Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

Smoking-associated gene expression alterations in nasal epithelium reveal immune impairment linked to lung cancer risk.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, 40% of which occur more than 15 years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk remain unclear. We thus set out to examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data and to explore the mechanisms of the persisting risk in former smokers. METHODS: We analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking statuses. We developed a computational model to assess smoking-associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. RESULTS: We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune- and interferon-related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. CONCLUSIONS: Our results provide initial evidence for germline-mediated personalized smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

Interactions Between Endocannabinoid and Endogenous Opioid Systems Prospectively Influence Postoperative Opioid Use in Pregnant Patients Undergoing Cesarean Delivery.

Both endocannabinoid (EC) and endogenous opioid systems are involved in nociceptive processing and may work together synergistically based on preclinical models. This study evaluated the interactive effects of preoperative beta-endorphin (BE) concentrations (a key analgesic endogenous opioid) in cerebrospinal fluid (CSF) and ECs (CSF and plasma 2-arachidonoylglycerol and plasma anandamide) on postoperative opioid use and pain intensity in a prospective cohort of n = 112 pregnant patients undergoing scheduled cesarean delivery. Maternal blood and CSF samples were collected preoperatively for BE and EC assays. Patients completed measures of outpatient opioid use (number of tablets used and days of use) and average pain intensity at 2 weeks postoperatively. Results of general linear model analyses controlling for maternal age, body mass index at time of delivery, and race revealed significant multiplicative interactions between EC and BE concentrations on number of opioid tablets used (based on pill count), days of opioid use, and total milligram morphine equivalents used in the 2-week follow-up period. Elevated preoperative plasma and CSF 2-arachidonoylglycerol predicted reduced outpatient opioid analgesic use, particularly for patients low in CSF BE. Similar analyses for pain intensity at 2-week follow-up indicated a significant interaction (P < .02) characterized by higher preoperative BE concentrations being associated with lower subsequent pain only for individuals with low preoperative plasma anandamide concentrations. Further exploration of interactions between EC and endogenous opioid inhibitory systems as they influence responses to opioid analgesics in other clinical pain populations may help guide the development of precision pain management approaches. PERSPECTIVE: In the postoperative setting of patients undergoing cesarean delivery, elevated ECs were linked to reduced outpatient opioid analgesic use in individuals who had low endogenous opioid concentrations in CSF. Further exploration of interactions between these 2 inhibitory systems as they impact responses to pain management interventions appears warranted.

Maternal depression, parenting, and child psychological outcomes in the context of maternal pain.

Parental chronic pain is associated with adverse outcomes in children, but the mechanisms of transmission are largely untested. Mothers with chronic pain (N = 400, Mage = 40.3 years, 90.5% White) and their children (Mage = 10.33 years, 83.3% White, 50.2% female) were recruited in 2016-2018 to test longitudinal pathways of risk transmission from maternal chronic pain to children's psychological symptoms, examining roles of parenting, maternal depression, and child distress tolerance. Maternal pain was associated with positive (ß = .28) and pain-specific (ß = .10) parenting behaviors. Maternal depression was associated with lower child distress tolerance (ß = -.03), which was associated with greater child psychological symptoms (ß = -.62). Parenting and maternal pain were not prospectively associated with child outcomes. When considering the dual-generational impacts of chronic pain, physical and psychological functioning should be examined.

Chronic Pain in Autistic Youth: Clinical Prevalence and Reflections on Tailoring Evidence-Based Interventions from an Interdisciplinary Treatment Team.

Though there is growing awareness of the overrepresentation of autistic patients in chronic pain clinics, potential adaptations for the assessment and treatment of chronic pain in this population have not yet been established. To address this gap, a retrospective review of electronic medical records and discussions by an interdisciplinary pain treatment team were summarized to inform potential biopsychosocial factors affecting the presentation, assessment, and treatment of chronic pain in autistic youth. Our sample included a record review of 95 patients receiving treatment in an interdisciplinary outpatient pediatric pain clinic. Results indicated that 9% (n = 9) of the patients presented to the clinic with a prior diagnosis of autism, but an additional 21% (n = 20) were identified as likely meeting criteria for autism based on the clinical assessment of the developmental history, behaviors observed during the clinical encounter(s), and expert clinical judgment, suggesting that the prevalence rate of autism may be closer to 30% in our outpatient pediatric pain clinic. Over half (52%) of the autistic youth presented to the clinic with widespread pain, 60% identified as female, and 6% identified as gender expansive or transgender. Qualitative insights revealed that most of the autistic patients had co-occurring sensory-processing challenges and difficulty in describing their pain, emotions, and somatic experiences and exhibited cognitive inflexibility and social challenges. We summarize our team's clinical reflections on how autism-relevant biopsychosocial vulnerability factors may contribute to the experience of pain in autistic youth and propose treatment targets and adaptations for the assessment and treatment of pain in this population. Finally, we recommend the need for interventions focused on sensorimotor integration, especially for autistic youth, and describe how pain clinics may be particularly helpful for identifying and supporting autistic females, for whom the potential role of autism in pain experiences had not been considered until receiving treatment in our clinic.

Updated recommendations on measures for clinical trials in pediatric chronic pain: a multiphase approach from the Core Outcomes in Pediatric Persistent Pain (Core-OPPP) Workgroup.

ABSTRACT: Many gaps remain in finding effective, safe, and equitable treatments for children and adolescents with chronic pain and in accessing treatments in different settings. A major goal of the field is to improve assessment of pain and related experience. Valid and reliable patient-reported outcome measures are critical for advancing knowledge of clinical interventions for pediatric chronic pain. Building on the work of the Ped-IMMPACT group, we previously updated a core outcome set (COS) for pediatric chronic pain clinical trials using stakeholder feedback from providers, youth, and parents. The new COS includes 3 mandatory domains: pain severity, pain-related interference with daily living, and adverse events and 4 optional domains: overall well-being, emotional functioning, physical functioning, and sleep quality. The aim of this study was to use a multiphased approach to recommend specific measures for each of the 7 domains identified in our new COS for pediatric chronic pain. We synthesized evidence through conducting the following: (1) a Delphi study of experts to identify candidate measures for the new COS domains, (2) a review phase to gather evidence for measurement properties for candidate measures, and (3) an expert consensus conference to reach agreement on measurement recommendations. Final recommendations included 9 patient-reported measures. Important contextual considerations are discussed, and guidance is provided regarding strengths and limitations of the recommendations. Implementation of these recommendations may be enhanced by widespread dissemination and ease of access to measurement tools.

Twenty-year Outcomes of a Pediatric Chronic Abdominal Pain Cohort: Early Adulthood Health Status and Offspring Physical and Behavioral Health.

Chronic abdominal pain (CAP) represents a common pediatric primary pain disorder that can have long-term effects on physical and mental health into adulthood. Pediatric CAP and Control cohorts recruited in childhood (∼11 years old, T1) and then assessed in emerging adulthood (∼20 years old, T2) were evaluated again for health outcomes in early adulthood (∼30 years old, T3) for the current study. Further, the study evaluated the mental and physical health of offspring of participants who had become parents. Participants who agreed to enroll at T3 (CAP: n = 90, Control: n = 55) completed measures regarding current health, health-related quality of life (HRQoL), and their child's health when applicable. Results indicated close to 20% of the CAP cohort reported recurrent CAP across all 3 timepoints. Participants with current CAP reported poorer HRQoL compared to participants with remitted CAP who reported poorer HRQoL compared to Control participants. The CAP cohort reported higher health-related anxiety compared to the Control cohort regardless of current pain status. CAP compared to Control participants reported greater emotional problems and fewer conduct problems in their children. Longitudinal studies are needed to assess the developmental course of pediatric chronic pain and intergenerational pathways of risk and resilience. Perspective: This article evaluates patterns of chronic abdominal pain from childhood into early adulthood. Patients with pediatric chronic abdominal pain continue to present with health-related anxiety in adulthood and report greater emotional problems in offspring.

Leftover Opioid Analgesics and Disposal Following Ambulatory Pediatric Surgeries in the Context of a Restrictive Opioid-Prescribing Policy.

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.

Sex Moderates the Relationship Between Nausea Severity and Heart Rate Variability in Adolescents and Young Adults.

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, 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.

Place and Pain: Association Between Neighborhood SES and Quantitative Sensory Testing Responses in Youth With Functional Abdominal Pain.

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.

Interventions for Parental Anxiety in Preparation for Pediatric Surgery: A Narrative Review.

The preoperative experience can cause significant anxiety for both pediatric patients and their parents in the lead up to a surgical procedure. Pediatric anxiety in a preoperative setting has been shown to have significant negative downstream effects on the clinical outcomes of children and the healthcare system as a whole. Studies have found that preoperative parental anxiety has significant negative effects on children, regarding anxiety and emotional response. Therefore, interventions for parental preoperative anxiety are important to reduce the child's anxiety. This review provides a brief overview of a broad range of strategies used to alleviate parental anxiety in a preoperative setting. Preoperative education, play-based interventions, music therapy, the presence of parents at induction of anesthesia, and integrative preoperative preparation programs have all demonstrated some evidence for reducing parental preoperative anxiety. The ultimate goal of using interventions for parental preoperative anxiety is to equip healthcare systems to better support families and optimize the perioperative outcomes of children.

Internet-delivered cognitive behavioral therapy for youth with functional abdominal pain: a randomized clinical trial testing differential efficacy by patient subgroup.

ABSTRACT: 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.

Examining Parent Adverse Childhood Experiences as a Distal Risk Factor in Pediatric Chronic Pain.

OBJECTIVES: Adverse childhood experiences (ACEs; ie, exposure to abuse, neglect, household dysfunction in childhood) are associated with poor mental and physical health outcomes across the lifespan. Emerging research suggests parent ACEs also confer risk for poor child outcomes. The relation between parent ACEs and child pain in youth with chronic pain has not yet been examined. The aim of the current longitudinal study was to examine the associations among parent ACEs, parent health, and child pain, in a clinical sample of youth with chronic pain. METHODS: In total, 192 youth (75.5% female, 10 to 18 y old) and one of their parents (92.2% female) were recruited from tertiary pediatric chronic pain clinics in Canada. At baseline, parents completed self-report measures of ACEs, chronic pain status, anxiety and depressive symptoms, and posttraumatic stress disorder symptoms. At a 3-month follow-up, youth completed self-report measures of pain intensity and pain interference. RESULTS: Regression and mediation analyses revealed that parent ACEs significantly predicted parent chronic pain status and depressive symptoms, but not parent anxiety or posttraumatic stress disorder symptoms. Moreover, parent ACEs were not significantly related to youth pain, either directly or indirectly through parent health variables. DISCUSSION: Findings suggest that an intergenerational cascade from parent ACEs to parent health to child pain was not present in the current sample. Further research that examines the role of parent ACEs in the development of child chronic pain, as well as other risk and resiliency factors that may mediate or moderate the association between parent ACEs and child chronic pain, is needed.

Incremental Visual Occlusion During Split-Belt Treadmill Walking Has No Gradient Effect on Adaptation or Retention.

Split-belt treadmills have become an increasingly popular means of quantifying ambulation adaptability. Multiple sensory feedback mechanisms, including vision, contribute to task execution and adaptation success. No studies have yet explored visual feedback effects on locomotor adaptability across a spectrum of available visual information. In this study, we sought to better understand the effects of visual information on locomotor adaptation and retention by directly comparing incremental levels of visual occlusion. Sixty healthy young adults completed a split-belt adaptation protocol, including a baseline, asymmetric walking condition (adapt), a symmetric walking condition (de-adapt), and another asymmetric walking condition (re-adapt). We randomly assigned participants into conditions with varied visual occlusion (i.e., complete and lower visual field occlusion, or normal vision). We captured kinematic data, and outcome measures included magnitude of asymmetry, spatial and temporal contributions to step length asymmetry, variability of the final adapted pattern, and magnitude of adaptation. We used repeated measures and four-way MANOVAs to examine the influence of visual occlusion and walking condition. Participants with complete, compared to lower visual field visual occlusion displayed less consistency in their walking pattern, evident via increased step length standard deviation (p = .007, d = 0.89), and compared to normal vision groups (p = .003 d = 0.81). We found no other group differences, indicating that varying levels of visual occlusion did not significantly affect locomotor adaptation or retention. This study offers insight into the role vision plays in locomotor adaptation and retention with clinical utility for improving variability in step control.

Faster or longer steps: Maintaining fast walking in older adults at risk for mobility disability.

BACKGROUND: The ability to walk at various speeds is essential to independence for older adults. Maintaining fast walking requires changes in spatial-temporal measures, increasing step length and/or decreasing step time. It is unknown how mobility affects the parameters that change between preferred and fast walking. RESEARCH QUESTION: How does preferred walking performance and measures of strength and mobility relate to the approach (decreasing step time or increasing step length) older adults at risk for mobility disability use to maintain fast walking speeds?. METHODS: Peak isokinetic dynamometry of knee and ankle and several mobility evaluations, including the Timed Up-and-Go, Short Physical Performance Battery, and Dynamic Gait Index, assessed mobility and strength in 57 participants, aged 65-80. Biomechanical gait analysis was used to analyze step length, step time, gait speed at preferred and fast gait speeds and ground reaction force during preferred walking. A score combining the differences between step length and time at fast and preferred speeds (Length-Time Difference) separated participants into two groups: (1) Length, representing a predominant increase in step length to walk fast and (2) Time, a predominant decrease in step time. RESULTS: Those who decreased step time to produce increased speed performed worse during repeated chair stands (p = .006) with no difference in isokinetic strength (p ≥ .15). During preferred walking, the Time group displayed increased propulsive impulse compared to the Length group (p = .007), despite no differences in preferred speed, step length, or time (p ≥ .50). SIGNIFICANCE: While kinetics of preferred walking differed between groups separated by Length-Time Difference, basic spatial-temporals of preferred walking did not in this homogenous population. Length-Time Difference relates to a common mobility assessment and could be easily calculated by clinicians to provide a quantitative and more sensitive measure of ambulatory performance.

Does Quantitative Sensory Testing Improve Prediction of Chronic Pain Trajectories? A Longitudinal Study of Youth With Functional Abdominal Pain Participating in a Randomized Controlled Trial of Cognitive Behavioral Treatment.

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 before the intervention and were followed for 12-month posttreatment. RESULTS: Whereas adolescents with FAP who exhibited stronger baseline conditioned pain modulation (CPM) reported decreases in pain-related interference over follow-up (b=-0.858, SE=0.396, P=0.032), those with weaker CPM exhibited high, relatively stable levels of pain-related interference over time (b=-0.642, SE=0.400, P=0.110). CPM status predicted changes in pain-related interference after controlling for the effects of treatment condition and psychosocial risk factors. Static measures of pain sensitivity (ie, 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 CPM may complement existing psychosocial risk measures in determining individualized pain-related risk profiles.

Core outcome set for pediatric chronic pain clinical trials: results from a Delphi poll and consensus meeting.

Appropriate outcome measures and high-quality intervention trials are critical to advancing care for children with chronic pain. Our aim was to update a core outcome set for pediatric chronic pain interventions. The first phase involved collecting providers', patients', and parents' perspectives about treatment of pediatric chronic pain to understand clinically meaningful outcomes to be routinely measured. The second phase was to reach consensus of mandatory and optional outcome domains following the OMERACT framework. A modified Delphi study with 2 rounds was conducted including 3 stakeholder groups: children with chronic pain (n = 93), their parents (n = 90), and health care providers who treat youth with chronic pain (n = 52). Quantitative and qualitative data from round 1 of the Delphi study were summarized to identify important outcomes, which were condensed to a list of 10 outcome domains. Round 2 surveys were analyzed to determine the importance of the 10 domains and their relative ranking in each stakeholder group. A virtual consensus conference was held with the steering committee to reach consensus on a set of recommended outcome domains for pediatric chronic pain clinical trials. It was determined, by unanimous vote, that pain severity, pain interference with daily living, overall well-being, and adverse events, including death, would be considered mandatory domains to be assessed in all trials of any type of intervention. Emotional functioning, physical functioning, and sleep were important but optional domains. Last, the research agenda identifies several important emerging areas, including biomarkers. Future work includes selecting appropriate validated measures to assess each outcome domain.

Does aerobic exercise training alter responses to opioid analgesics in individuals with chronic low back pain? A randomized controlled trial.

ABSTRACT: 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.