Search

There have been some modest recent advancements in the research of Complex Regional Pain Syndrome, yet the amount and quality of the work in this complicated multifactorial disease remains low (with some notable exceptions; e.g., the recent work on the dorsal root ganglion stimulation). The semi-systematic (though in some cases narrative) approach to review is necessary so that we might treat our patients while waiting for “better research.” This semi-systematic review was conducted by experts in the field, (deliberately) some of whom are promising young researchers supplemented by the experience of “elder statesman” researchers, who all mention the system they have used to examine the literature. What we found is generally low- to medium-quality research with small numbers of subjects; however, there are some recent exceptions to this. The primary reason for this paucity of research is the fact that this is a rare disease, and it is very difficult to acquire a sufficient sample size for statistical significance using traditional statistical approaches. Several larger trials have failed, probably due to using the broad general diagnostic criteria (the “Budapest” criteria) in a multifactorial/multi-mechanism disease. Responsive subsets can often be identified in these larger trials, but not sufficient to achieve statistically significant results in the general diagnostic grouping. This being the case the authors have necessarily included data from less compelling protocols, including trials such as case series and even in some instances case reports/empirical information. In the humanitarian spirit of treating our often desperate patients with this rare syndrome, without great evidence, we must take what data we can find (as in this work) and tailor a treatment regime for each patient.

Objective Advanced age is associated with a higher risk of both pain and dementia, with many studies finding that dementia often heightens sensitivity to pain. Vascular dementia (VaD) is the second most common type of dementia. Only a few observational or retrospective studies have examined pain responsiveness in VaD, suggesting that it could increase pain unpleasantness (i.e., pain affect). This study compared thermal pain psychophysics between a cohort of patients with VaD and healthy control (HC) subjects. Design Single-center, cross-sectional, between-subjects design. Subjects Verbally communicative patients with probable VaD (n = 23) and age- and sex-matched HCs (n = 23). Methods A thermal psychophysics protocol assessed “mild pain” and “moderate pain” thresholds (temperature in degrees Celsius) and associated unpleasantness ratings (0–20 scale) in both the VaD and HC groups. Psychophysics were compared between groups by way of a mixed-effects analysis, controlling for depressive symptoms. Results There were no significant differences between groups for pain thresholds (main effect P = 0.086, Cohen’s d: mild = 0.55, moderate = 0.27). However, unpleasantness ratings were higher in the VaD group than in the HC group (main effect P = 0.003; mild pain P = 0.022, Cohen’s d = 0.79; moderate pain P = 0.057, Cohen’s d = 0.6). Conclusions These results are consistent with prior observational findings suggesting that VaD could make patients more susceptible to pain, particularly its affective component.

AIMS There is little information on how often or within what contexts individuals with OAB use compensatory behaviors ("coping") to manage symptoms. We sought to examine how frequently women with OAB report using coping behaviors and whether these are associated with psychosocial factors. METHODS One hundred twenty adult women with OAB completed the OAB questionnaire (OAB-q), ICIQ-FLUTS questionnaire, PROMIS Anxiety and Depression, Perceived Stress Scale, patient perception of bladder condition, and demographic and clinical data. Responses from five items from the OAB-q Quality-of-Life scale asking about coping with OAB symptoms (i.e., "compensatory coping behaviors") were summed to generate a total Coping Score. Linear regression was used to identify associations between individual coping behaviors, total Coping Scores, and exposure variables. RESULTS Most (88%) subjects reported using at least one compensatory coping behavior at least "a little of the time," with "locating the nearest restroom in a new place" the most frequent. Higher BMI, lower education, using OAB medication, and urgency incontinence as well as urinary symptom severity were all associated with higher coping scores. Beyond the influence of OAB severity, higher anxiety (β = 0.15, 95% CI [0.05-0.26], p = 0.004) and stress (β = 0.16 [0.03-0.25], p = 0.02) were significantly associated with higher total coping scores, although depression was not. CONCLUSIONS Compensatory bladder behaviors (coping) were common in women with OAB and were associated with greater urinary symptom severity and higher anxiety and stress. Further study is needed to understand how coping behaviors and psychosocial factors relate, as these may represent important opportunities for interventions.

Background and objectiveAlthough total knee arthroplasty (TKA) is an effective treatment for severe knee osteoarthritis (OA), a subset of patients experience significant postoperative pain and dissatisfaction. Several clinical trials support the analgesic benefits of genicular nerve radiofrequency ablation (GN-RFA) for non-operative knee OA, but only one prior trial has examined the effects of this intervention given preoperatively on postoperative outcomes following TKA, showing no analgesic benefit of cooled GN-RFA. The current study evaluated whether conventional thermal GN-RFA performed preoperatively resulted in significant improvements in pain and function following TKA.MethodsThis was a single-center, prospective, randomized, sham-controlled, double-blinded pilot trial in which patients received either conventional GN-RFA (n=30) or sham (n=30) between 2 and 4 weeks prior to their TKA. Baseline measures were obtained preprocedurally on the day of intervention, with follow-up outcomes obtained preoperatively on the day of surgery, and at 2 and 6 weeks postoperatively.ResultsPatients receiving GN-RFA showed no significant improvements relative to sham controls in the primary outcome, pain intensity at rest at 6-week follow-up. Secondary outcomes, including pain with ambulation and physical function, also showed no significant differences between groups at any follow-up assessment.ConclusionsConventional GN-RFA of the superior lateral, superior medial, and inferior medial genicular nerves when performed prior to TKA did not provide clinically significant pain relief or improvement in functional status at 2 or 6 weeks postoperatively.Trial registration numberNCT02947321.

OBJECTIVES: Youth with functional abdominal pain (FAP) experience significant pain-related distress and functional impairment. Although quantitative sensory testing protocols have identified alterations in pain modulatory systems that distinguish youth with FAP from healthy controls, the extent to which evoked pain responses predict subsequent trajectories of pain symptoms and disability over and above established psychosocial risk factors is unclear. METHODS: The present study included 183 adolescents with FAP who were enrolled in a randomized controlled trial comparing an 8-week, internet-delivered program of cognitive behavior therapy (n = 90) or pain education (n = 93). Participants completed a quantitative sensory testing protocol prior to the intervention and were followed for 12-months post-treatment. RESULTS: Whereas adolescents with FAP who exhibited stronger baseline conditioned pain modulation reported decreases in pain-related interference over follow-up (b=−.858, SE=.396, p=.032), those with weaker conditioned pain modulation exhibited high, relatively stable levels of pain-related interference over time (b=−.642, SE=.400, p=.110). Conditioned pain modulation status predicted changes in pain-related interference after controlling for the effects of treatment condition and psychosocial risk factors. Static measures of pain sensitivity (i.e., pain threshold, pain tolerance) and temporal summation of second pain were not associated with changes in measures of abdominal pain, gastrointestinal symptom severity, or pain-related interference over follow-up. DISCUSSION: The present findings contribute to a growing literature on the predictive utility of quantitative sensory testing indices and suggest that conditioned pain modulation may complement existing psychosocial risk measures in determining individualized pain-related risk profiles. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02327377

BACKGROUND: Nausea is a common complaint among children, and is particularly prevalent in children with functional abdominal pain (FAP), with nearly half of children with FAP also endorsing nausea. Dysfunction of the autonomic nervous system (ANS), which can be indexed by heart rate variability (HRV), leads to abnormalities in gastric electrical activity that are associated with GI symptoms. AIMS: To evaluate that relationship between nausea severity and HRV in adolescents and young adults with a history of FAP and to assess for sex differences. METHODS: Participants were pediatric patients with a diagnosis of FAP who were recruited from a pediatric GI clinic between 1993 and 2007 for a prospective study of the course of FAP. Study analyses focused on the cross-sectional relationship between HRV, indexed by standard deviation of the R-R interval (SDRRI) and high frequency (HF) power, and nausea severity collected during a follow-up visit in late adolescence and young adulthood. RESULTS: Controlling for age and BMI, a significant nausea by sex interaction emerged for both SDRRI and HF power. Tests of conditional effects of nausea by sex showed that the inverse relation between nausea severity and both SDRRI and HF was significant for females but not for males. CONCLUSIONS: This is the first study to evaluate the relationship between nausea severity and HRV. Greater nausea severity was associated with lower HRV in females but not in males. Further validation of these results may provide insight into novel treatment approaches for females with nausea that target vagal tone.

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.

PURPOSE OF REVIEW: Individuals with chronic pain are significantly more likely to have experienced overwhelming trauma early and often in key developmental years. There is increasing acknowledgment that childhood trauma disrupts how individuals process and cope with both physical and emotional pain. Emerging studies acknowledge elevated rates of non-suicidal self-injury (NSSI) in chronic pain populations. This review provides a theoretical framework to understand the relationship between NSSI behavior and pain experience in persons with chronic pain and childhood trauma histories. We discuss how NSSI may act to regulate neurobiological (e.g., endogenous opioid systems) and psychological (e.g., heightened negative affect and emotion dysregulation) systems affected by childhood trauma, leading to temporary pain relief and a cycle of negative reinforcement perpetuating NSSI. As these concepts are greatly understudied in pain populations, this review focuses on key areas relevant to chronic pain that may provide a testable, conceptual framework to support hypothesis generation, future empirical investigation, and intervention efforts. RECENT FINDINGS: See Fig. 1. SUMMARY: See Fig. 1.

The dysfunctional chronic pain (Dysfunctional CP) phenotype is an empirically identifiable CP subtype with unclear pathophysiological mechanisms that cuts across specific medical CP diagnoses. This study tested whether the multidimensional pain and psychosocial features that characterize the dysfunctional CP phenotype are associated broadly with elevated oxidative stress (OS). Measures of pain intensity, bodily extent of pain, catastrophizing cognitions, depression, anxiety, sleep disturbance, pain interference, and function were completed by 84 patients with chronic osteoarthritis before undergoing total knee arthroplasty. Blood samples were obtained at the initiation of surgery before incision or tourniquet placement. Plasma levels of F2-isoprostanes and isofurans, the most highly specific measures of in vivo OS, were quantified using gas chromatography/negative ion chemical ionization mass spectrometry. The results indicated that controlling for differences in age, sex, and body mass index, higher overall OS (mean of isoprostanes and isofurans) was associated with significantly (P0.05) greater pain intensity, more widespread pain, greater depressive symptoms and pain catastrophizing, higher pain interference, and lower function. OS measures were not significantly associated with sleep disturbance or anxiety levels (P0.10). The results build on prior case-control findings suggesting that presence of a CP diagnosis is associated with elevated OS, highlighting that it may specifically be individuals displaying characteristics of the dysfunctional CP phenotype who are characterized by elevated OS. Clinical implications of these findings remain to be determined.

OBJECTIVES: Prior work in a cohort of youth with functional abdominal pain (FAP) identified patient subgroups (High Pain Dysfunctional, High Pain Adaptive, Low Pain Adaptive) that predicted differences in the course of FAP from childhood into young adulthood. We aimed to replicate these subgroups in a new sample of adolescents with FAP using the original classification algorithm and to extend subgroup characteristics to include parental characteristics and health service use. METHODS: Adolescents (n = 278; ages 11-17 years, 66% females) presenting to a gastroenterology clinic for abdominal pain and their parents (92% mothers) completed self-report measures; adolescents also completed a 7-day pain diary. RESULTS: The replicated patient subgroups exhibited distress and impairment similar to subgroups in the original sample. Moreover, in novel findings, the High Pain Dysfunctional subgroup differed from other subgroups by the predominance of mother-daughter dyads jointly characterized by high levels of anxiety, depressive symptoms, pain behavior, and pain catastrophizing. The High Pain Dysfunctional subgroup used more health care services than Low Pain Adaptive but did not differ from High Pain Adaptive. DISCUSSION: Findings replicate and extend the original FAP classification and suggest that the subgroups have unique patient and parent features that may reflect distinct illness mechanisms requiring different treatments.

OBJECTIVE/BACKGROUND: Sleep disturbances have been commonly reported as comorbid in youth with pain conditions, but prior research specific to functional abdominal pain (FAP) is limited. This study describes individual factors associated with increased risk for sleep disturbance and characterizes the relationship between sleep disturbance and pain-related variables. PARTICIPANTS: Participants included 278 adolescents (age 11 to 17 years, M age = 15 years; 89% Caucasian; 65% female) with FAP. METHODS: Participants reported on sleep disturbances, abdominal pain severity, functional disability, somatic symptoms, and healthcare utilization. RESULTS: Female adolescents reported greater sleep disturbance than male adolescents (t(276) = 5.52, p < .001, Cohen’s d = 0.70) and increased age was associated with greater sleep disturbance (r =.20, p =.001). In hierarchical regressions controlling for age, sex, and abdominal pain, greater sleep disturbance was significantly associated with greater functional disability (β =.32), non-gastrointestinal somatic symptoms (β =.35), and emergency department visits (β =.29). CONCLUSIONS: Results suggest that sleep disturbance is common and should be assessed in youth presenting with FAP and may be a potential target for intervention.

Aerobic exercise is believed to be an effective chronic low back pain (CLBP) intervention, although its mechanisms remain largely untested. This study evaluated whether endogenous opioid (EO) mechanisms contributed to the analgesic effects of an aerobic exercise intervention for CLBP. Individuals with CLBP were randomized to a 6-week, 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 44). Before and after the intervention, participants underwent separate laboratory sessions to assess responses to evoked heat pain after receiving saline placebo or intravenous naloxone (opioid antagonist) in a double-blinded, crossover fashion. Chronic pain intensity and interference were assessed before and after the intervention. Endogenous opioid analgesia was indexed by naloxone-placebo condition differences in evoked pain responses (blockade effects). Relative to controls, exercise participants reported significantly greater pre-post intervention decreases in chronic pain intensity and interference (Ps < 0.04) and larger reductions in placebo condition evoked pain responsiveness (McGill Pain Questionnaire-Short Form [MPQ]-Total). At the group level, EO analgesia (MPQ-Total blockade effects) increased significantly pre-post intervention only among female exercisers (P = 0.03). Dose-response effects were suggested by a significant positive association in the exercise group between exercise intensity (based on meeting heart rate targets) and EO increases (MPQ-Present Pain Intensity; P = 0.04). Enhanced EO analgesia (MPQ-Total) was associated with a significantly greater improvement in average chronic pain intensity (P = 0.009). Aerobic exercise training in the absence of other interventions appears effective for CLBP management. Aerobic exercise-related enhancements in endogenous pain inhibition, in part EO-related, likely contribute to these benefits.

Posttraumatic stress disorder (PTSD) symptoms and other negative psychosocial factors have been implicated in the transition from acute to persistent pain. Women (N = 375) who presented to an inner-city emergency department (ED) with complaints of acute pain were followed up for 3 months. They completed a comprehensive battery of questionnaires at an initial visit and provided ratings of pain intensity at the site of pain presented in the ED during 3 monthly phone calls. Latent class growth analyses were used to detect possible trajectories of change in pain intensity from the initial visit to 3 months later. A 3-trajectory solution was found, which identified 3 groups of participants. One group (early recovery; n = 93) had recovered to virtually no pain by the initial visit, whereas a second group (delayed recovery; n = 120) recovered to no pain only after 1 month. A third group (no recovery; n = 162) still reported elevated pain at 3 months after the ED visit. The no recovery group reported significantly greater PTSD symptoms, anger, sleep disturbance, and lower social support at the initial visit than both the early recovery and delayed recovery groups. Results suggest that women with high levels of PTSD symptoms, anger, sleep disturbance, and low social support who experience an acute pain episode serious enough to prompt an ED visit may maintain elevated pain at this pain site for at least 3 months. Such an array of factors may place women at an increased risk of developing persistent pain following acute pain.

Background Ethnic differences in placebo and nocebo responses are an important, yet underresearched, patient factor that might contribute to treatment disparities. Purpose The purpose of this study was to examine ethnic differences in pain trajectories following a verbal suggestion paired with a masked, inert substance (i.e., saline). Methods Using a quasiexperimental design, we examined differences between 21 non-Hispanic Black (NHB) participants and 20 non-Hispanic White (NHW) participants in capsaicin-related pain rating trajectories following a nondirectional verbal suggestion + saline infusion. All participants were told that the substance would “either increase pain sensation, decrease it, or leave it unchanged.” A spline mixed model was used to quantify the interaction of ethnicity and time on ratings. Results There was a significant Ethnicity × Time interaction effect (β = −0.28, p = .002); NHB individuals reported significantly greater increases in pain following, but not before, the verbal suggestion + saline infusion. Sensitivity analyses showed no change in primary results based on differences in education level, general pain sensitivity, or condition order. Conclusions The present results showed ethnic differences in pain response trajectories following a verbal suggestion + saline infusion and suggest that future research rigorously examining possible ethnic differences in placebo/nocebo responses is warranted.

This prospective observational study evaluated preoperative predictors of complex regional pain syndrome (CRPS) outcomes in the 6 months following total knee arthroplasty (TKA). Participants were n = 110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and pro-inflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6-week and 6-month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a "warm CRPS" phenotype. Six-week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (P'slt; .05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (P'slt; .05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (P'slt; .01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (P'slt; .05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk. PERSPECTIVE: This article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.

BACKGROUND: Racial disparities in trauma care have been reported for a range of outcomes, but the extent to which these remain after accounting for socioeconomic and environmental factors remains unclear. The objective of this study was to evaluate the unique contributions of race, health insurance, community distress, and rurality/urbanicity on trauma outcomes after carefully controlling for specific injury-related risk factors. METHODS: All adult (age >=18) trauma patients admitted to a single Level 1 trauma center with a statewide, largely rural, catchment area from January 2010 to December 2020 were retrospectively reviewed. Primary outcomes were mortality, rehabilitation referral, and receipt of opioids in the emergency department. Demographic, socioeconomic, and injury characteristics as well as indicators of community distress and rurality based on home address were abstracted from a trauma registry database. RESULTS: Analyses revealed that Black patients (n=13,073) were younger, more likely to be male, more likely to suffer penetrating injuries, and more likely to suffer assault-based injuries compared to White patients (n=10,946; all p

To develop and validate a prediction model for postdischarge opioid use in patients undergoing cesarean birth.We conducted a prospective cohort study of patients undergoing cesarean birth. Patients were enrolled postoperatively, and they completed pain and opioid use questionnaires 14 days after cesarean birth. Clinical data were abstracted from the electronic health record (EHR). Participants were prescribed 30 tablets of hydrocodone 5 mg-acetaminophen 325 mg at discharge and were queried about postdischarge opioid use. The primary outcome was total morphine milligram equivalents used. We constructed three proportional odds predictive models of postdischarge opioid use: a full model with 34 predictors available before hospital discharge, an EHR model that excluded questionnaire data, and a reduced model. The reduced model used forward selection to sequentially add predictors until 90% of the full model performance was achieved. Predictors were ranked a priori based on data from the literature and prior research. Predictive accuracy was estimated using discrimination (concordance index).Between 2019 and 2020, 459 participants were enrolled and 279 filled the standardized study prescription. Of the 398 with outcome measurements, participants used a median of eight tablets (interquartile range 1-18 tablets) after discharge, 23.5% used no opioids, and 23.0% used all opioids. Each of the models demonstrated high accuracy predicting postdischarge opioid use (concordance index range 0.74-0.76 for all models). We selected the reduced model as our final model given its similar model performance with the fewest number of predictors, all obtained from the EHR (inpatient opioid use, tobacco use, and depression or anxiety).A model with three predictors readily found in the EHR-inpatient opioid use, tobacco use, and depression or anxiety-accurately estimated postdischarge opioid use. This represents an opportunity for individualizing opioid prescriptions after cesarean birth.

Inconsistent results of psychological treatments for pediatric functional abdominal pain (FAP) may be due to heterogeneity of patients' pain-related psychological characteristics. This randomized controlled trial tested whether statistically derived patient subgroups (high pain dysfunctional [HPD], high pain adaptive [HPA], and low pain adaptive [LPA]) moderated response to cognitive behavior therapy (CBT) for adolescents with FAP and their parents (n = 278 dyads; patients were 66% female, mean [SD] age was 14.62 [1.88] years, and parents were 95% female). Randomization to Internet-delivered CBT vs Internet-delivered pain education (EDU) was stratified by patient subgroup. Follow-up assessments of gastrointestinal (GI) symptoms (primary outcome), abdominal pain, and pain interference were at midtreatment, posttreatment, 6 months, and 12 months. Data were analysed using linear mixed effects models. Significant treatment × subgroup × time interaction effects showed that patient subgroup significantly moderated the effect of treatment on GI symptoms (t[853 = -2.93, P = 0.003) and abdominal pain (t(844) = -2.14, P = 0.03) across the treatment period. Among HPD youth, those in CBT had significantly greater GI symptom reduction than those in EDU through posttreatment. By contrast, among HPA and LPA youth, symptom improvement did not differ by treatment condition. Furthermore, among all patients assigned to CBT, HPD youth demonstrated significantly greater reductions in GI symptoms compared with HPA and LPA youth and greater reductions in abdominal pain compared with LPA youth. All subgroups maintained symptom reductions throughout the follow-up period. Results suggest that subgrouping FAP patients may inform treatment allocation and optimize treatment response.

Total knee arthroplasty (TKA) is effective for pain reduction in most patients, but 15% or more report unsatisfactory long-term pain outcomes. We tested whether oxidative stress (OS) related to extended tourniquet application during TKA and subsequent ischemic reperfusion (IR) contributed to adverse post-TKA pain outcomes. Blood samples were obtained in 91 patients with osteoarthritis (63% female) undergoing TKA before tourniquet placement (T1), 45 minutes after tourniquet inflation (T2), and 15 minutes after tourniquet removal (T3). Plasma levels of F 2 -isoprostanes and isofurans, the most specific measures of in vivo OS, were quantified. Pain intensity and function were assessed at baseline and again at 6 weeks and 6 months after TKA. Results indicated that higher Combined OS (F 2 -isoprostanes + isofurans/2) at T1 baseline and larger increases in Combined OS from T1 to T2 were associated with higher baseline-corrected past 24-hour worst and average pain intensity (numeric rating scale) and higher past week McGill Pain Questionnaire-2 total scores at 6-month follow-up ( P 's0.05). Increases in Combined OS from T1 to T3, which should most directly capture OS and IR injury related to tourniquet use, were not associated with short-term or long-term post-TKA pain outcomes. Longer ischemia duration was unexpectedly associated with lower baseline-corrected pain intensity at 6-month follow-up. Combined OS was not linked to functional outcomes at either follow-up. Elevated perioperative OS seems to exert small but significant adverse effects on long-term post-TKA pain outcomes, although this OS seems unrelated to IR injury associated with extended tourniquet use.

Preclinical research has demonstrated that exposure to acute stress is associated with attenuated pain perception, so called stress-induced analgesia (SIA). Mechanisms of SIA in humans have not been reliably demonstrated. This study examined the role of the endogenous opioid system in the impact of combined interpersonal and mental stressors on evoked pain responses in 84 participants (34 women). Using a within-subject, double-blinded, counterbalanced design, participants were administered either oral placebo or the opioid antagonist naltrexone (50 mg) across two testing sessions. In each session, they experienced two evoked pain stimuli (cold pressor test [CPT], heat pain) after an extended rest period (rest condition) and after exposure to an acute stressor (a combination of public speaking and mental arithmetic challenge; stress condition). Results showed that both stress and opioid blockade produced significant changes in hormonal and cardiovascular measures, consistent with successful induction of acute stress. Stress was associated with attenuated pain perception (SIA) as indicated by significantly increased CPT tolerance. These effects were particularly pronounced in individuals experiencing the stress condition first. More importantly, SIA effects on CPT tolerance were abolished by opioid blockade. There were no significant SIA effects on heat pain responses. This study demonstrates that the endogenous opioid system may mediate effects of acute stress on pain perception, although this effect seems to be qualified by the type of evoked pain stimuli experienced.

Objective Neighborhood socioeconomic status (SES) is linked to self-reported pain severity and disability but its association with evoked pain responsiveness in individuals with chronic pain remains unclear. The present study examined relations between neighborhood SES, assessed through the area deprivation index (ADI), and static and dynamic pain response indices. It was hypothesized that youth with functional abdominal pain (FAP) living in lower SES neighborhoods would exhibit lower pain threshold, lower pain tolerance, and reduced conditioned pain modulation (CPM) compared to youth living in higher SES neighborhoods. Methods Participants were 183 youth with FAP and their parents. Youth completed a quantitative sensory testing protocol. Family addresses were used to compute ADI scores. Thermal stimuli for pain threshold and tolerance were delivered to participants’ forearms using thermodes. CPM, an index of descending pain inhibition, was determined using a thermode as test stimulus and a hot water bath as conditioning stimulus. Results As hypothesized, youth with FAP living in lower SES neighborhoods exhibited weaker CPM. Contrary to hypotheses, lower neighborhood SES was associated with neither pain thresholds nor with pain tolerance. Conclusions These findings demonstrated the independent contribution of place of residence—an often neglected component of the biopsychosocial model—to efficiency of descending pain inhibition. Understanding the mechanisms that account for such associations between place and pain could guide the development of public health and policy initiatives designed to mitigate chronic pain risk in underserved and economically marginalized communities.

Previous research has shown that African Americans (AA) report higher pain intensity and pain interference than other racial/ethnic groups as well as greater levels of other risk factors related to worse pain outcomes, including PTSD symptoms, pain catastrophizing, and sleep disturbance. Within a Conservation of Resources theory framework, we tested the hypothesis that socioeconomic status (SES) factors (i.e., income, education, employment, perception of income meeting basic needs) largely account for these racial/ethnic differences. Participants were 435 women [AA, 59.1%; Hispanic/Latina (HL), 25.3%; Non-Hispanic/White (NHW), 15.6%] who presented to an Emergency Department (ED) with an acute pain-related complaint. Data were extracted from psychosocial questionnaires completed at the participants’ baseline interview. Structural Equation Modeling was used to examine whether racial/ethnic differences in pain intensity and pain interference were mediated by PTSD symptoms, pain catastrophizing, sleep quality, and sleep duration, and whether these mediation pathways were, in turn, accounted for by SES factors. Results indicated that SES factors accounted for the mediation relationships linking AA race to pain intensity via PTSD symptoms and the mediation relationships linking AA race to pain interference via PTSD symptoms, pain catastrophizing, and sleep quality. Results suggested that observed racial/ethnic differences in AA women’s pain intensity, pain interference, and common risk factors for elevated pain may be largely due to racial/ethnic differences in SES. These findings highlight the role of social inequality in persistent health disparities facing inner-city, AA women.

Factors contributing to development of complex regional pain syndrome (CRPS) are not fully understood. This study examined possible epigenetic mechanisms that may contribute to CRPS after traumatic injury. DNA methylation profiles were compared between individuals developing CRPS (n = 9) and those developing non-CRPS neuropathic pain (n = 38) after undergoing amputation following military trauma. Linear Models for Microarray (LIMMA) analyses revealed 48 differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites between groups (unadjusted P's < 0.005), with the top gene COL11A1 meeting Bonferroni-adjusted P < 0.05. The second largest differential methylation was observed for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. For all but 7 of the significant CpG sites, the CRPS group was hypomethylated. Numerous functional Gene Ontology-Biological Process categories were significantly enriched (false discovery rate-adjusted q value

OBJECTIVE: Evidence supports high rates of co-occurrence of posttraumatic stress disorder (PTSD) and chronic pain disorders involving central sensitization (CS). The nature of this relationship, however, remains relatively unexplored. In this study, we aimed to (1) assess how both trauma exposure and current PTSD symptoms are related to clinical manifestations of CS, and (2) test whether PTSD symptoms explain the relationship between trauma exposure and CS. Because experiential avoidance has been shown to impact the relationship between trauma and health outcomes, we (3) explored experiential avoidance as a possible mediator or moderator of the trauma-CS relationship. METHODS: A sample of 202 adult patients (79% female) with chronic pain completed validated self-report measures of trauma exposure, current PTSD symptoms, experiential avoidance, and three manifestations of CS: widespread pain, greater pain severity, and polysomatic symptom reporting. We used path analysis and multivariate regression to assess our study aims. RESULTS: Both trauma exposure and PTSD symptoms were significantly associated with all three clinical indicators of CS. PTSD symptoms partially explained the relationship between trauma exposure and widespread pain, pain intensity, and polysomatic symptoms. Experiential avoidance did not mediate or moderate the trauma-CS relationship. CONCLUSION: Our findings suggest that trauma exposure is linked to elevated clinical markers of CS, but a critical factor in this relationship is the mediating effect of current PTSD symptoms.

Acute vaso-occlusive pain episodes in sickle cell disease (SCD) are associated with increased rates of hospitalization and early mortality. Despite the observation that women have higher rates of acute vaso-occlusive pain episodes than men, sex-specific risk factors for acute vaso-occlusive pain have not been identified. We tested the hypothesis that acute vaso-occlusive pain is temporally associated with the onset of menstruation in women with SCD.Initially, using a cross-sectional study design, we administered questionnaires, including validated measures of SCD pain frequency and severity within the last 30 days, as well as menstrual symptoms in a discovery group (n = 103). We then confirmed our findings by administering the same questionnaires online in a replication group (n = 118). A validated questionnaire was used to define dysmenorrhea.In the initial discovery group, 28% (29 of 103) reported acute vaso-occlusive pain episodes temporally associated with menstruation, and 72% (74 of 103) did not. Of the 29 reporting acute vaso-occlusive pain associated with menstruation, 90% (26) and 10% (3) did and did not meet criteria for dysmenorrhea, respectively. In the replication group, 36% (43 of 118) reported acute vaso-occlusive pain temporally associated with menstruation. Of the 43 reporting acute vaso-occlusive pain associated with menstruation, 60% (26) and 40% (17) did and did not meet criteria for dysmenorrhea, respectively.In both the discovery and replication groups, we demonstrate that acute vaso-occlusive pain is temporally associated with the onset of menstruation that women with SCD can distinguish from dysmenorrhea.

Background and objectivesTo expand the evidence base needed to enable personalized pain medicine, we evaluated whether self-reported cumulative exposure to medical opioids and subjective responses on first opioid use predicted responses to placebo-controlled opioid administration.MethodsIn study 1, a survey assessing cumulative medical opioid exposure and subjective responses on first opioid use was created (History of Opioid Medical Exposure (HOME)) and psychometric features documented in a general sample of 307 working adults. In study 2, 49 patients with chronic low back pain completed the HOME and subsequently rated back pain intensity and subjective opioid effects four times after receiving saline placebo or intravenous morphine (four incremental doses) in two separate double-blinded laboratory sessions. Placebo-controlled morphine effects were derived for all outcomes.ResultsTwo HOME subscales were supported: cumulative opioid exposure and euphoric response, both demonstrating high test–retest reliability (Intraclass Correlation Coefficients > 0.93) and adequate internal consistency (Revelle’s Omega Total = 0.73–0.77). In study 2, higher cumulative opioid exposure scores were associated with significantly greater morphine-related reductions in back pain intensity (p=0.02), but not with subjective drug effects. Higher euphoric response subscale scores were associated with significantly lower overall perceived morphine effect (p=0.003), less sedation (p=0.04), greater euphoria (p=0.03) and greater desire to take morphine again (p=0.02).DiscussionSelf-reports of past exposure and responses to medical opioid analgesics may have utility for predicting subsequent analgesic responses and subjective effects. Further research is needed to establish the potential clinical and research utility of the HOME.Trial registration numberNCT02469077.

ObjectivesAccurately assessing the probability of significant respiratory depression following opioid administration can potentially enhance perioperative risk assessment and pain management. We developed and validated a risk prediction tool to estimate the probability of significant respiratory depression (indexed by naloxone administration) in patients undergoing noncardiac surgery.DesignRetrospective cohort study.SettingSingle academic centre.ParticipantsWe studied n=63 084 patients (mean age 47.1±18.2 years; 50% men) who underwent emergency or elective non-cardiac surgery between 1 January 2007 and 30 October 2017.InterventionsA derivation subsample reflecting two-thirds of available patients (n=42 082) was randomly selected for model development, and associations were identified between predictor variables and naloxone administration occurring within 5 days following surgery. The resulting probability model for predicting naloxone administration was then cross-validated in a separate validation cohort reflecting the remaining one-third of patients (n=21 002).ResultsThe rate of naloxone administration was identical in the derivation (n=2720 (6.5%)) and validation (n=1360 (6.5%)) cohorts. The risk prediction model identified female sex (OR: 3.01; 95% CI: 2.73 to 3.32), high-risk surgical procedures (OR: 4.16; 95% CI: 3.78 to 4.58), history of drug abuse (OR: 1.81; 95% CI: 1.52 to 2.16) and any opioids being administered on a scheduled rather than as-needed basis (OR: 8.31; 95% CI: 7.26 to 9.51) as risk factors for naloxone administration. Advanced age (OR: 0.971; 95% CI: 0.968 to 0.973), opioids administered via patient-controlled analgesia pump (OR: 0.55; 95% CI: 0.49 to 0.62) and any scheduled non-opioids (OR: 0.63; 95% CI: 0.58 to 0.69) were associated with decreased risk of naloxone administration. An overall risk prediction model incorporating the common clinically available variables above displayed excellent discriminative ability in both the derivation and validation cohorts (c-index=0.820 and 0.814, respectively).ConclusionOur cross-validated clinical predictive model accurately estimates the risk of serious opioid-related respiratory depression requiring naloxone administration in postoperative patients.

Background Opioid analgesics are commonly prescribed for postoperative analgesia following pediatric surgery and often result in leftover opioid analgesics in the home. To reduce the volume of leftover opioids and overall community opioid burden, the State of Tennessee enacted a policy to reduce initial opioid prescribing to a 3-day supply for most acute pain incidents. We aimed to evaluate the extent of leftover opioid analgesics following pediatric ambulatory surgeries in the context of a state-mandated restrictive opioid-prescribing policy. We also aimed to evaluate opioid disposal rates, methods of disposal, and reasons for nondisposal. Methods Study personnel contacted the parents of 300 pediatric patients discharged with an opioid prescription following pediatric ambulatory surgery. Parents completed a retrospective telephone survey regarding opioid use and disposal. Data from the survey were combined with data from the medical record to evaluate proportion of opioid doses prescribed that were left over. Results The final analyzable sample of 185 patients (62% response rate) were prescribed a median of 12 opioid doses (interquartile range [IQR], 12-18), consumed 2 opioid doses (IQR, 0-4), and had 10 opioid doses left over (IQR, 7-13). Over 90% (n = 170 of 185) of parents reported they had leftover opioid analgesics, with 83% of prescribed doses left over. A significant proportion (29%, n = 54 of 185) of parents administered no prescribed opioids after surgery. Less than half (42%, n = 71 of 170) of parents disposed of the leftover opioid medication, most commonly by flushing down the toilet, pouring down the sink, or throwing in the garbage. Parents retaining leftover opioids (53%, n = 90 of 170) were most likely to keep them in an unlocked location (68%, n = 61 of 90). Parents described forgetfulness and worry that their child will experience pain in the future as primary reasons for not disposing of the leftover opioid medication. Conclusions Despite Tennessee's policy aimed at reducing leftover opioids, a significant proportion of prescribed opioids were left over following pediatric ambulatory surgeries. A majority of parents did not engage in safe opioid disposal practices. Given the safety risks related to leftover opioids in the home, further interventions to improve disposal rates and tailor opioid prescribing are warranted after pediatric surgery.

Background Patient-reported opioid use is an important outcome for studies of postoperative pain and opioid use, however the accuracy of patient-reported opioid use is unknown. Objective To evaluate the accuracy of retrospective patient-reported analgesic use versus real-time analgesic use data obtained via electronic medication caps. Study Design This study used a descriptive cross-sectional study design. Data from 132 patients who underwent cesarean delivery at a metropolitan academic medical center were analyzed to compare 2 methods of measuring opioid consumption postoperatively. At discharge, patients received 30 5-mg hydrocodone/325-mg acetaminophen tablets in electronically enabled Smart Cap bottles that recorded medication bottle access. Patients were phoned 2 weeks post-discharge to assess patient-report of opioid use over the post-discharge period. Intra-class correlations (ICCs) were used to assess correspondence between retrospective patient-reported opioid use and Smart Cap data. Likelihood Chi-Square tests assessed differences between demographic and clinical characteristics in persons who accurately, over-, and under-reported opioid use as compared to Smart Cap data. Results Participants ranged from 18-41 years old (mean 30.6), and most (74% [92/124] were Caucasian with private or military insurance (66% [80/122]). Patient-reported opioid use corresponded highly with Smart Cap data (ICC = .85, 95% C.I.=.80-.90, p Conclusions Retrospective self-reporting is a reasonably accurate method to assess opioid use over a 2-week time period after cesarean delivery.

We tested whether aerobic exercise training altered morphine analgesic responses or reduced morphine dosages necessary for adequate analgesia. Patients with chronic back pain were randomized to an 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 45). Before and after the intervention, participants underwent 3 laboratory sessions (double-blinded, crossover) to assess effects of saline placebo, i.v. morphine (0.09 mg/kg), and i.v. naloxone (12 mg) on low back pain and evoked heat pain responses. Differences in evoked and back pain measures between the placebo and morphine conditions indexed morphine analgesia, with pre-post intervention changes the primary outcome. Endogenous opioid analgesia was indexed by differences in evoked and low back pain measures between the naloxone and placebo conditions. A Sex X Intervention interaction on the analgesic effects of morphine on visual analogue scale back pain intensity was observed (P = 0.046), with a similar trend for evoked pain threshold (P = 0.093). Male exercisers showed reduced morphine analgesia pre-post intervention, whereas male controls showed increased analgesia (with no differences in females). Of clinical significance were findings that relative to the control group, aerobic exercise produced analgesia more similar to that observed after receiving ≈7 mg morphine preintervention (P < 0.045). Greater pre-post intervention increases in endogenous opioid function (from any source) were significantly associated with larger pre-post intervention decreases in morphine analgesia (P < 0.046). The overall pattern of findings suggests that regular aerobic exercise has limited direct effects on morphine responsiveness, reducing morphine analgesia in males only.

Background US opioid prescribing and use escalated over the last two decades, with parallel increases in opioid misuse, opioid-related deaths, and concerns about diversion. Postoperatively prescribed opioids contribute to these problems. Policy makers have addressed this issue by limiting postoperative opioid prescribing. However, until recently, little data existed to guide prescribers on opioid needs postoperatively. This meta-analysis quantitatively integrated the growing literature regarding extent of opioids leftover after surgery and identified factors associated with leftover opioid proportions. Methods We conducted a meta-analysis of observational studies quantifying postoperative opioid consumption in North American adults, and evaluated effect size moderators using robust variance estimation meta-regression. Medline, EMBASE, Cumulative Index of Nursing and Allied Health Literature, and Cochrane Database of Systematic Reviews were searched for relevant articles published January 1, 2000 to November 10, 2018. The Methodological Index for Non-Randomized Studies (MINORS) tool assessed risk of study bias. The proportion effect size quantified the primary outcome: proportion of prescribed postoperative opioids leftover at the time of follow-up. Primary meta-regression analyses tested surgical type, amount of opioids prescribed, and study publication year as possible moderators. Secondary meta-regression models included surgical invasiveness, age, race, gender, postoperative day of data collection, and preoperative opioid use. Results We screened 911 citations and included 44 studies (13,068 patients). The mean weighted effect size for proportion of postoperative opioid prescriptions leftover was 61% (95% CI, 56-67%). Meta-regression models revealed type of surgical procedure and level of invasiveness had a statistically significant effect on proportion of opioids leftover. Proportion of opioids leftover was greater for “other soft tissue” surgeries than abdominal/pelvic surgeries, but did not differ significantly between orthopedic and abdominal/pelvic surgeries. Minimally invasive compared to open surgeries resulted in a greater proportion of opioids leftover. Limitations include predominance of studies from academic settings, inconsistent reporting of confounders, and a possible publication bias toward studies reporting smaller leftover opioid proportions. Conclusions and implications of key findings A significant proportion of opioids are leftover postoperatively. Surgery type and level of invasiveness affect postoperative opioid consumption. Integration of such factors into prescribing guidelines may help minimize opioid overprescribing while adequately meeting analgesic needs.

Migraine headache is a pain condition characterized by severe and recurrent unilateral head pain. Among other mechanisms, central pain sensitization processes seem to be involved in the disorder. An experimental protocol based on slowly repeated evoked pain (SREP) has been shown to indicate pain sensitization in fibromyalgia patients and differentiate these patients from healthy individuals and rheumatoid arthritis patients. This study examined SREP sensitization in migraine patients and explored its potential usefulness as a central sensitization marker. The SREP protocol was administered to 40 episodic migraine (EM) patients not currently experiencing a headache and 40 healthy controls. SREP consisted of a series of 9 suprathreshold painful pressure stimuli of 5 s duration and a 30 s interstimulus interval. SREP sensitization was indexed by the increase in pain ratings across the stimuli. Pain threshold, pain tolerance and temporal summation of pain were also assessed. SREP sensitization was observed in EM, but not in healthy individuals (p

Objective Fibromyalgia is a chronic pain syndrome characterized by central sensitization. A novel protocol based on slowly repeated evoked pain (SREP) appears to be a useful marker of pain sensitization in fibromyalgia patients. Whether SREP enhances diagnostic accuracy beyond key clinical symptoms that characterize fibromyalgia has not been examined. Methods Fifty fibromyalgia patients, 30 rheumatoid arthritis patients, and 50 healthy individuals were evaluated to assess clinical pain, as well as fatigue, insomnia, pain catastrophizing, and negative mood. The SREP protocol consisted of a series of nine low-intensity painful pressure stimuli of five seconds’ duration with 30-second interstimulus intervals. SREP sensitization was indexed by increases in pain intensity ratings across stimuli. Results SREP sensitization was observed in fibromyalgia but not in rheumatoid arthritis or healthy individuals. As expected, fibromyalgia patients exhibited a more negative psychosocial profile than did rheumatoid arthritis patients and healthy individuals. SREP was positively associated with clinical pain, fatigue, insomnia, and catastrophizing, but not with negative mood. SREP discriminated fibromyalgia cases from rheumatoid arthritis and healthy individuals even when current clinical pain was included in the analysis. Combining fatigue, insomnia, and SREP led to near perfect diagnostic accuracy (99%) in differentiating fibromyalgia from healthy individuals and 86.3% accuracy in discriminating fibromyalgia from rheumatoid arthritis. Conclusions These results provide further evidence of SREP as a marker of pain sensitization in fibromyalgia and suggest that it captures aspects of fibromyalgia not fully captured by clinical features. Combining SREP with assessment of clinical features could potentially improve fibromyalgia diagnosis.

BACKGROUND/OBJECTIVES: Inner-city Black women may be more susceptible to post-traumatic stress disorder (PTSD) than White women, although mechanisms underlying this association are unclear. Living in urban neighborhoods distinguished by higher chronic stress may contribute to racial differences in women’s cognitive, affective, and social vulnerabilities, leading to greater trauma-related distress including PTSD. Yet social support could buffer the negative effects of psychosocial vulnerabilities on women’s health. METHODS/DESIGN: Mediation and moderated mediation models were tested with 371 inner-city women, including psychosocial vulnerability (i.e., catastrophizing, anger, social undermining) mediating the pathway between race and PTSD, and social support moderating psychosocial vulnerability and PTSD. RESULTS: Despite comparable rates of trauma, Black women reported higher vulnerability and PTSD symptoms, and lower support compared to White Hispanic and non-Hispanic women. Psychosocial vulnerability mediated the pathway between race and PTSD, and social support moderated vulnerability, reducing negative effects on PTSD. When examining associations by race, the moderation effect remained significant for Black women only. CONCLUSIONS: Altogether these psychosocial vulnerabilities represent one potential mechanism explaining Black women’s greater risk of PTSD, although cumulative psychosocial vulnerability may be buffered by social support. Despite higher support, inner-city White women’s psychosocial vulnerability may actually outweigh support’s benefits for reducing trauma-related distress.

We sought to determine whether women with overactive bladder who required third line therapy would demonstrate greater central sensitization, indexed by temporal summation to heat pain stimuli, than those with overactive bladder.We recruited 39 women with overactive bladder from the urology clinic who were planning to undergo interventional therapy for medication refractory overactive bladder with onabotulinumtoxinA bladder injection or sacral neuromodulation. We also recruited 55 women with overactive bladder who were newly seen at our urology clinic or who responded to advertisements for study participation. Participants underwent quantitative sensory testing using a thermal temporal summation protocol. The primary study outcome was the degree of temporal summation as reflected in the magnitude of positive slope of the line fit to the series of 10 stimuli at a 49C target temperature. We compared the degree of temporal summation between the study groups using linear regression.Women in the group undergoing third line therapy showed significantly higher standardized temporal summation slopes than those in the nontreatment group (β = 1.57, 95% CI 0.18-2.96, t = 2.25, p = 0.027). On exploratory analyses a history of incontinence surgery or hysterectomy was associated with significantly greater temporal summation.In this study the degree of temporal summation was elevated in women undergoing third line overactive bladder therapy compared to women with overactive bladder who were not undergoing that therapy. These findings suggest there may be pathophysiological differences, specifically in afferent nerve function and processing, in some women with overactive bladder.

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 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.

Complex regional pain syndrome (CRPS) is a persistent pain condition that remains incompletely understood and challenging to treat. Historically, a wide range of different outcome measures have been used to capture the multidimensional nature of CRPS. This has been a significant limiting factor in the advancement of our understanding of the mechanisms and management of CRPS. In 2013, an international consortium of patients, clinicians, researchers, and industry representatives was established, to develop and agree on a minimum core set of standardised outcome measures for use in future CRPS clinical research, including but not limited to clinical trials within adult populations. The development of a core measurement set was informed through workshops and supplementary work, using an iterative consensus process. "What is the clinical presentation and course of CRPS, and what factors influence it?" was agreed as the most pertinent research question that our standardised set of patient-reported outcome measures should be selected to answer. The domains encompassing the key concepts necessary to answer the research question were agreed as follows: pain, disease severity, participation and physical function, emotional and psychological function, self-efficacy, catastrophizing, and patient's global impression of change. The final core measurement set included the optimum generic or condition-specific patient-reported questionnaire outcome measures, which captured the essence of each domain, and 1 clinician-reported outcome measure to capture the degree of severity of CRPS. The next step is to test the feasibility and acceptability of collecting outcome measure data using the core measurement set in the CRPS population internationally.

Objective Newborns requiring hospitalisation frequently undergo painful procedures. Prevention of pain in infants is of prime concern because of adverse associations with physiological and neurological development. However, pain mitigation is currently guided by behavioural observation assessments that have not been validated against direct evidence of pain processing in the brain. The aim of this study was to determine whether cry presence or amplitude is a valid indicator of pain processing in newborns. Design Prospective observational cohort. Setting Newborn nursery. Patients Healthy infants born at >37 weeks and Interventions We prospectively studied newborn cortical responses to light touch, cold and heel stick, and the amplitude of associated infant vocalisations using our previously published paradigms of time-locked electroencephalogram (EEG) with simultaneous audio recordings. Results Latencies of cortical peak responses to each of the three stimuli type were significantly different from each other. Of 54 infants, 13 (24%), 19 (35%) and 35 (65%) had cries in response to light touch, cold and heel stick, respectively. Cry in response to non-painful stimuli did not predict cry in response to heel stick. All infants with EEG data had measurable pain responses to heel stick, whether they cried or not. There was no association between presence or amplitude of cries and cortical nociceptive amplitudes. Conclusions In newborns with distinct brain responses to light touch, cold and pain, cry presence or amplitude characteristics do not provide adequate behavioural markers of pain signalling in the brain. New bedside assessments of newborn pain may need to be developed using brain-based methodologies as benchmarks in order to provide optimal pain mitigation.

Objective With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (e.g., pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Setting Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). Methods As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. Perspective The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Conclusions Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

OBJECTIVE: With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (eg, pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain.SETTING: Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM).METHODS: As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions.PERSPECTIVE: The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms.CONCLUSIONS: Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

Clinical diagnosis of complex regional pain syndrome (CRPS) is a dichotomous (yes/no) categorization, a format necessary for clinical decision making. Such dichotomous diagnostic categories do not convey an individual's subtle gradations in the severity of the condition over time and have poor statistical power when used as an outcome measure in research. This prospective, international, multicenter study slightly modified and further evaluated the validity of the CRPS Severity Score (CSS), a continuous index of CRPS severity. Using a prospective design, medical evaluations were conducted in 156 patients with CRPS to compare changes over time in CSS scores between patients initiating a new treatment program and patients on stable treatment regimens. New vs stable categorizations were supported by greater changes in pain and function in the former. Results indicated that CSS values in the stable CRPS treatment group exhibited much less change over time relative to the new treatment group, with intraclass correlations nearly twice as large in the former. A calculated smallest real difference value revealed that a change in the CSS of ≥4.9 scale points would indicate real differences in CRPS symptomatology (with 95% confidence). Across groups, larger changes in CRPS features on the CSS over time were associated in the expected direction with greater changes in pain intensity, fatigue, social functioning, ability to engage in physical roles, and general well-being. The overall pattern of findings further supports the validity of the CSS as a measure of CRPS severity and suggests it may prove useful in clinical monitoring and outcomes research.

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.

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.

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 (>/ 0.44, P 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.

Objective: Prescribed opioids for chronic pain management contribute significantly to the opioid crisis. There is a need to understand the real-world benefits that, despite risks, lead chronic pain patients to persist in opioid use. Negative reinforcement models of addiction posit that individuals use substances to reduce aversive states but have seldom been applied to prescribed opioids. Using ecological momentary assessment, we examined reciprocal associations between opioid use and physical pain, for which opioids are prescribed, and negative affect (NA), for which they are not. Method: Chronic low back pain patients on long-term opioid therapy (n = 34) without significant past-year opioid misuse reported multiple times daily via smartphone over 2 weeks (nobservations = 2,285). We hypothesized that pain and NA would be positively associated with subsequent opioid use, and that use would be negatively associated with subsequent pain and NA. Results: Time-lagged multilevel models indicated that participants were more likely to use opioids and in larger doses following elevated pain and NA. There was also an interaction of concurrent pain and NA on opioid dose. In turn, participants reported reduced pain and NA following larger doses. Additionally, individuals at high risk for opioid misuse, compared with low risk, took larger doses following pain, but also experienced smaller subsequent pain and NA reductions. Conclusions: Opioid use was bidirectionally associated with pain and NA. Findings fit negative reinforcement models associated with risk of developing opioid use disorder. Educating patients and providers about negative reinforcement may help reduce opioid use and opioid-associated risks. (PsycINFO Database Record (c) 2019 APA, all rights reserved)

Objectives Sleep disturbance and chronic pain are related. The present study evaluated both direct and indirect (mediated) pathways through which sleep disturbance might be related to chronic pain intensity and function. Methods In total, 87 individuals (64% female) with chronic low back pain but not using opioids daily completed questionnaires assessing their sleep disturbance, chronic pain intensity, function, depression, anxiety, positive affect, and catastrophizing. Results Greater sleep disturbance was associated with greater pain intensity, worse function, greater emotional distress, lower positive affect, and higher levels of catastrophizing. Cross-sectional mediation analyses revealed that the positive associations between sleep disturbance and chronic pain intensity were conveyed statistically not only by significant indirect effects of elevated emotional distress, lower positive affect, and greater catastrophizing associated with sleep disturbance, but also by significant direct effects of sleep disturbance on chronic pain intensity. Similarly, we found that the associations between sleep disturbance and impaired function were conveyed statistically not only by significant indirect effects of elevated chronic pain intensity associated with sleep disturbance, but also by significant direct effects of sleep disturbance on function. Discussion Sleep disturbance was related significantly with chronic pain intensity and function by both direct and indirect pathways. These results are consistent with an emerging literature highlighting the potential significance of sleep disturbance in chronic pain patients, and provide further support for addressing sleep disturbance in the assessment and management of chronic pain.

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.

Use of opioid analgesics for management of chronic nonmalignant pain has become common, yet there are presently no well-validated predictors of optimal opioid analgesic efficacy. We examined whether psychosocial factors (eg, depressive symptoms) predicted changes in spontaneous low back pain after administration of opioid analgesics, and whether endogenous opioid (EO) function mediated these relationships. Participants with chronic low back pain but who were not chronic opioid users (N = 89) underwent assessment of low back pain intensity pre- and post-drug in 3 (counterbalanced) conditions: (1) placebo, (2) intravenous naloxone, and (3) intravenous morphine. Comparison of placebo condition changes in back pain intensity to those under naloxone and morphine provided indexes of EO function and opioid analgesic responses, respectively. Results showed that (1) most psychosocial variables were related significantly and positively to morphine analgesic responses for low back pain, (2) depressive symptoms, trait anxiety, pain catastrophizing, and pain disability were related negatively to EO function, and (3) EO function was related negatively to morphine analgesic responses for low back pain. Bootstrapped mediation analyses showed that links between morphine analgesic responses and depressive symptoms, trait anxiety, pain catastrophizing, and perceived disability were partially mediated by EO function. Results suggest that psychosocial factors predict elevated analgesic responses to opioid-based medications, and may serve as markers to identify individuals who benefit most from opioid therapy. Results also suggest that people with greater depressive symptoms, trait anxiety, pain catastrophizing, and perceived disability may have deficits in EO function, which may predict enhanced response to opioid analgesics.

The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) is designed to be an evidence-based multidimensional chronic pain classification system that will facilitate more comprehensive and consistent chronic pain diagnoses, and thereby enhance research, clinical communication, and ultimately patient care. Core diagnostic criteria (dimension 1) for individual chronic pain conditions included in the initial version of AAPT will be the focus of subsequent empirical research to evaluate and provide evidence for their reliability and validity. Challenges to validating diagnostic criteria in the absence of clear and identifiable pathophysiological mechanisms are described. Based in part on previous experience regarding the development of evidence-based diagnostic criteria for psychiatric disorders, headache, and specific chronic pain conditions (fibromyalgia, complex regional pain syndrome, temporomandibular disorders, pain associated with spinal cord injuries), several potential approaches for documentation of the reliability and validity of the AAPT diagnostic criteria are summarized. Perspective The AAPT is designed to be an evidence-based multidimensional chronic pain classification system. Conceptual and methodological issues related to demonstrating the reliability and validity of the proposed AAPT chronic pain diagnostic criteria are discussed.

A variety of approaches have been used to develop diagnostic criteria for chronic pain. The published evidence of the reliability and validity of existing diagnostic criteria is limited, and these criteria have typically not been used in clinical practice. The availability of a widely accepted, consistently applied, and evidence-based taxonomy of diagnostic criteria would improve the quality of clinical research on chronic pain and would be of great value in clinical practice. To address the need for evidence-based diagnostic criteria for the major chronic pain conditions, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration and the American Pain Society (APS) have collaborated on the development of the ACTTION-APS Pain Taxonomy (AAPT). AAPT provides a multidimensional framework that is applied systematically in the development of diagnostic criteria. This article (1) describes the background and rationale for AAPT; (2) presents the AAPT taxonomy and the specific conditions for which diagnostic criteria have been developed (to be published separately); (3) briefly reviews the 5 dimensions that constitute the AAPT multidimensional framework and describes the 7 accompanying articles that discuss these dimensions and other important issues involving AAPT; and (4) provides an overview of next steps, specifically, the general processes by which the initial set of diagnostic criteria (for which the evidence base has been drawn from the literature, systematic reviews, and secondary analyses of existing databases) will undergo additional assessments of reliability and validity. Perspective To address the need for evidence-based diagnostic criteria for the major chronic pain conditions, the AAPT provides a multidimensional framework that is applied systematically in the development of diagnostic criteria. The long-term objective of AAPT is to advance the scientific understanding of chronic pain and its treatment.