Deceptive and Non-deceptive Placebos to Reduce Pain – An Experimental Study in Healthy People Objectives: Recent research has shown that placebos are effective even if they are openly prescribed to participants. However, it is unclear how such “open-label placebos” (OLPs) compare to deceptive placebo (DP) and what the mechanisms of actions are. In this study, we therefore compared two versions of OLP to DP and no treatment (NT). Methods: Using a standard heat pain paradigm, 117 healthy volunteers underwent a baseline and post-treatment pain assessment. With the exception of NT, all groups received an inert placebo cream after the first assessment. OLP was administered by either evoking positive expectancies or by raising hope for placebo analgesia, thus distinguishing for the first time conceptually between expectancy and hope in experimental pain research. The primary outcome was pre-post change in pain tolerance. Results: Increase in pain tolerance was larger in the three treatment groups compared to NT, while the treatment groups did not differ from each other. Further results showed that participants receiving DP reported a large reduction of subjective pain intensity and unpleasantness, while no such reduction was found for the two OLP groups. The two OLP versions did not differ in terms of their analgesic effects. Discussion: The study provided evidence for traditional placebo analgesia based on deception. For OLP, we found that OLP indeed increased pain tolerance; however, participants receiving OLP were reluctant to report any subjective analgesic effects. Combined with previous studies, the present findings suggest that the effects of OLP are weaker in healthy volunteers than in clinical samples. The work received no funding from National Institutes of Health (NIH); Wellcome Trust; Howard Hughes Medical Institute (HHMI); or any other organization. Conflict of interest: The authors have no conflict of interest to declare. Reprints: Tobias Kube, PhD, University of Koblenz-Landau, Department of Clinical Psychology and Psychotherapy, Ostbahnstraße 10, D-76829 Landau, Germany (e-mail: kube@uni-landau.de). Received June 12, 2019 Received in revised form November 6, 2019 Accepted November 10, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Conditioned Pain Modulation in Chronic Low Back Pain: A Systematic Review of Literature Objective: The objective of the review is to determine whether conditioned pain modulation (CPM) is impaired in adults with chronic low back pain when compared to pain-free individuals. Methods: First a systematic search of the literature was undertaken using the databases: MEDLINE, Scopus, CINAHL and Web of Science. Second, the citations of included studies were reviewed for additional studies. Observational, cross-sectional, case-control studies published in English between January 1990 through August 2019 were considered. Studies that investigated the efficiency of standardized CPM regimens among defined cases of chronic low back pain and in comparison, with pain-free healthy controls were included. After initial title and abstract screening, two authors reviewed the full texts of the eligible articles independently. Risk of bias was carried out using assessment of four categories: blinding of the outcome assessors, representativeness of cases to the specified population, comparability of cases and controls and control of confounding variables. Results: In total, 643 records were identified, of which seven studies were included. Overall, the results of the studies reported mixed conclusions on the efficiency of CPM in chronic low back pain. Three studies identified significant differences for conditioned pain modulation between chronic low back pain and pain-free controls and the other four studies reported no significant differences. The common methodological limitations were unclear reporting about blinding of the outcome assessors and inadequate control of confounding factors. Conclusion: Further high-quality research is strongly recommended to determine the function of endogenous pain modulatory mechanisms in chronic low back pain. Conflict of Interest and Source of funding: None declared. Reprints: Y. V. Raghava Neelapala, MPT, Department of Physiotherapy, Manipal College of Health Professions, Manipal Academy of Higher Education, Karnataka, India- 576104 (e-mail: yv.raghava@manipal.edu). Received May 13, 2019 Received in revised form October 12, 2019 Accepted October 23, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Parents Reliably Identify Pain Dismissal by Pediatric Providers Objectives: Approximately 40% of children and adolescents with chronic pain report at least one dismissal experience, citing medical providers and parents as the primary and most distressing dismissers. Previous research indicates gender differences in pain dismissal experience and observer pain perception. This study examined parental reactions to dismissive provider-child scenarios and the influence of provider and patient gender on perceptions. Methods: Community parents (N=326) completed an online survey. Parents were randomized to listen to one of eight vignettes of a provider-child chronic pain scenario. Vignettes varied by type of scenario (appropriate vs. dismissive) X provider gender X patient gender. Results: Overall parents rated the dismissive scenario more negatively. There was a significant interaction between provider gender and scenario regarding likelihood to bring their own child to this provider and a significant three-way interaction regarding provider belief of the pain complaint. When asked how they would feel if this was their own child, parents who heard the dismissive scenario reported more negative reactions. When asked what they would say to the provider, parents in the dismissive condition were more likely to defend their child and request a second opinion. Discussion: Parents consistently identified dismissive language in a child and provider scenario. Female providers and gender-matched dyads seem to be more polarizing in terms of likelihood to bring their child to the provider and belief of pain, respectively. Providers within these groups may need to be especially cautious with their language when responding to pediatric chronic pain complaints. The authors declare no conflict of interest. Reprints: Eva Igler, MA, PO Box 413, Milwaukee, WI 53201 (e-mail: evaigler@uwm.edu). Received May 13, 2019 Received in revised form October 10, 2019 Accepted October 29, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Relationships between Psychological, Social, Physical Activity and Sleep Measures and Somatosensory Function in Individuals with Spinal Pain: A Systematic Review and Meta-analysis Objective: Somatosensory abnormalities are linked to clinical pain outcomes in individuals with spinal pain. However, a range of factors might confound the relationship between altered somatosensory function and clinical pain outcomes. This systematic review aimed to evaluate the literature to assess the level of evidence of associations between psychological, social, physical activity, and sleep measures and somatosensory function (assessed via sensory psychophysical testing) among individuals with spinal pain. Methods: A comprehensive literature search was conducted in six electronic databases from their inception to June 2018. Two reviewers independently assessed the methodological quality using a modified QUIPS tool and supplemented with recommendations from CHARMS checklist and QUADAS-2 tool. The level of evidence was assessed using the GRADE system. Data were pooled to evaluate the strength of the relationships of interest. Results: Among the 17 factors identified in the included studies, pain catastrophizing, depression, and pain-related fear have significant negative (small to fair) associations with pain thresholds. A “very low” to “moderate” quality of evidence was found for all the investigated factors. Subgroup analysis revealed a smaller effect size for pain catastrophizing/fear of movement and pain thresholds in individuals with LBP. Conclusion: Psychological factors are negatively associated with pain thresholds and they need to be adjusted when establishing predictive relationships between somatosensory function and pain outcomes in individuals with spinal pain. Conflicts of Interest and Source of Funding: The authors have no conflict of interest to declare. Rani Othman had received a doctoral scholarship from King Abdulaziz University to pursue PhD studies at the School of Physiotherapy, University of Otago. Reprints: Rani Othman, MPhty, Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand (e-mail: rani.othman@postgrad.otago.ac.nz). Received April 7, 2019 Received in revised form October 1, 2019 Accepted October 23, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Effects of Adding Oxycodone to Ropivacaine on Labor Analgesia: A Randomized Controlled Trial Background: It has been reported that oxycodone is superior to the other opioids for the treatment of visceral pain. During the first stage of labor, pain is mainly caused by uterine contractions (visceral pain). It appears that oxycodone is more suitable for labor analgesia. During this study, we investigated the effects of adding oxycodone to ropivacaine on epidural analgesia during labor. Methods: Eighty nulliparous parturients were randomly divided into two groups. Group A received 0.2▒mg/mL oxycodone plus 0.1% ropivacaine for epidural analgesia and Group C (control group) received 0.1% ropivacaine alone for epidural analgesia. The onset time and duration of analgesia, duration of labor stages, delivery outcome, analgesic effect, Bromage scores, blood pressure, heart rate and neonatal Apgar scores were recorded. Umbilical arterial blood was collected to analyze. Side effects, if any, were also recorded. Results: The visual analogue scale (VAS) of pain was lower at 2 h and 4 h after analgesia, and 10▒cm cervical dilatation in group A compared to group C (P=0.021, P=0.018, and P=0.009, respectively). The onset time of analgesia was shorter in group A than that in group C (13.3±2.8 vs. 14.9±3.6▒min, P=0.032). There were no significant differences between the two groups in terms of the duration of labor stages, delivery outcome, Bromage score, neonatal Apgar score and umbilical arterial blood pH. The duration of analgesia was significantly longer in group A than in group C (326.2±56.5 vs. 68.4±10.5▒min, P=0.000), but the incidence of pruritus was higher in group A than in group C (10% vs. 0%, P=0.115). Conclusions: This study demonstrates that epidural oxycodone may accelerate the onset of analgesia and obviously prolong the duration of analgesia during labor without increasing adverse effects associated with the neonate. However, it may cause a higher incidence of maternal pruritus. (Registration number: ChiCTR1800016483). Trial registration: Registered at http://www.chictr.org.cn, registration number: ChiCTR1800016483. Fund was supported: No. Author contributions: Z.Y acquired the data, C.S designed the trial and analyzed the data, Z.H and Z.W drafted the manuscript. Conflicts of interest: None declared. Reprints: W. Zhang, MD, Department of Anesthesiology, Maternity and Child Health Hospital of Jiaxing university, jiaxing 314000, China (e-mail: zhang650679@163.com). Received March 16, 2019 Received in revised form October 22, 2019 Accepted October 29, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The Benefit of Dexmedetomidine on Postoperative Cognitive Function is Unrelated to the Modulation on Peripheral Inflammation: A Single Center, Prospective, Randomized Study Background: Dexmedetomidine potentially confers advantage to reduce the incidence of postoperative delirium in surgical patients. Anti-inflammation is another remarkable effect of this sedative drug. In this study, we aimed to investigate whether the effect of dexmedetomidine on the postoperative cognitive function is via inhibiting peripheral inflammation. Methods: A prospective, randomized controlled study was conducted with patients 65 years of age or older who received total knee hip arthroplasty from January 2019 to May 2019. The patients were randomly assigned to receive a spinal anesthesia supplemented with propofol or dexmedetomidine for sedation. Incidence of postoperative delirium was the primary endpoint and was determined with the Confusion Assessment Method, and incidence of postoperative cognitive dysfunction was assessed with the Mini-Mental State Examination. Blood samples were collected postoperatively to test the plasma concentrations of IL-6, TNF-α and S100β. Results: 366 patients were randomly assigned to two groups. Patients received dexmedetomidine sedation had lower incidences of postoperative delirium and better postoperative cognitive function than the patients sedated with propofol. There was no difference in postoperative plasma concentrations of TNF-α and IL-6 between the two groups. The concentration of S100β at 48 hours after surgery was higher in patients sedated with propofol than patients received dexmedetomidine sedation. Conclusion: Intraoperative sedation with dexmedetomidine conferred better postoperative neurocognitive function for elderly patients received total knee hip arthroplasty. This effect was unrelated to the modulation of dexmedetomidine on peripheral inflammation. Sources of support that require acknowledgment: This work was supported by the National Natural Science Foundation of China (81171031, 81571039 and 81870837). Conflicts of interest: Dr. Bin Mei and Dr. Guanghong Xu contributed equally to this study. Reprints: Xuesheng Liu, MD, PhD, Department of anesthesiology, the first affiliated hospital of Anhui medical university, Hefei city, Anhui province, China, No. 218 Jixi road, Hefei city, Anhui province, China. Postcode: 230032 (e-mail: liuxuesheng@ahmu.edu.cn). Received May 30, 2019 Received in revised form October 12, 2019 Accepted October 20, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Illusion-enhanced Virtual Reality Exercise for Neck Pain: A Replicated Single Case Series Objectives: Body illusions have shown promise in treating some chronic pain conditions. We hypothesised that neck exercises performed in virtual reality (VR) with visual feedback of rotation amplified, would reduce persistent neck pain. Methods: In a multiple-baseline replicated single case series, 8 blinded individuals with persistent neck pain completed a four-phase intervention (initial n=12, 4 dropouts): A. “Baseline”; B. “VR” during which participants performed rotation exercises in virtual reality with no manipulation of visual feedback, C. “VR-enhanced” during which identical exercises were performed but visual feedback overstated the range of motion being performed; D. “Follow-up”. Primary outcomes were twice-daily measures of pain-free range of motion and pain intensity. During the baseline and follow-up phases, measures were taken but no intervention took place. Results: No differences in primary outcomes were found between VR and Baseline, VR-enhanced and VR, or VR-enhanced and Follow-up. Discussion: Our hypothesis, that neck exercises performed in VR with visual feedback of rotation amplified, would reduce persistent neck pain was not supported. Possible explanations and future directions are discussed. Author contributions: Daniel S. Harvie, Michele Sterling, Ross T. Smith, A. Meulders and G. Lorimer Moseley conceived and designed the experiment, wrote the paper, and reviewed drafts of the paper. Daniel S. Harvie, A. Meulders, and B. Michiels analysed the data and prepared the figures and tables. The data were collected by Daniel S. Harvie. Software was written and provided by Ross T. Smith. Conflicts of Interest and Source of Funding: This project is supported by the Physiotherapy Research Foundation and a Griffith University and University of South Australia Collaboration Grant. DSH is supported by an Early Career Research Fellowship from the National Health and Medical Research Council of Australia. GLM is supported by a Principal Research Fellowship from the National Health and Medical Research Council of Australia. In the last 5 years, GLM has received support from: Seqiris, Kaiser Permanente, Workers’ Compensation Boards in Australia, Europe and North America, AIA Australia, the International Olympic Committee, Port Adelaide Football Club and Arsenal Football Club. Professional and scientific bodies have reimbursed him for travel costs related to presentation of research on pain at scientific conferences/symposia. He has received speaker fees for lectures on pain and rehabilitation. He receives book royalties from NOIgroup publications, Dancing Giraffe Press & OPTP. DSH and RTS are exploring opportunities to create and commercialize therapeutic applications of virtual reality. The contribution of AM is supported by a Senior Research Fellowship of the Research Foundation Flanders (FWO-Vlaanderen), Belgium, (grant ID 12E3717N) and by a Vidi grant from the Netherlands Organization for Scientific Research (NWO), The Netherlands (grant ID 452-17-002). The contribution of BM is supported by a project grant of the Research Foundation Flanders (FWO-Vlaanderen), Belgium, (grant ID G059314N). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Reprints: Daniel Harvie, PhD, Griffith University, Gold Coast Campus, Southport QLD 4222 (e-mail: d.harvie@griffith.edu.au). Received April 14, 2019 Received in revised form September 24, 2019 Accepted October 29, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Does Repeated Painful Stimuli Change Cerebral Near-infrared Spectroscopy Response in Healthy Term Large for Gestational Age Newborns? Objective: To evaluate the effect of repeated painful stimuli on short-term pain response in healthy, term, large for gestational age (LGA) newborns by measuring the regional cerebral oxygen saturation (rScO2), behavioral and physiological responses. Methods: We compared term LGA infants who received repeated painful stimuli (study group) to term, appropriate for gestational age (AGA) infants (control group). A pulse oximeter and a near-infrared spectroscopy probes were connected to babies during the study period and babies were recorded by video, from which the crying time, and Neonatal Infant Pain Scale (NIPS), were obtained. The heart rate (HR), peripheral oxygen saturation (SpO2) and rScO2 data were sampled every 1 second and exported to a personal computer via digital output during the study period. The maximum HR, the minimum SpO2, peak, baseline and mean rScO2 measurements following skin puncture were recorded. Data was compared within one group and between the two groups. Results: After the heel prick, crying time (P<0.001) and NIPS scores (P=0.024) increased and SpO2 levels decreased significantly (P=0.012) in the study group versus the control group. Although mean rScO2 increased significantly within one group (P<0.001), it was not significant between the two groups. The percent change in rScO2 was greater in the study group [5.2 (2.5-9.3)] compared to the control group [2.8(1.1-8.2), P=0.037)]. Conclusion: We showed that rScO2 values changed significantly within the first few days of life in babies who received more painful stimuli compared to the control group, similar to behavioral and physiological responses. Abbrevations: AGA, (appropriate for gestational age); LGA, (large for gestational age); NIPS, (neonatal infant pain scale); NIRS, (near-infrared spectroscopy); rScO2, (regional cerebral oxygen saturation); SpO2, (peripheral oxygen saturation). Funding: The authors have no funding to declare. Acknowledgement: We would like to thank Professor Dilsat Save for helping us with the statistical analysis. Conflicts of Interest: The authors have no conflict of interests to declare. Reprints: Hulya Ozdemir, MD, in Neonatology, Department of Pediatrics, Division of Neonatology, Marmara University Faculty of Medicine, Fevzi Cakmak Mah. Sinan Cad. No:41 Ust Kaynarca Pendik, Istanbul,Turkey (e-mail: hulyazeynep@yahoo.com). Received January 3, 2019 Received in revised form August 27, 2019 Accepted September 30, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Interpersonal Dyadic Influences of Pain Catastrophizing Between Caregivers and Children with Chronic Pain Objectives: Pain catastrophizing is an important predictor of pain-related outcomes. Caregiver and child levels of catastrophizing about child chronic pain are associated cross-sectionally, yet predictive associations testing interpersonal influences within caregiver-child dyads are lacking. The present study tested caregiver and child influences on partner catastrophizing about child pain over 1 month following initiation of interdisciplinary pain treatment and examined whether change in pain catastrophizing was associated with child pain interference. Methods: 113 caregiver-child dyads (Mage=14.41) completed measures at the time of initiating care at a pediatric tertiary outpatient pain management clinic (baseline) and approximately 1 month later. Caregivers and children independently reported on catastrophizing about child pain and child pain interference at baseline and 1 month follow up. Results: Caregiver and child pain catastrophizing decreased over 1 month following initial interdisciplinary pain evaluation, with average scores remaining in the moderate to high range. Change in caregiver, but not child, catastrophizing about child pain was predicted by partner baseline pain catastrophizing. Decreases in catastrophizing about child pain were associated with within person improvement in ratings of child pain interference. Discussion: In the short period following initial pain evaluation, caregivers and children evidenced reductions in pain catastrophizing, which were associated with increased child function. Findings highlight the important role of child cognitive-affective responses to pain in influencing caregiver catastrophizing about child pain. Understanding the individual contributions children and caregivers make to interpersonal pain processes will inform future family-level clinical interventions. Funding: This investigation was supported by funding from the William and Gretchen Kimball Endowment for Pediatric Pain Management. Conflicts: None reported. Reprints: Delana Parker, PhD, Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, School of Medicine (e-mail: dmparker@ucla.edu). Received March 6, 2019 Received in revised form July 31, 2019 Accepted September 20, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Parental Proxy PROMIS Pain Interference Scores are only Modestly Concordant with their Child’s Scores: An Effect of Child Catastrophizing Objectives: Pediatric patients with chronic musculoskeletal conditions such as idiopathic scoliosis awaiting surgical correction can experience pain that interferes with their daily functioning. Reports of this interference are commonly gathered from patients through the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Scale and through parent-proxy scores. However, the child and parent/caregiver reports vary. In order to provide appropriate treatment for young patients with pain, the nature of the discrepancies and under which circumstances the reports differ needs to be understood. This report offers new information on the level of concordance among parent and child report of pain interference within this patient population, and which parent and child characteristics may influence concordance rates. Methods: Patients (age=10-17▒y) with a history of musculoskeletal disorders, including idiopathic scoliosis, under consideration for surgical correction of that scoliosis and parent/caregiver dyads (n=103) completed the PROMIS Pain Interference Scale during an orthopedic pre-surgical visit. The current data was taken from a larger study examining post-surgical pain among patients undergoing orthopedic surgical procedures to correct scoliosis. The purpose of the current study was to measure the degree of agreement between parent and child reports of pain interference and discovery of relationships among predictors of pain interference score correspondence among dyads. Results: Correspondence between parent/caregiver and child reports of pain interference was modest (Intra-class correlation=0.530). 46% of dyads had similar pain interference scores, while 24% of parents reported higher pain interference in comparison to their child, the remaining 30% reported lower pain interference in relation to their child’s report. Among patients where discrepancies appeared, using logistic regression models, only child catastrophizing scores were associated with differences in parent and child estimation of child’s pain interference scores. No parental characteristics predicted discrepancies between dyad pain interference reports. Discussion: Parent-proxy and child reports generally correspond, but when discrepant, 24% of parents reported higher pain interference in relationship to the child report of pain interference and 31% noted less intense pain interference than their child’s pain interference. Given these results, care should be taken when interpreting parent reports of child pain interference, especially when a child reports higher degrees of pain interference. Institutional Review Board Approval obtained from the Institutional Review Boards of the University of Michigan Medical School (IRBMED); 2800 Plymouth Road, Building 520, Room 3214, Ann Arbor, MI 48109-2800; Phone: 734-763-4768; Approval ID: HUM00086972. Funding and Disclosures: No external funding supported this work and no conflicts of interest. Reprints: Eric L. Scott, PhD, Department of Pediatrics, D2234 MPB, 1500 East Medical Ctr. Dr., SPC 5718, Ann Arbor, MI 48109-5718 (e-mail: erlscott@med.umich.edu). Received February 4, 2019 Received in revised form September 10, 2019 Accepted September 30, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.