Innovations and advances in modelling and measuring pain in animals.

Best practices in preclinical algesiometry (pain behaviour testing) have shifted over the past decade as a result of technological advancements, the continued dearth of translational progress and the emphasis that funding institutions and journals have placed on rigour and reproducibility. Here we describe the changing trends in research methods by analysing the methods reported in preclinical pain publications from the past 40 years, with a focus on the last 5 years. We also discuss how the status quo may be hampering translational success. This discussion is centred on four fundamental decisions that apply to every pain behaviour experiment: choice of subject (model organism), choice of assay (pain-inducing injury), laboratory environment and choice of outcome measures. Finally, we discuss how human tissues, which are increasingly accessible, can be used to validate the translatability of targets and mechanisms identified in animal pain models.

AGA Clinical Practice Update on Pain Management in Inflammatory Bowel Disease: Commentary.

DESCRIPTION: Pain is a common symptom among patients with inflammatory bowel disease (IBD). Although pain typically occurs during episodes of inflammation, it is also commonly experienced when intestinal inflammation is quiescent. Many gastroenterologists are at a loss how to approach pain symptoms when they occur in the absence of gut inflammation. We provide guidance in this area as to the evaluation, diagnosis, and treatment of pain among patients with IBD. METHODS: This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. This expert commentary incorporates important as well as recently published studies in this field, and it reflects the experiences of the authors. Formal ratings regarding the quality of evidence or strength of the presented considerations were not included because systematic reviews were not performed.

A multistudy analysis reveals that evoked pain intensity representation is distributed across brain systems.

Information is coded in the brain at multiple anatomical scales: locally, distributed across regions and networks, and globally. For pain, the scale of representation has not been formally tested, and quantitative comparisons of pain representations across regions and networks are lacking. In this multistudy analysis of 376 participants across 11 studies, we compared multivariate predictive models to investigate the spatial scale and location of evoked heat pain intensity representation. We compared models based on (a) a single most pain-predictive region or resting-state network; (b) pain-associated cortical-subcortical systems developed from prior literature ("multisystem models"); and (c) a model spanning the full brain. We estimated model accuracy using leave-one-study-out cross-validation (CV; 7 studies) and subsequently validated in 4 independent holdout studies. All spatial scales conveyed information about pain intensity, but distributed, multisystem models predicted pain 20% more accurately than any individual region or network and were more generalizable to multimodal pain (thermal, visceral, and mechanical) and specific to pain. Full brain models showed no predictive advantage over multisystem models. These findings show that multiple cortical and subcortical systems are needed to decode pain intensity, especially heat pain, and that representation of pain experience may not be circumscribed by any elementary region or canonical network. Finally, the learner generalization methods we employ provide a blueprint for evaluating the spatial scale of information in other domains.

Optimal pain management for patients with cancer in the modern era.

Pain is a common symptom among patients with cancer. Adequate pain assessment and management are critical to improve the quality of life and health outcomes in this population. In this review, the authors provide a framework for safely and effectively managing cancer-related pain by summarizing the evidence for the importance of controlling pain, the barriers to adequate pain management, strategies to assess and manage cancer-related pain, how to manage pain in patients at risk of substance use disorder, and considerations when managing pain in a survivorship population. CA Cancer J Clin 2018;68:182-196. © 2018 American Cancer Society.

How side effects can improve treatment efficacy: a randomized trial.

While treatment side effects may adversely impact patients, they could also potentially function as indicators for effective treatment. In this study, we investigated whether and how side effects can trigger positive treatment expectations and enhance treatment outcomes. In this pre-registered trial (DRKS00026648), 77 healthy participants were made to believe that they will receive fentanyl nasal sprays before receiving thermal pain in a controlled experimental setting. However, nasal sprays did not contain fentanyl, rather they either contained capsaicin to induce a side effect (mild burning sensation) or saline (inert). After the first session, participants were randomized to two groups and underwent functional MRI. One group continued to believe that the nasal sprays could contain fentanyl while the other group was explicitly informed that no fentanyl was included. This allowed for the independent manipulation of the side effects and the expectation of pain relief. Our results revealed that nasal sprays with a side effect lead to lower pain than inert nasal sprays without side effects. The influence of side effects on pain was dependent on individual beliefs about how side effects are related to treatment outcome, as well as on expectations about received treatment. Functional MRI data indicated an involvement of the descending pain modulatory system including the anterior cingulate cortex and the periaqueductal gray during pain after experiencing a nasal spray with side effects. In summary, our data show that mild side effects can serve as a signal for effective treatment thereby influencing treatment expectations and outcomes, which is mediated by the descending pain modulatory system. Using these mechanisms in clinical practice could provide an efficient way to optimize treatment outcome. In addition, our results indicate an important confound in clinical trials, where a treatment (with potential side effects) is compared to placebo.

Temporal-spectral signaling of sensory information and expectations in the cerebral processing of pain.

The perception of pain is shaped by somatosensory information about threat. However, pain is also influenced by an individual's expectations. Such expectations can result in clinically relevant modulations and abnormalities of pain. In the brain, sensory information, expectations (predictions), and discrepancies thereof (prediction errors) are signaled by an extended network of brain areas which generate evoked potentials and oscillatory responses at different latencies and frequencies. However, a comprehensive picture of how evoked and oscillatory brain responses signal sensory information, predictions, and prediction errors in the processing of pain is lacking so far. Here, we therefore applied brief painful stimuli to 48 healthy human participants and independently modulated sensory information (stimulus intensity) and expectations of pain intensity while measuring brain activity using electroencephalography (EEG). Pain ratings confirmed that pain intensity was shaped by both sensory information and expectations. In contrast, Bayesian analyses revealed that stimulus-induced EEG responses at different latencies (the N1, N2, and P2 components) and frequencies (alpha, beta, and gamma oscillations) were shaped by sensory information but not by expectations. Expectations, however, shaped alpha and beta oscillations before the painful stimuli. These findings indicate that commonly analyzed EEG responses to painful stimuli are more involved in signaling sensory information than in signaling expectations or mismatches of sensory information and expectations. Moreover, they indicate that the effects of expectations on pain are served by brain mechanisms which differ from those conveying effects of sensory information on pain.

Low-dose ketamine safely reduces acute pain in the ED with a more rapid and shorter effect than morphine.

SOURCE CITATION: Guo J, Zhao F, Bian J, et al. Low-dose ketamine versus morphine in the treatment of acute pain in the emergency department: a meta-analysis of 15 randomized controlled trials. Am J Emerg Med. 2024;76:140-149. 38071883.

Extracorporeal Shock-Wave Lithotripsy and Endoscopy for the Treatment of Pain in Chronic Pancreatitis : A Sham-Controlled, Randomized Trial.

BACKGROUND: No randomized controlled trials have substantiated endoscopic decompression of the pancreatic duct in patients with painful chronic pancreatitis. OBJECTIVE: To investigate the pain-relieving effect of pancreatic duct decompression in patients with chronic pancreatitis and intraductal stones. DESIGN: 24-week, parallel-group, randomized controlled trial (ClinicalTrials.gov: NCT03966781). SETTING: Asian Institute of Gastroenterology in India from February 2021 to July 2022. PARTICIPANTS: 106 patients with chronic pancreatitis. INTERVENTION: Combined extracorporeal shock-wave lithotripsy (ESWL) and endoscopic retrograde pancreatography (ERP) compared with sham procedures. MEASUREMENTS: The primary end point was pain relief on a 0- to 10-point visual analog scale (VAS) at 12 weeks. Secondary outcomes were assessed after 12 and 24 weeks and included 30% pain relief, opioid use, pain-free days, questionaries, and complications to interventions. RESULTS: 52 patients in the ESWL/ERP group and 54 in the sham group were included. At 12 weeks, the ESWL/ERP group showed better pain relief compared with the sham group (mean difference in change, -0.7 [95% CI, -1.3 to 0] on the VAS; P = 0.039). The difference between groups was not sustained at the 24-week follow-up, and no differences were seen for 30% pain relief at 12- or 24-week follow-up. The number of pain-free days was increased (median difference, 16.2 days [CI, 3.9 to 28.5 days]), and the number of days using opioids was reduced (median difference, -5.4 days [CI, -9.9 to -0.9 days]) in the ESWL/ERP group compared with the sham group at 12-week follow-up. Safety outcomes were similar between groups. LIMITATION: Single-center study and limited duration of follow-up. CONCLUSION: In patients with chronic pancreatitis and intraductal stones, ESWL with ERP provided modest short-term pain relief. PRIMARY FUNDING SOURCE: Asian Institute of Gastroenterology and Aalborg University Hospital.

Celiac plexus radiosurgery for pain management in advanced cancer: a multicentre, single-arm, phase 2 trial.

BACKGROUND: Refractory upper abdominal pain or lower back pain (retroperitoneal pain syndrome) related to celiac plexus involvement characterises pancreatic and other upper gastrointestinal malignancies and is an unmet need. We hypothesised that ablative radiation delivered to the celiac plexus would decrease pain. METHODS: This multicentre, single-arm, phase 2 study was done at eight hospitals in five countries (Israel, Poland, Canada, the USA, and Portugal). Eligible patients aged 18 years or older with an average pain level of 5-10 on the Brief Pain Inventory short form (BPI-SF), an Eastern Cooperative Oncology Group performance status score of 0-2, and either pancreatic cancer or other tumours involving the celiac axis, received a single fraction of 25 Gy of external-beam photons to the celiac plexus. The primary endpoint was complete or partial pain response based on a reduction of the BPI-SF average pain score of 2 points or more from baseline to 3 weeks after treatment. All evaluable patients with stable pain scores were included in response assessment. The trial is registered with ClinicalTrials.gov, NCT03323489, and is complete. FINDINGS: Between Jan 3, 2018, and Dec 28, 2021, 125 patients were treated, 90 of whom were evaluable. Patients were followed up until death. Median age was 65·5 years (IQR 58·3-71·8), 50 (56%) were female and 40 (44%) were male, 83 (92%) had pancreatic cancer, and 77 (86%) had metastatic disease. Median baseline BPI-SF average pain score was 6 (IQR 5-7). Of the 90 evaluable patients at 3 weeks, 48 (53%; 95% CI 42-64) had at least a partial pain response. The most common grade 3-4 adverse events, irrespective of attribution, were abdominal pain (35 [28%] of 125) and fatigue (23 [18%]). 11 serious adverse events of grade 3 or worse were recorded. Two grade 3 serious adverse events were probably attributed to treatment by the local investigators (abdominal pain [n=1] and nausea [n=1]), and nine were possibly attributed to treatment (seven were grade 3: blood bilirubin increased [n=1], duodenal haemorrhage [n=2], abdominal pain [n=2], and progressive disease [n=2]; and two were grade 5: gastrointestinal bleed from suspected varices 24 days after treatment [n=1] and progressive disease [advanced pancreatic cancer] 89 days after treatment [n=1]). INTERPRETATION: Celiac plexus radiosurgery could potentially be a non-invasive palliative option for patients with retroperitoneal pain syndrome. Further investigation by means of a randomised comparison with conventional celiac block or neurolysis is warranted. FUNDING: Gateway for Cancer Research and the Israel Cancer Association.

PROCESS Trial: Effect of Duloxetine Premedication for Postherpetic Neuralgia Within 72 Hours of Herpes Zoster Reactivation-A Randomized Controlled Trial.

BACKGROUND: Postherpetic neuralgia (PHN) is the most common chronic complication of herpes zoster (HZ) and results in severe refractory neuropathic pain. This study aimed at evaluating the efficacy of premedication with duloxetine in the prevention of PHN. METHODS: The PROCESS trial is a multicenter, randomized, open-label, blinded-endpoint trial used a 1:1 duloxetine:control ratio. Adults 50 years or older with HZ who presented with vesicles within 72 hours were recruited. The primary outcome was the incidence of PHN at 12 weeks. PHN was defined as any pain intensity score other than 0 mm on the visual analog scale (VAS) at week 12 after the onset of the rash. The secondary outcomes were the number of participants with VAS >0 and VAS ≥3. The modified intention-to-treat (mITT) principle and per-protocol (PP) principle were used for the primary outcome analysis. RESULTS: A total of 375 participants were randomly assigned to the duloxetine group and 375 were assigned to the control group. There was no significant difference in the incidence of PHN in the duloxetine group compared with the control group in the mITT analysis (86 [22.9%] of 375 vs 108 [28.8%] of 375; P = .067). PP analysis produced similar results. However, there were significant differences between the 2 groups in the number of participants with VAS >0 and VAS ≥3 (P < .05 for all comparisons). CONCLUSIONS: Although absolute prevention of PHN does not occur, this trial found that premedication with duloxetine can reduce pain associated with HZ, and therefore can have clinically relevant benefits. Clinical Trials Registration. Clinicaltrials.gov, NCT04313335. Registered on 18 March 2020.

Pain quality patterns in delayed onset muscle soreness of the lower back suggest sensitization of fascia rather than muscle afferents: a secondary analysis study.

Delayed onset muscle soreness (DOMS) of the lower back is considered a surrogate for acute low back pain (aLBP) in experimental studies. Of note, it is often unquestioningly assumed to be muscle pain. To date, there has not been a study analyzing lumbar DOMS in terms of its pain origin, which was the aim of this study. Sixteen healthy individuals (L-DOMS) were enrolled for the present study and matched to participants from a previous study (n = 16, L-PAIN) who had undergone selective electrical stimulation of the thoracolumbar fascia and the multifidus muscle. DOMS was induced in the lower back of the L-DOMS group using eccentric trunk extensions performed until exhaustion. On subsequent days, pain on palpation (100-mm analogue scale), pressure pain threshold (PPT), and the Pain Sensation Scale (SES) were used to examine the sensory characteristics of DOMS. Pain on palpation showed a significant increase 24 and 48 h after eccentric training, whereas PPT was not affected (p > 0.05). Factor analysis of L-DOMS and L-PAIN sensory descriptors (SES) yielded a stable three-factor solution distinguishing superficial thermal ("heat pain ") from superficial mechanical pain ("sharp pain") and "deep pain." "Heat pain " and "deep pain" in L-DOMS were almost identical to sensory descriptors from electrical stimulation of fascial tissue (L-PAIN, all p > 0.679) but significantly different from muscle pain (all p < 0.029). The differences in sensory description patterns as well as in PPT and self-reported DOMS for palpation pain scores suggest that DOMS has a fascial rather than a muscular origin.

Concomitant use of pre-emptive analgesia with local and general anesthesia in rat uterine pain surgical model.

Preemptive analgesia is used for postoperative pain management, providing pain relief with few adverse effects. In this study, the effect of a preemptive regime on rat behavior and c-fos expression in the spinal cord of the uterine surgical pain model was evaluated. It was a lab-based experimental study in which 60 female Sprague-Dawley rats; eight to 10 weeks old, weighing 150-300 gm were used. The rats were divided into two main groups: (i) superficial pain group (SG) (with skin incision only), (ii) deep pain group (with skin and uterine incisions). Each group was further divided into three subgroups based on the type of preemptive analgesia administered i.e., "tramadol, buprenorphine, and saline subgroups." Pain behavior was evaluated using the "Rat Grimace Scale" (RGS) at 2, 4, 6, 9 and 24 h post-surgery. Additionally, c-fos immunohistochemistry was performed on sections from spinal dorsal horn (T12-L2), and its expression was evaluated using optical density and mean cell count 2 hours postoperatively. Significant reduction in the RGS was noted in both the superficial and deep pain groups within the tramadol and buprenorphine subgroups when compared to the saline subgroup (p ≤ .05). There was a significant decrease in c-fos expression both in terms of number of c-fos positive cells and the optical density across the superficial laminae and lamina X of the spinal dorsal horn in both SD and DG (p ≤ .05). In contrast, the saline group exhibited c-fos expression primarily in laminae I-II and III-IV for both superficial and deep pain groups and lamina X in the deep pain group only (p ≤ .05). Hence, a preemptive regimen results in significant suppression of both superficial and deep components of pain transmission. These findings provide compelling evidence of the analgesic efficacy of preemptive treatment in alleviating pain response associated with uterine surgery.

Oral resveratrol in adults with knee osteoarthritis: A randomized placebo-controlled trial (ARTHROL).

BACKGROUND: Resveratrol is a natural compound found in red wine. It has demonstrated anti-inflammatory properties in preclinical models. We compared the effect of oral resveratrol in a new patented formulation to oral placebo for individuals with painful knee osteoarthritis. METHODS AND FINDINGS: ARTHROL was a double-blind, randomized, placebo-controlled, Phase 3 trial conducted in 3 tertiary care centers in France. We recruited adults who fulfilled the 1986 American College of Rheumatology criteria for knee osteoarthritis and reported a pain intensity score of at least 40 on an 11-point numeric rating scale (NRS) in 10-point increments (0, no pain, to 100, maximal pain). Participants were randomly assigned (1:1) by using a computer-generated randomization list with permuted blocks of variable size (2, 4, or 6) to receive oral resveratrol (40 mg [2 caplets] twice a day for 1 week, then 20 mg [1 caplet] twice a day; resveratrol group) or matched oral placebo (placebo group) for 6 months. The primary outcome was the mean change from baseline in knee pain on a self-administered 11-point pain NRS at 3 months. The trial was registered at ClinicalTrials.gov: (NCT02905799). Between October 20, 2017 and November 8, 2021, we assessed 649 individuals for eligibility, and from November 9, 2017, we recruited 142 (22%) participants (mean age 61.4 years [standard deviation (SD) 9.6] and 101 [71%] women); 71 (50%) were randomly assigned to the resveratrol group and 71 (50%) to the placebo group. At baseline, the mean knee pain score was 56.2/100 (SD 13.5). At 3 months, the mean reduction in knee pain was -15.7 (95% confidence interval (CI), -21.1 to -10.3) in the resveratrol group and -15.2 (95% CI, -20.5 to -9.8) in the placebo group (absolute difference -0.6 [95% CI, -8.0 to 6.9]; p = 0.88). Serious adverse events (not related to the interventions) occurred in 3 (4%) in the resveratrol group and 2 (3%) in the placebo group. Our study has limitations in that it was underpowered and the effect size, estimated to be 0.55, was optimistically estimated. CONCLUSIONS: In this study, we observed that compared with placebo, oral resveratrol did not reduce knee pain in people with painful knee osteoarthritis. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02905799.

Virtual reality for pain management in hospitalized patients with cancer: A randomized controlled trial.

BACKGROUND: Hospitalized patients with cancer often experience acute and/or chronic pain. Although virtual reality (VR) has been extensively studied across a wide range of clinical settings, no studies have yet evaluated potential impact on pain management in this patient population. METHODS: Prospective randomized controlled trial at an urban academic hospital comparing VR against an active control to mitigate moderate-severe cancer disease and treatment-related pain. RESULTS: A total of 128 adult hospitalized patients with cancer (any tumor type) were randomized to 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy delivered by handheld tablet. Participants in the two arms were similar in age, sex, race, presence of metastatic disease, concurrent pain specialist consultation, and baseline opioid use. Although both groups experienced improved self-reported pain scores (primary outcome), those randomized to VR experienced significantly greater reduction in pain immediately after intervention compared with active control (p = .03). This difference was sustained for 24 hours as well (p = .004). Within-group analysis showed significant improvement in VR arm of pain bothersomeness (p = .05) and general distress (p = .03) as well. CONCLUSION: Among hospitalized adult patients with moderate-severe pain related to cancer and cancer therapies, VR provided more nonpharmacologic pain relief than active control and this benefit sustained long after conclusion of the intervention. PLAIN LANGUAGE SUMMARY: Virtual reality (VR), a developing technology that immerses the user in new environments, has been shown to improve pain in different patient populations. To test the role of VR in improving pain in hospitalized patients with cancer who report moderate-severe pain, we compared the impact of a 10-minute immersive VR intervention to that of a 10-minute two-dimensional guided imagery experience to improve self-reported pain scores. We found that, although both interventions improved pain, VR did so significantly more. Moreover, participants assigned to VR had sustained improvement in pain 24 hours later.

Dose-intensified stereotactic body radiotherapy for painful vertebral metastases: A randomized phase 3 trial.

BACKGROUND: The purpose of this randomised study was to determine whether dose-intensified stereotactic body radiotherapy (SBRT) for painful vertebral metastases results in increased rates of pain improvement compared with conventional external beam radiotherapy (cEBRT) (control) 6 months after treatment. METHODS: This randomized, controlled phase 3 trial was conducted between November 2016 and January 2023, when it was stopped early. Patients were eligible if they were aged 18 years or older; had one or two painful, stable, or potentially unstable vertebral metastases; and had a life expectancy of 1 year or longer according to the investigator's estimates. Patients received 48.5 grays (Gy) in 10 fractions (with epidural involvement) or 40 Gy in five fractions (without epidural involvement) in the SBRT group and 30 Gy in 10 fractions or 20 Gy in five fractions in the cEBRT group, respectively. The primary end point was an improvement in the pain score at the treated site by at least 2 points (on a visual analog scale from 0 to 10 points) at 6-month follow-up. Data were analyzed on an intention-to-treat and per-protocol basis. RESULTS: Of 214 patients who were screened for eligibility, 63 were randomized 1:1 between SBRT (33 patients with 36 metastases) and cEBRT (30 patients with 31 metastases). The median age of all patients was 66 years, and 40 patients were men (63.5%). In the intention-to-treat analysis, the 6-month proportion of patients who had metastases with pain reduction by 2 or more points was significantly higher in the SBRT group versus the control group (69.4% vs. 41.9%, respectively; two-sided p = .02). Changes in opioid medication intake relative to baseline were nonsignificant between the groups. No differences were observed in vertebral compression fracture or adverse event rates between the groups. CONCLUSIONS: Dose-intensified SBRT improved pain score more effectively than cEBRT at 6 months.

Effect of Lower Extremity Nerve Decompression in Patients With Painful Diabetic Peripheral Neuropathy: The Diabetic Neuropathy Nerve Decompression Randomized, Observation Group and Placebo Surgery-Controlled Clinical Trial.

OBJECTIVE: To evaluate the effect of nerve decompression on pain in patients with lower extremity painful diabetic peripheral neuropathy (DPN). BACKGROUND: Currently, no treatment provides lasting relief for patients with DPN. The benefits of nerve decompression remain inconclusive. METHODS: This double-blinded, observation and same-patient sham surgery-controlled randomized trial enrolled patients aged 18 to 80 years with lower extremity painful DPN who failed 1 year of medical treatment. Patients were randomized to nerve decompression or observation group (2:1). Decompression-group patients were further randomized and blinded to nerve decompression in either the right or left leg and sham surgery in the opposite leg. Pain (11-point Likert score) was compared between decompression and observation groups and between decompressed versus sham legs at 12 and 56 months. RESULTS: Of 2987 screened patients, 78 were randomized. At 12 months, compared with controls (n=37), both the right-decompression group (n=22) and left-decompression group (n=18) reported lower pain (mean difference for both: -4.46; 95% CI: -6.34 to -2.58 and -6.48 to -2.45, respectively; P < 0.0001). Decompressed and sham legs equally improved. At 56 months, compared with controls (n=m 14), pain was lower in both the right-decompression group (n=20; mean difference: -7.65; 95% CI: -9.87 to -5.44; P < 0.0001) and left-decompression group (n=16; mean difference: -7.26; 95% CI: -9.60 to -4.91; P < 0.0001). The mean pain score was lower in decompressed versus sham legs (mean difference: 1.57 95% CI: 0.46 to 2.67; P =0.0002). CONCLUSIONS: Although nerve decompression was associated with reduced pain, the benefit of surgical decompression needs further investigation as a placebo effect may be responsible for part or all of these effects.

Temporal summation of second pain is affected by cognitive load.

This work attempted to clarify the interaction of cognition and pain sensitization during a paradigm of Temporal Summation of Second Pain (TSSP). We analyzed pain ratings and electroencephalographic (EEG) activity obtained from 21 healthy participants during the presentation of four experimental conditions that differed in the manipulation of attention to painful stimuli or working memory load (Attention to hand & TSSP; 0-back & TSSP (low cognitive load); 2-back & TSSP (high cognitive load); 2-back (without pain)). We found that the TSSP was reduced when the attention was diverted and the cognitive load increased, and this reduction was accompanied by higher midfrontal theta activity and lower posterior alpha and central beta activity. Although it is well established that TSSP is a phenomenon that occurs at the spinal level, here we show that it is also affected by supraspinal attentional mechanisms. Delivery of painful repeated stimuli did not affect the performance of the 2-back task but was associated with smaller amplitudes of attentional event-related potentials (ERPs) after standard stimuli (not the target). The study of brain activity during TSSP allowed to clarify the role of top-down attentional modulation in pain sensitization processes. Results contribute to a better understanding of cognitive dysfunction in pain conditions and reinforce the use of therapeutic strategies based on distracting attention away from pain.

Music Therapy During Basic Daily Care in Critically Ill Children: A Randomized Crossover Clinical Trial.

OBJECTIVE: To assess whether music therapy (MT) is effective to reduce pain during daily personal hygiene care (DPHC), a procedure performed in all patients in a pediatric intensive care unit. METHODS: Fifty critically ill children were enrolled in a crossover controlled clinical trial with random ordering of the intervention, that is, passive MT, and standard conditions, and blind assessment of pain on film recordings. The primary outcome was variation of the Face Legs Activity Cry Consolability (FLACC) score (range, 0-10) comparing before and during DPHC. Secondary outcomes were changes in heart rate, respiratory rate, and mean arterial blood pressure, and administration of analgesic or sedative drugs during DPHC. Mixed-effects linear model analysis was used to assess effect size (95% CI). RESULTS: The median (Q25-Q75) age and weight of the patients were 3.5 years (1.0-7.6 years) and 15.0 kg (10.0-26.8 kg). Consecutive DPHC were assessed on days 3 (2-5) and 4 (3-7) of hospitalization. In standard conditions, FLACC score was 0.0 (0.0-3.0) at baseline and 3.0 (1.0-5.5) during DPHC. With MT, these values were, respectively, 0.0 (0.0-1.0) and 2.0 (0.5-4.0). Rates of FLACC scores of >4 during DPHC, which indicates severe pain, were 42% in standard conditions and 17% with MT (P = .013). Mixed-effects model analysis found smaller increases in FLACC scores (-0.54 [-1.08 to -0.01]; P = .04) and heart rate (-9.00; [-14.53; -3.40]; P = .001) with MT. CONCLUSIONS: MT is effective to improve analgesia in critically ill children exposed to DPHC. TRIAL REGISTRATION: This study was recorded (April 16, 2019) before patient recruitment on the National Library of Medicine registry (NCT03916835; https://clinicaltrials.gov/ct2/show/NCT03916835).

Probiotic and high-fat diet: effects on pain assessment, body composition, and cytokines in male and female adolescent and adult rats.

Obesity in adolescence is increasing in frequency and is associated with elevated proinflammatory cytokines and chronic pain in a sex-dependent manner. Dietary probiotics may mitigate these detrimental effects of obesity. Using a Long-Evans adolescent and adult rat model of overweight (high-fat diet (HFD) - 45% kcal from fat from weaning), we determined the effect of a single-strain dietary probiotic [Lactiplantibacillus plantarum 299v (Lp299v) from weaning] on the theoretically increased neuropathic injury-induced pain phenotype and inflammatory cytokines. We found that although HFD increased fat mass, it did not markedly affect pain phenotype, particularly in adolescence, but there were subtle differences in pain in adult male versus female rats. The combination of HFD and Lp299v augmented the increase in leptin in adolescent females. There were many noninteracting main effects of age, diet, and probiotic on an array of cytokines and adipokines with adults being higher than adolescents, HFD higher than the control diet, and a decrease with probiotic compared with placebo. Of particular interest were the probiotic-induced increases in IL12p70 in female adolescents on an HFD. We conclude that a more striking pain phenotype could require a higher and longer duration caloric diet or a different etiology of pain. A major strength of our study was that a single-strain probiotic had a wide range of inhibiting effects on most proinflammatory cytokines. The positive effect of the probiotic on leptin in female adolescent rats is intriguing and worthy of exploration.NEW & NOTEWORTHY A single-strain probiotic (Lp299v) had a wide range of inhibiting effects on most proinflammatory cytokines (especially IL12p70) measured in this high-fat diet rat model of mild obesity. The positive effect of probiotic on leptin in female adolescent rats is intriguing and worthy of exploration.

Associations of pain sensitivity and conditioned pain modulation with physical activity: findings from the Multicenter Osteoarthritis Study (MOST).

OBJECTIVE: Individuals with chronic pain due to knee osteoarthritis (OA) are insufficiently physically active, and alterations of facilitatory and inhibitory nociceptive signaling are common in this population. Our objective was to examine the association of these alterations in nociceptive signaling with objective accelerometer-based measures of physical activity in a large observational cohort. DESIGN: We used data from the Multicenter Osteoarthritis Study. Measures of peripheral and central pain sensitivity included pressure pain threshold at the knee and mechanical temporal summation at the wrist, respectively. The presence of descending pain inhibition was assessed by conditioned pain modulation (CPM). Physical activity was quantitatively assessed over 7 days using a lower back-worn activity monitor. Summary metrics included steps/day, activity intensity, and sedentary time. Linear regression analyses were used to evaluate the association of pain sensitivity and the presence of descending pain inhibition with physical activity measures. RESULTS: Data from 1873 participants was analyzed (55.9% female, age = 62.8 ± 10.0 years). People having greater peripheral and central sensitivity showed lower step counts. CPM was not significantly related to any of the physical activity measures, and none of the exposures were significantly related to sedentary time. CONCLUSIONS: In this cohort, greater peripheral and central sensitivity were associated with reduced levels of objectively-assessed daily step counts. Further research may investigate ways to modify or treat heightened pain sensitivity as a means to increase physical activity in older adults with knee OA.