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The association between endogenous opioid function and morphine responsiveness: a moderating role for endocannabinoids.
Bruehl S, Burns JW, Morgan A, Koltyn K, Gupta R, Buvanendran A, Edwards D, Chont M, Kingsley PJ, Marnett L, Stone A, Patel S
(2019) Pain 160: 676-687
MeSH Terms: Adult, Analgesics, Opioid, Chronic Pain, Double-Blind Method, Endocannabinoids, Exercise, Female, Humans, Low Back Pain, Male, Middle Aged, Morphine, Naloxone, Opioid Peptides, Pain Measurement, Regression Analysis, Surveys and Questionnaires, Treatment Outcome
Show Abstract · Added April 12, 2019
We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.
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18 MeSH Terms
Painful Bladder Symptoms Related to Somatic Syndromes in a Convenience Sample of Community Women with Overactive Bladder Symptoms.
Kowalik CG, Cohn JA, Delpe S, Kaufman MR, Wein A, Dmochowski RR, Reynolds WS
(2018) J Urol 200: 1332-1337
MeSH Terms: Adult, Chronic Pain, Female, Humans, Middle Aged, Pain Measurement, Pelvic Pain, Prognosis, Severity of Illness Index, Surveys and Questionnaires, Urinary Bladder, Overactive
Show Abstract · Added September 16, 2019
PURPOSE - We investigated the relationship of painful bladder filling and urinary urgency to somatic and chronic pain symptoms in women with overactive bladder without an interstitial cystitis/bladder pain syndrome diagnosis.
MATERIALS AND METHODS - Women who met overactive bladder criteria based on symptoms were recruited, including 183 (83.9%) from the community and 35 (16.1%) from the urology clinic to complete validated questionnaires assessing urinary symptoms, somatic symptoms and pain syndromes. Participants were categorized into 1 of 3 groups, including 1) neither symptom, 2) either symptom or 3) both symptoms, based on their reports of painful urinary urgency and/or painful bladder filling. Multivariable regression analyses were performed to determine factors predictive of having painful urgency and/or painful filling.
RESULTS - Of 218 women with overactive bladder 101 (46%) had neither painful bladder filling nor urinary urgency, 94 (43%) had either symptom and 23 (11%) had both symptoms. When controlling for age, women with either or both urological pain symptoms were more likely to have irritable bowel syndrome, chronic pelvic pain and temporomandibular disorder than women in the neither group. Additionally, these women had higher pain intensity and somatic symptoms scores than women with neither symptom.
CONCLUSIONS - The majority of women with overactive bladder who had not been diagnosed with interstitial cystitis/bladder pain syndrome reported painful urgency and/or painful filling. Experiencing painful urgency and/or filling was associated with an increased somatic symptom burden and greater pain intensity. These findings support the hypothesis that overactive bladder and interstitial cystitis/bladder pain syndrome diagnoses may represent a continuum of bladder hypersensitivity.
Copyright © 2018. Published by Elsevier Inc.
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Intensive Care Unit Delirium and Intensive Care Unit-Related Posttraumatic Stress Disorder.
Marra A, Pandharipande PP, Patel MB
(2017) Surg Clin North Am 97: 1215-1235
MeSH Terms: Antipsychotic Agents, Brain Diseases, Cognition Disorders, Conscious Sedation, Critical Care, Critical Illness, Delirium, Early Ambulation, Exercise Therapy, Family, Humans, Pain Measurement, Stress Disorders, Post-Traumatic, Ventilator Weaning
Show Abstract · Added June 26, 2018
Delirium is one of the most common behavioral manifestations of acute brain dysfunction in the intensive care unit (ICU) and is a strong predictor of worse outcome. Routine monitoring for delirium is recommended for all ICU patients using validated tools. In delirious patients, a search for all reversible precipitants is the first line of action and pharmacologic treatment should be considered when all causes have been ruled out, and it is not contraindicated. Long-term morbidity has significant consequences for survivors of critical illness and for their caregivers. ICU patients may develop posttraumatic stress disorder related to their critical illness experience.
Published by Elsevier Inc.
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Sex Differences in the Psychophysical Response to Contact Heat in Moderate Cognitive Impairment Alzheimer's Disease: A Cross-Sectional Brief Report.
Cowan RL, Beach PA, Atalla SW, Dietrich MS, Bruehl SP, Deng J, Wang J, Newhouse PA, Gore JC, Monroe TB
(2017) J Alzheimers Dis 60: 1633-1640
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Anxiety, Cognitive Dysfunction, Cross-Sectional Studies, Depression, Female, Hot Temperature, Humans, Male, Mental Status and Dementia Tests, Pain, Pain Measurement, Pain Perception, Pain Threshold, Physical Stimulation, Psychophysics, Sex Characteristics, Thermosensing
Show Abstract · Added March 19, 2018
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.
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20 MeSH Terms
The Impact of Alzheimer's Disease on the Resting State Functional Connectivity of Brain Regions Modulating Pain: A Cross Sectional Study.
Monroe TB, Beach PA, Bruehl SP, Dietrich MS, Rogers BP, Gore JC, Atalla SW, Cowan RL
(2017) J Alzheimers Dis 57: 71-83
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Brain, Brain Mapping, Cross-Sectional Studies, Female, Hot Temperature, Humans, Magnetic Resonance Imaging, Male, Neural Pathways, Pain, Pain Measurement, Pain Threshold, Psychophysics, Rest
Show Abstract · Added April 6, 2017
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.
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17 MeSH Terms
Differential expression of systemic inflammatory mediators in amputees with chronic residual limb pain.
Chamessian A, Van de Ven T, Buchheit T, Hsia HL, McDuffie M, Gamazon ER, Walsh C, Bruehl S, Buckenmaier C', Shaw A
(2017) Pain 158: 68-74
MeSH Terms: Adolescent, Adult, Amputees, Case-Control Studies, Catastrophization, Chronic Pain, Female, Humans, Inflammation Mediators, Male, Pain Measurement, Phantom Limb, Psychometrics, Statistics, Nonparametric, Up-Regulation, Young Adult
Show Abstract · Added April 13, 2017
Chronic postsurgical pain impacts most amputees, with more than half experiencing neuralgic residual limb pain. The transition from normal acute postamputation pain to chronic residual limb pain likely involves both peripheral and central inflammatory mechanisms. As part of the Veterans Integrated Pain Evaluation Research study, we investigated links between systemic inflammatory mediator levels and chronic residual limb pain. Subjects included 36 recent active duty military traumatic amputees with chronic residual limb pain and 40 without clinically significant pain. Blood samples were obtained and plasma concentrations of an array of inflammatory mediators were analyzed. Residual limb pain intensity and pain catastrophizing were assessed to examine associations with inflammatory mediators. Pro-inflammatory mediators including tumor necrosis factor (TNF)-α, TNF-β, interleukin (IL)-8, ICAM-1, Tie2, CRP, and SAA were elevated in patients with chronic residual limb pain. Across all patients, residual limb pain intensity was associated positively with levels of several proinflammatory mediators (IL-8, TNF-α, IL-12, TNF-β, PIGF, Tie2, SAA, and ICAM-1), and inversely with concentrations of the anti-inflammatory mediator IL-13, as well as IL-2 and Eotaxin-3. Pain catastrophizing correlated positively with IL-8, IL-12, TNF-β, PIGF, and ICAM-1, and inversely with IL-13. Significant associations between catastrophizing and residual limb pain intensity were partially mediated by TNF-α, TNF- β, SAA, and ICAM-1 levels. Results suggest that chronic postamputation residual limb pain is associated with excessive inflammatory response to injury or to inadequate resolution of the postinjury inflammatory state. Impact of pain catastrophizing on residual limb pain may be because of part to common underlying inflammatory mechanisms.
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16 MeSH Terms
Temporal summation to thermal stimuli is elevated in women with overactive bladder syndrome.
Reynolds WS, Brown ET, Danford J, Kaufman M, Wein A, Dmochowski R, Bruehl S
(2017) Neurourol Urodyn 36: 1108-1112
MeSH Terms: Adult, Afferent Pathways, Aged, Central Nervous System Sensitization, Female, Hot Temperature, Humans, Hyperesthesia, Middle Aged, Pain, Pain Measurement, Pain Perception, Pain Threshold, Urinary Bladder, Overactive
Show Abstract · Added September 16, 2019
INTRODUCTION - This study sought to provide a preliminary assessment of whether spinally mediated afferent hyperactivity (i.e., central sensitization) might contribute to manifestations of overactive bladder syndrome (OAB) in women as indexed by elevated temporal summation of evoked heat pain stimuli.
METHODS - We recruited 20 adult women with OAB who were planning to undergo interventional therapy for OAB with either onabotulinumtoxinA injection or sacral neuromodulation and 23 healthy controls without OAB symptoms to undergo quantitative sensory testing with cutaneous thermal pain temporal summation. The primary study outcome was the degree of temporal summation, as reflected in the magnitude of positive slope of the line fitted to the series of 10 stimuli at the 49°C target temperatures. Linear regression and analysis of covariance were utilized to compare the degree of temporal summation between study groups.
RESULTS - The standardized slope of temporal summation trials for women with OAB was significantly higher than for controls (β = 3.43, 95% confidence interval = 0.6-6.2, P = 0.017). The adjusted means ±SE of the standardized temporal summation slopes for the full OAB and control groups were 3.0 ± 0.5 (95% confidence interval = 2.0, 4.1) and 1.7 ± 0.5 (95% confidence interval = 0.7, 2.7), respectively.
CONCLUSION - In this preliminary study, we demonstrated that women with OAB refractory to primary and secondary therapies exhibited greater thermal cutaneous temporal summation than women without OAB symptoms. This suggests that central sensitization, indexed by temporal summation, may be an underlying factor contributing to OAB in some women. Neurourol. Urodynam. 36:1108-1112, 2017. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
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Contact heat sensitivity and reports of unpleasantness in communicative people with mild to moderate cognitive impairment in Alzheimer's disease: a cross-sectional study.
Monroe TB, Gibson SJ, Bruehl SP, Gore JC, Dietrich MS, Newhouse P, Atalla S, Cowan RL
(2016) BMC Med 14: 74
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Analgesia, Cognitive Dysfunction, Communication, Cross-Sectional Studies, Female, Hot Temperature, Humans, Male, Middle Aged, Pain, Pain Measurement, Pain Perception, Severity of Illness Index
Show Abstract · Added April 10, 2017
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.
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Pain Phenotypes and Associated Clinical Risk Factors Following Traumatic Amputation: Results from Veterans Integrated Pain Evaluation Research (VIPER).
Buchheit T, Van de Ven T, Hsia HL, McDuffie M, MacLeod DB, White W, Chamessian A, Keefe FJ, Buckenmaier CT, Shaw AD
(2016) Pain Med 17: 149-61
MeSH Terms: Adult, Amputation, Amputation, Traumatic, Analgesia, Cross-Sectional Studies, Depression, Female, Humans, Male, Neuroma, Pain Measurement, Phantom Limb, Risk Factors, Surveys and Questionnaires, Veterans, Young Adult
Show Abstract · Added October 20, 2015
OBJECTIVE - To define clinical phenotypes of postamputation pain and identify markers of risk for the development of chronic pain.
DESIGN - Cross-sectional study of military service members enrolled 3-18 months after traumatic amputation injury.
SETTING - Military Medical Center.
SUBJECTS - 124 recent active duty military service members.
METHODS - Study subjects completed multiple pain and psychometric questionnaires to assess the qualities of phantom and residual limb pain. Medical records were reviewed to determine the presence/absence of a regional catheter near the time of injury. Subtypes of residual limb pain (somatic, neuroma, and complex regional pain syndrome) were additionally analyzed and associated with clinical risk factors.
RESULTS - A majority of enrolled patients (64.5%) reported clinically significant pain (pain score ≥ 3 averaged over previous week). 61% experienced residual limb pain and 58% experienced phantom pain. When analysis of pain subtypes was performed in those with residual limb pain, we found evidence of a sensitized neuroma in 48.7%, somatic pain in 40.8%, and complex regional pain syndrome in 19.7% of individuals. The presence of clinically significant neuropathic residual limb pain was associated with symptoms of PTSD and depression. Neuropathic pain of any severity was associated with symptoms of all four assessed clinical risk factors: depression, PTSD, catastrophizing, and the absence of regional analgesia catheter.
CONCLUSIONS - Most military service members in this cohort suffered both phantom and residual limb pain following amputation. Neuroma was a common cause of neuropathic pain in this group. Associated risk factors for significant neuropathic pain included PTSD and depression. PTSD, depression, catastrophizing, and the absence of a regional analgesia catheter were associated with neuropathic pain of any severity.
Published by Oxford University Press on behalf of the American Academy of Pain Medicine. 2016. This work is written by US Government employees and is in the public domain in the US.
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Patterns and severity of vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia.
Lavoie Smith EM, Li L, Chiang C, Thomas K, Hutchinson RJ, Wells EM, Ho RH, Skiles J, Chakraborty A, Bridges CM, Renbarger J
(2015) J Peripher Nerv Syst 20: 37-46
MeSH Terms: Adolescent, Antineoplastic Agents, Phytogenic, Child, Child, Preschool, Female, Humans, Infant, Male, Pain Measurement, Peripheral Nervous System Diseases, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Severity of Illness Index, Vincristine
Show Abstract · Added November 10, 2016
Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine-induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1-18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©-Five (PNPS©-5). Of children who provided a full TNS©-PV score, 85/109 (78%) developed VIPN (TNS©-PV ≥4). Mean TNS©-PV, grading scale, and pain scores were low. CTCAE©-derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8-12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2-3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.
© 2015 Peripheral Nerve Society.
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