23 AG046379–01A1 and R01 AG061325–01.

Footnotes

Competing interests: The authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jaanp.com).

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Supplementary Table
NIHMS1797780-supplement-Supplementary_Table.pdf (265.3KB, pdf)

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