Central Sensitization: The Missing Link Between Psychological Distress and Poor Outcome Following Primary Total Knee Arthroplasty.

BACKGROUND: While preoperative psychological distress is known to predict risk for worse total knee arthroplasty (TKA) outcomes, distress may be too broad and nonspecific a predictor in isolation. We tested whether there are distinct preoperative TKA patient types based jointly on psychological status and measures of altered pain processing that predict adverse clinical outcomes. METHODS: In 112 TKA patients, we preoperatively assessed psychological status (depression, anxiety, and catastrophizing) and altered pain processing via a simple quantitative sensory testing protocol capturing peripheral and central pain sensitization. Outcomes (pain, function, opioid use) were prospectively evaluated at 6 weeks and 6 months after TKA. Cluster analyses were used to empirically identify TKA patient subgroups. RESULTS: There were 3 distinct preoperative TKA patient subgroups identified from the cluster analysis. A low-risk (LR) group was characterized by low psychological distress and low peripheral and central sensitization. In addition, 2 subgroups with similarly elevated preoperative psychological distress were identified, differing by pain processing alterations observed: high-risk centralized pain and high-risk peripheral pain. Relative to LR patients, high-risk centralized pain patients displayed significantly worse function and greater opioid use at 6 months after TKA (P values <.05). The LR and high-risk peripheral pain patient subgroups had similar 6-month outcomes (P values >.05). CONCLUSIONS: Among patients who have psychological comorbidity, only patients who have central sensitization were at elevated risk for poor functional outcomes and increased opioid use. Central sensitization may be the missing link between psychological comorbidity and poor TKA clinical outcomes. Preoperative testing for central sensitization may have clinical utility for improving risk stratification in TKA patients who have psychosocial risk factors.

Psychophysics of Pain: A Methodological Introduction.

For over 100 years, psychophysics ..÷ the scientific study between physical stimuli and sensation ... has been successfully employed in numerous scientific and healthcare disciplines, as an objective measure of sensory phenomena. This manuscript provides an overview of fundamental psychophysical concepts, emphasizing pain and research application..÷defining common terms, methods, and procedures.Psychophysics can provide systematic and objective measures of sensory perception that can be used by nursing scientists to explore complex, subjective phenomena..÷such as pain perception. While there needs to be improved standardization of terms and techniques, psychophysical approaches are diverse and may be tailored to address or augment current research paradigms. The interdisciplinary nature of psychophysics..÷like nursing..÷provides a unique lens for understanding how our perceptions are influenced by measurable sensations. While the quest to understand human perception is far from complete, nursing science has an opportunity to contribute to pain research by using the techniques and methods available through psychophysical procedures.

Increased pain unpleasantness and pain-related fMRI activation in the periaqueductal gray in Alzheimer's disease.

Background: Pain continues to be underrecognized and undertreated in people with Alzheimer's disease (AD). The periaqueductal gray (PAG) is essential to pain processing and modulation yet is damaged by AD. While evidence exists of altered neural processing of pain in AD, there has not been a focused investigation of the PAG during pain in people with AD. Purpose: To investigate the role of the PAG in sensory and affective pain processing for people living with AD. Methods: Participants from a larger study completed pain psychophysics assessments and then a perceptually-matched heat pain task (warmth, mild, and moderate pain) during a functional MRI scan. In this cross-sectional study, we examined blood oxygenation level-dependent (BOLD) responses in the PAG and other pain-related regions in participants with AD (n = 18) and cognitively intact older adults (age- and sex-matched, n = 18). Associations of BOLD percent signal change and psychophysics were also examined. Results: There were significant main effects of AD status on the temperature needed to reach each perception of warmth or pain, where people with AD reached higher temperatures. Furthermore, participants with AD rated mild and moderate pain as more unpleasant than controls. PAG BOLD activation was greater in AD relative to controls during warmth and mild pain percepts. No significant differences were found for moderate pain or in other regions of interest. Greater PAG activation during mild pain was associated with higher affective/unpleasantness ratings of mild pain in participants with AD but not in controls. Conclusion: Results suggest a role for the PAG in altered pain responses in people with AD. The PAG is the primary source of endogenous opioid pain inhibition in the neuroaxis, thus, altered PAG function in AD suggests possible changes in descending pain inhibitory circuits. People with AD may have a greater risk of suffering from pain compared to cognitively intact older adults.

Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer's Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals.

BACKGROUND: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer's disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. OBJECTIVE: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele. METHODS: Forty-nine cognitively healthy subjects aged 30-89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. RESULTS: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. CONCLUSION: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

Thermal Psychophysics and Associated Brain Activation Patterns Along a Continuum of Healthy Aging.

OBJECTIVE: To examine psychophysical and brain activation patterns to innocuous and painful thermal stimulation along a continuum of healthy older adults. DESIGN: Single center, cross-sectional, within-subjects design. METHODS: Thermal perceptual psychophysics (warmth, mild, and moderate pain) were tested in 37 healthy older adults (65-97 years, median = 73 years). Percept thresholds (oC) and unpleasantness ratings (0-20 scale) were obtained and then applied during functional magnetic resonance imaging scanning. General linear modeling assessed effects of age on psychophysical results. Multiple linear regressions were used to test the main and interaction effects of brain activation against age and psychophysical reports. Specifically, differential age effects were examined by comparing percent-signal change slopes between those above/below age 73 (a median split). RESULTS: Advancing age was associated with greater thresholds for thermal perception (z = 2.09, P = 0.037), which was driven by age and warmth detection correlation (r = 0.33, P = 0.048). Greater warmth detection thresholds were associated with reduced hippocampal activation in "older" vs "younger" individuals (>/<73 years; beta < 0.40, P < 0.01). Advancing age, in general, was correlated with greater activation of the middle cingulate gyrus (beta > 0.44, P < 0.01) during mild pain. Differential age effects were found for prefrontal activation during moderate pain. In "older" individuals, higher moderate pain thresholds and greater degrees of moderate pain unpleasantness correlated with lesser prefrontal activation (anterolateral prefrontal cortex and middle-frontal operculum; beta < -0.39, P < 0.009); the opposite pattern was found in "younger" individuals. CONCLUSIONS: Advancing age may lead to altered thermal sensation and (in some circumstances) altered pain perception secondary to age-related changes in attention/novelty detection and cognitive functions.

Sex Differences in Brain Regions Modulating Pain Among Older Adults: A Cross-Sectional Resting State Functional Connectivity Study.

Objective: A long-standing hypothesis is that when compared with males, females may be at increased risk of experiencing greater pain sensitivity and unpleasantness. The purpose of this study was to examine sex differences in pain psychophysics and resting state functional connectivity (RSFC) in core pain regions in an age- and sex-matched sample of healthy older adults. Design: Between groups, cross-sectional. Setting: Vanderbilt University and Medical Center. Subjects: The sample in the analyses reported here consisted of 19 cognitively intact males matched with 19 cognitively intact females of similar ages (median ages: females = 70 years, males = 68 years). Methods: Psychophysical assessment of experimental thermal pain and RSFC. Results: There were no significant differences in perceptual thresholds or unpleasantness ratings in response to thermal stimuli. Older males showed greater RSFC between the affective and sensory networks and between affective and descending modulatory networks. Conversely, older females showed greater RSFC between the descending modulatory network and both sensory and affective networks. The strongest evidence for sex differences emerged in the associations of thermal pain with RSFC between the anterior cingulate cortex (ACC) and amygdala and between the ACC and periaqueductal gray matter in older females relative to older males. Conclusions: We found no differences in pain sensitivity or pain affect between older males and older females. Additionally, we found that older females exhibited a greater association between thermal pain sensitivity and RSFC signal between regions typically associated with pain affect and the descending modulatory system. One interpretation of these findings is that older females may better engage the descending pain modulatory system. This better engagement possibly translates into older females having similar perceptual thresholds for temperature sensitivity and unpleasantness associated with mild and moderate pain. These findings contrast with studies demonstrating that younger females find thermal pain more sensitive and more unpleasant.

Sex Differences in the Psychophysical Response to Contact Heat in Moderate Cognitive Impairment Alzheimer's Disease: A Cross-Sectional Brief Report.

BACKGROUND: People with Alzheimer's disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD. OBJECTIVE: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD. METHODS: Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score <24, median = 16) communicative people who completed thermal psychophysics. RESULTS: There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p = 0.004, unpleasantness: p < 0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen's d = 0.72, p = 0.051, moderate: Cohen's d = 0.80, p = 0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen's d = 0.80, p = 0.072, moderate: Cohen's d = 1.32, p = 0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs = 0.29 and rs = 0.20 respectively, p > 0.05). CONCLUSIONS: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.

The Impact of Alzheimer's Disease on the Resting State Functional Connectivity of Brain Regions Modulating Pain: A Cross Sectional Study.

BACKGROUND: It is currently unknown why people with Alzheimer's disease (AD) receive less pain medication and report pain less frequently. OBJECTIVE: The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures. METHODS: Controls (n = 23, 13 = female) and age-matched people with AD (n = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated in sensory and affective dimensions of pain, descending pain modulation, and the default mode network. RESULTS: People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only. CONCLUSIONS: While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration.

Contact heat sensitivity and reports of unpleasantness in communicative people with mild to moderate cognitive impairment in Alzheimer's disease: a cross-sectional study.

BACKGROUND: Compared to healthy controls, people with Alzheimer's disease (AD) have been shown to receive less pain medication and report pain less frequently. It is unknown if these findings reflect less perceived pain in AD, an inability to recognize pain, or an inability to communicate pain. METHODS: To further examine aspects of pain processing in AD, we conducted a cross-sectional study of sex-matched adults ≥65 years old with and without AD (AD: n = 40, female = 20, median age = 75; control: n = 40, female = 20, median age = 70) to compare the psychophysical response to contact-evoked perceptual heat thresholds of warmth, mild pain, and moderate pain, and self-reported unpleasantness for each percept. RESULTS: When compared to controls, participants with AD required higher temperatures to report sensing warmth (Cohen's d = 0.64, p = 0.002), mild pain (Cohen's d = 0.51, p = 0.016), and moderate pain (Cohen's d = 0.45, p = 0.043). Conversely, there were no significant between-group differences in unpleasantness ratings (p > 0.05). CONCLUSIONS: The between-group findings demonstrate that when compared to controls, people with AD are less sensitive to the detection of thermal pain but do not differ in affective response to the unpleasant aspects of thermal pain. These findings suggest that people with AD may experience greater levels of pain and potentially greater levels of tissue or organ damage prior to identifying and reporting injury. This finding may help to explain the decreased frequency of pain reports and consequently a lower administration of analgesics in AD.

Sex differences in psychophysical and neurophysiological responses to pain in older adults: a cross-sectional study.

BACKGROUND: Neuroimaging studies in younger adults have demonstrated sex differences in brain processing of painful experimental stimuli. Such differences may contribute to findings that women suffer disproportionately from pain. It is not known whether sex-related differences in pain processing extend to older adults. METHODS: This cross-sectional study investigated sex differences in pain reports and brain response to pain in 12 cognitively healthy older female adults and 12 cognitively healthy age-matched older male adults (age range 65-81, median = 67). Participants underwent psychophysical assessments of thermal pain responses, functional MRI, and psychosocial assessment. RESULTS: When compared to older males, older females reported experiencing mild and moderate pain at lower stimulus intensities (i.e., exhibited greater pain sensitivity; Cohen's d = 0.92 and 0.99, respectively, p < 0.01) yet did not report greater pain-associated unpleasantness. Imaging results indicated that, despite the lower stimulus intensities required to elicit mild pain detection in females, they exhibited less deactivations than males in regions associated with the default mode network (DMN) and in regions associated with pain affect (bilateral dorsolateral prefrontal cortex, somatomotor area, rostral anterior cingulate cortex (rACC), and dorsal ACC). Conversely, at moderate pain detection levels, males exhibited greater activation than females in several ipsilateral regions typically associated with pain sensation (e.g., primary (SI) and secondary somatosensory cortices (SII) and posterior insula). Sex differences were found in the association of brain activation in the left rACC with pain unpleasantness. In the combined sample of males and females, brain activation in the right secondary somatosensory cortex was associated with pain unpleasantness. CONCLUSIONS: Cognitively healthy older adults in the sixth and seventh decades of life exhibit similar sex differences in pain sensitivity compared to those reported in younger individuals. However, older females did not find pain to be more unpleasant. Notably, increased sensitivity to mild pain in older females was reflected via less brain deactivation in regions associated with both the DMN and in pain affect. Current findings elevate the rACC as a key region associated with sex differences in reports of pain unpleasantness and brain deactivation in older adults. Also, pain affect may be encoded in SII in both older males and females.

Specific Physician Orders Improve Pain Detection and Pain Reports in Nursing Home Residents: Preliminary Data.

Despite evidence that many nursing home residents' pain is poorly managed, reasons for this poor management remain unanswered. The aim of this study was to determine if specific order sets related to pain assessment would improve pain management in nursing home (NH) residents. Outcomes included observed nurse pain assessment queries and resident reports of pain. The pretest/post-test study was performed in a 240-bed for-profit nursing home in the mid-southern region of the United States and participants were 43 nursing home residents capable of self-consent. Medical chart abstraction was performed during a 2-week (14-day) period before the implementation of specific order sets for pain assessment (intervention) and a 2-week (14-day) period after the intervention. Trained research assistants observed medication administration passes and performed participant interviews after each medication pass. One month after intervention implementation, 1 additional day of observations was conducted to determine data reliability. Nurses were observed to ask residents about pain more frequently, and nurses continued to ask about pain at higher rates 1 month after the intervention was discontinued. The proportion of residents who reported pain also significantly increased in response to increased nurse queries (e.g., "Do you have any pain right now?"), which underscores the importance of nurses directly asking residents about pain. Notably 70% of this long-stay NH population only told the nurses about their pain symptoms when asked directly. Findings uncover that using specific pain order sets seems to improve the detection of pain, which should be a routine part of nursing assessment.

Medical evaluation of children with chronic abdominal pain: impact of diagnosis, physician practice orientation, and maternal trait anxiety on mothers' responses to the evaluation.

This study examined the effects of diagnosis (functional versus organic), physician practice orientation (biomedical versus biopsychosocial), and maternal trait anxiety (high versus low) on mothers' responses to a child's medical evaluation for chronic abdominal pain. Mothers selected for high (n=80) and low (n=80) trait anxiety imagined that they were the mother of a child with chronic abdominal pain described in a vignette. They completed questionnaires assessing their negative affect and pain catastrophizing. Next, mothers were randomly assigned to view one of four video vignettes of a physician-actor reporting results of the child's medical evaluation. Vignettes varied by diagnosis (functional versus organic) and physician practice orientation (biomedical versus biopsychosocial). Following presentation of the vignettes, baseline questionnaires were re-administered and mothers rated their satisfaction with the physician. Results indicated that mothers in all conditions reported reduced distress pre- to post-vignette; however, the degree of the reduction differed as a function of diagnosis, presentation, and anxiety. Mothers reported more post-vignette negative affect, pain catastrophizing, and dissatisfaction with the physician when the physician presented a functional rather than an organic diagnosis. These effects were significantly greater for mothers with high trait anxiety who received a functional diagnosis presented by a physician with a biomedical orientation than for mothers in any other condition. Anxious mothers of children evaluated for chronic abdominal pain may be less distressed and more satisfied when a functional diagnosis is delivered by a physician with a biopsychosocial rather than a biomedical orientation.

Diagnosis of complex regional pain syndrome: signs, symptoms, and new empirically derived diagnostic criteria.

This review will discuss the relevant history of the taxonomy and eventual development of diagnostic criteria of what is currently called complex regional pain syndrome. The authors will take their discussion through the early days (at which time the disorder was called reflex sympathetic dystrophy) through consensus-developing conferences to the current conceptualization of the criteria as published by the International Association for the Study of Pain's Task Force on Taxonomy in 1994. The authors will also mention the recent work of the closed workshop held in Budapest in 2004, where clinical and research criteria were proposed; these criteria were published in 2005. The review will also address issues of staging and subtyping the syndrome, as well as a discussion of the salient signs, symptoms, and tests appropriate for use in the diagnosis.

The psychological assessment of candidates for spinal cord stimulation for chronic pain management.

It is known that, in spite of meeting appropriate clinical criteria for spinal cord stimulation (SCS) and having undergone flawless procedures, a significant number of patients who fail the therapy continues to exist. It is the purpose of this article to focus on the development of psychosocial indicators of success for SCS, if any. Referring to specialist literature authors present a review of what is known, what is not known, and what remains controversial on this topic. After reading this article we hope the reader will understand the importance of a psychological evaluation as part of the development of standards for identifying appropriate patients for this therapy. To improve treatment outcomes of SCS, seems to be essential to perform psychosocial evaluations on all persons clinically indicated for SCS to exclude those patients, who most probably, on a psychosocial level, will fail the procedure. To maximize treatment efficacy, authors believe spinal cord stimulation for chronic pain control must be part of a comprehensive program. An accurate preoperative psychosocial assessment and a course of psychological assistance both before and after therapy seems to be crucial for improving outcomes.

Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is a heterogeneous disorder that falls in the spectrum of neuropathic pain disorders. It is maintained by abnormalities throughout the neuraxis (the peripheral, autonomic, and central nervous systems). The pathophysiology of CRPS is not fully known. There are no scientifically well-established treatments. The diagnostic criteria for CRPS at this time are purely clinical, and the use of diagnostic tests has not been demonstrated. The most appropriate management of CRPS uses a multidisciplinary approach, with the inclusion of medical and psychologic intervention, and physical and occupational therapy. The key is gradual, persistent, functional improvement. The rational use of pain therapies must be grounded in a thorough knowledge of the neurobiology of pain, its endogenous modulation, and the clinical presentation. Potential peripheral pathophysiologic targets (and possible treatments) include increased spontaneous firing and responsiveness of peripheral afferent fibers mediated by inflammatory and other algogenic substances (somatosensory blocks, corticosteroids), altered levels of expression and functioning of multiple ion channels (local anesthetics, calcium channel blockers, anticonvulsants), abnormal interneuronal communication, and increased peripheral expression of adrenergic receptors and sympathetic excitation (sympathetic blocks, alpha-adrenergic antagonists, alpha-2 agonists). CRPS is also perpetuated by central mechanisms, with pathophysiologic targets (and possible treatments) including reorientation of dorsal horn terminals (desensitization techniques), functional reduction in inhibitory interneuron activity (tricyclic antidepressants, gabapentin, opioids), central sensitization and increased central excitability (gabapentin, topiramate, spinal cord stimulation, somatosensory blocks), impaired descending nociceptive inhibition (tricyclic antidepressants, opioids), and adaptive changes in the cortical centers underlying the sensory-discriminative and affective-motivational dimensions of pain (psychologic, physical, and occupational therapies). The treatment choices should be aimed at remodulating, normalizing, disrupting, or preventing the progression of abnormalities in pain processing. Sympathetic nerve blocks should be performed at least once to assess if sympathetically maintained pain is present. To the extent that peripheral somatosensory nerve blocks can diminish nociceptive input to the central nervous system, these techniques may help reduce the nociceptive sensitization of spinal neurons. Pain relief, however it is achieved and however temporary it is, is intended to facilitate participation in functional therapies to normalize use and to improve motion, strength, and dexterity. Psychologic therapies, such as biofeedback and cognitive-behavioral techniques targeting pain, stress, and mood disorders, are valuable adjunctive treatments for pain control and can facilitate functional improvement.

An updated interdisciplinary clinical pathway for CRPS: report of an expert panel.

The goal of treatment in patients with complex regional pain syndrome (CRPS) is to improve function, relieve pain, and achieve remission. Current guidelines recommend interdisciplinary management, emphasizing 3 core treatment elements: pain management, rehabilitation, and psychological therapy. Although the best therapeutic regimen or the ideal progression through these modalities has not yet been established, increasing evidence suggests that some cases are refractory to conservative measures and require flexible application of the various treatments as well as earlier consideration of interventions such as spinal cord stimulation (SCS). While existing treatment guidelines have attempted to address the comprehensive management of CRPS, all fail to provide guidance for contingent management in response to a sudden change in the patient's medical status. This paper reviews the current pathophysiology as it is known, reviews the purported treatments, and provides a modified clinical pathway (guideline) that attempts to expand the scope of previous guidelines.