Background Burn injury (BI) is one of the most devastating traumas, causing acute and long-term immune dysregulation and organ dysfunction. BI, by polygenic pathways, affects the central nervous system, which is manifested as chronic neurological dysfunction that extends well beyond complete wound healing. In this study, we examined BI-induced systemic inflammation and brain neuroinflammation and their impact on neurobehavior in mice. Methods Male C57BL/6 J mice were subjected to BI. Cytokine array and enzyme-linked immunosorbent assay were utilized to evaluate cytokine levels in the serum and brain, respectively. Tissue metabolism disturbance was assessed using targeted metabolomic analyses. Spleen monocytes/macrophages and brain microglia/macrophages were analyzed using flow cytometry analyses. Neurobehavioral changes after BI were assessed using a battery of behavioral tests. Results Systemic inflammation extended to the recovery phase after BI. Using cytokine array with 111 targets, we found that the levels of 19 circulating pro-inflammatory cytokines/chemokines were increased at 14 days after BI, including TNFα (30%) and M-CSF (19%). In the spleen, the number of monocytes/macrophages increased from 5% to ∼35% in BI mice. Concurrently, the levels of anti-inflammatory mediators, 3-indolepropoinc acid and indolelactic acid, were diminished after BI. Brain microgliosis and macrophage infiltration, together with disturbed metabolic homeostasis, were observed in BI mice. In the hippocampus, IL-6 level was elevated after BI. BI mice exhibited persistent pain, anxiety, and depressive-like behavior, and cognitive impairment when examined at 30 days after injury by which time the burn wounds had healed. Conclusions In burn-injured mice, brain neuroinflammation and disrupted brain metabolic switch were concomitant with systemic inflammation. Mice exhibited neurobehavioral changes even after burn wounds had healed.

OBJECTIVE:Chronic low back pain (cLBP) is a common condition that impacts quality of life and function. There are many evidence-based treatments to address cLBP; however, treatment effects are modest, perhaps in part due to individual variation in treatment response. The Biomarkers for Evaluating Spine Treatments (BEST) trial was designed as the collaborative centerpiece of the Back Pain Consortium (BACPAC) research program. This consortium was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) as part of the Helping to End Addiction Long-term (HEAL) Initiative. DESIGN:The BEST trial was a sequential multiple assignment randomized trial (SMART) designed with the primary goal of identifying in whom different treatments show optimal response. The primary focus of the study was to use patient features, including biomarkers and phenotypic measures, to identify subsets of persons with cLBP who respond best to specific common treatments. METHODS:Four interventions were chosen for the trial: Enhanced Self-Care, Acceptance and Commitment Therapy, Duloxetine, and Evidence-Based Exercise and Manual Therapy. Following a run-in period and baseline assessment, participants were randomized to 1 of the 4 treatments for the first 12-week intervention period. Participants were reassessed and based on their self-reported response to initial treatment, continued that initial treatment, were augmented with an additional randomly assigned treatment, or were switched to a new treatment. CONCLUSION:This trial was designed to deliver rich phenotypic data that will both potentially aid in the discovery of phenotypic characteristics that predict treatment response and provide a greater mechanistic understanding of cLBP. CLINICAL TRIAL REGISTRATION NUMBER:The Biomarkers for Evaluating Spine Treatments (BEST) trial is registered on ClinicalTrials.gov (Registration number: NCT05396014; https://clinicaltrials.gov/study/NCT05396014).

Background:Chronic low back pain (cLBP) imposes a significant public health burden. Digital health interventions are increasingly used for chronic pain management, yet effective home-based therapies remain limited. We aimed to evaluate a novel, remotely delivered avatar-based video-guided acupuncture imagery treatment (AB-VGAIT) for cLBP. Methods:This parallel-group, randomised, controlled trial was performed at Massachusetts General Hospital (MA USA). Eligible participants, aged 18-75 years, had been experiencing cLBP for over six months and had at least 4/10 clinical pain on the low back pain numeric rating scale ranging from 0 to 10. Enrolled participants were randomly assigned (1:1) to either the AB-VGAIT or the avatar-based video-guided touch imagery treatment (AB-VGTIT; control) group. Participants underwent eight treatment sessions of either AB-VGAIT or AB-VGTIT over a 4-week period, wherein avatar-based, animated videos guided participants to imagine acupuncture (AB-VGAIT) or cotton stabs (AB-VGTIT) stimulation. Outcome evaluators and statisticians were blinded to group assignments, however participant blinding was not feasible due to the visual and interactive nature of the intervention. The primary outcome was the change from baseline in pain bothersomeness after 4 weeks of treatment. This study was registered with ClinicalTrials.gov, NCT03765879. Findings:Between June 22, 2021 and July 27, 2024, 60 participants were enrolled (n = 30 per group). Five (8.33%) participants did not complete the study, two (6.67%) in the AB-VGAIT group and three (10%) in the AB-VGTIT group. Although both groups demonstrated significant reductions in pain bothersomeness from baseline (AB-VGAIT: -1.71 [-2.38 to -1.04], p < 0.001; AB-VGTIT: -1.24 [-1.92 to -0.55], p = 0.001), no between-group difference was observed between AB-VGAIT and AB-VGTIT (-0.47 [-1.43 to 0.49], p = 0.586). Subgroup analyses stratified by sex, age, and baseline pain severity were consistent with the overall between-group findings. No serious adverse events occurred. Interpretation:Short duration, limited treatment frequency, and small sample size may restrict generalisability. No significant difference was observed between AB-VGAIT and AB-VGTIT; although both interventions yielded significant improvements in pain relief, suggesting each may offer a promising remote, self-administered digital intervention for cLBP. The scalable, non-invasive nature may help to bridge treatment gaps, particularly for individuals with limited access to in-person care. Future larger-scale trials are warranted to validate efficacy and generalisability. Funding:National Institutes of Health/National Center for Complementary and Integrative Health.

IntroductionGabapentin (GBP) is widely prescribed to older patients for pain management. Recent clinical studies highlight that GBP adversely affect cognitive function in older patients. GBP binds to the α2δ1 subunit of L-type voltage-gated Ca2+ channels to inhibit Ca2+ channel current. It is being increasingly recognized that GBP affects neuronal activity in multifaceted ways. However, the molecular mechanism underlying GBP’s impact on cognitive function in older subjects remains unelucidated.MethodsAged mice (18-month-old, female) were subjected to spared nerve injury (SNI) or sham surgery and treated with GBP for 60 days. Learning and memory were assessed using novel object recognition (NOR) test and contextual and cued fear conditioning test (FCT). Adeno-associated viral vector (AAV) was used for gene overexpression in the brain. Brain tissue was analyzed by Western blot, qRT-PCR, and protein activity assay.ResultsLong-term GBP treatment impaired learning and memory in aged mice with or without nerve injury-induced pain as GBP-treated aged mice had lower novel object recognition index in NOR test and shorter freezing time in FCT, respectively. In the hippocampus of GBP-treated mice, increased levels of p-tau (S416) and p-tau (S262) were observed, together with increased CaMKIIα and decreased Sirt1 expression. AAV-mediated Sirt1 overexpression in the hippocampus or systemic administration of the Sirt1 activator resveratrol prevented cognitive impairment and tau hyperphosphorylation via enhancing Sirt1 activity in GBP-treated mice.ConclusionLong-term GBP treatment is detrimental to cognitive function in aged mice. GBP suppressed Sirt1 expression, leading to elevated CaMKIIα level and hyperphosphorylation of tau, and boosting Sirt1 activity curbed the adverse effect of GBP on memory in aged mice.

Microtubules (MTs) have been postulated as one of the molecular targets underlying loss of consciousness induced by inhalational anesthetics. Microtubule-targeting chemotherapy drugs and opioids affect MT stability and function. However, the impact of prolonged administration of these drugs on anesthetic potency and anesthesia induction and emergence times remain unelucidated. Epothilone D, paclitaxel, vinblastine or opioid morphine were administered alone for a prolonged period (> 2 weeks) to male CD1 mice and their sensitivity to incremental concentrations of isoflurane were examined using loss of righting reflex (LORR) response as a measure of sensivity. The induction and emergence time after administration and termination of fixed concentration of isoflurance (1.2

OBJECTIVES:This study aims to investigate the modulatory effects of transcutaneous auricular vagus nerve stimulation (taVNS) and transcutaneous greater auricular nerve stimulation (tGANS) on the brainstem's vagus nerve pathway hubs-the nucleus tractus solitarius (NTS), locus coeruleus (LC), and raphe nucleus (RN)-in individuals with chronic low back pain (cLBP). MATERIALS AND METHODS:A total of 70 patients with cLBP were randomly assigned to receive four weeks of either taVNS or tGANS. Resting-state functional and structural magnetic resonance imaging (fMRI/sMRI) data were collected at baseline and post treatment. Analyses focused on static and dynamic functional connectivity (sFC/dFC) and fractional anisotropy (FA) using the NTS, LC, and RN--three brainstem nuclei within the central vagus nerve pathway-as seed regions. RESULTS:Overall, 51 participants completed the treatment. Both groups showed significant pain improvement, with no significant difference between the taVNS and tGANS groups. taVNS was found to influence connectivity between the NTS and cingulate cortex, sensorimotor areas, thalamus, insula, operculum, and prefrontal cortex; between the LC and primary motor area and amygdala; and between the RN and sensory and prefrontal regions. In contrast, tGANS affected connectivity between the NTS and temporoparietal junction; between the LC and prefrontal cortex; and between the RN and insula and hippocampus. Changes in FA further supported the sFC findings. Notably, in the taVNS group, an increase in FA was negatively correlated with a decrease in sFC between the LC and precentral cortex. CONCLUSIONS:Both taVNS and tGANS can modulate functional and structural connectivity between brainstem nuclei of the central vagus nerve pathway and multiple cortical/subcortical regions, albeit through different neural circuits. CLINICAL TRIAL REGISTRATION:The Clinicaltrials.gov registration number for the study is NCT03959111.

Objective Chronic low back pain (cLBP) is a significant public health problem in the United States. A method to identify treatments that are most likely effective for an individual patient based on their unique characteristics is needed.Methods The Biomarkers for Evaluating Spine Treatments (BEST) Trial is a sequential, multiple assignment, randomized trial designed to estimate an optimal treatment or combination of treatments to reduce pain intensity and interference at 24 weeks in individuals with cLBP.Results We describe the patient-reported characteristics of the BEST Trial at the Baseline visit. Data collection for extensive required phenotyping is reported. We analyzed the run-in period of the BEST Trial to evaluate predictors of run-in failure. The BEST Trial enrolled 1019 participants and randomized 805 participants (61.6% female, mean age 50.4, 12.5% Black or African American) to the first stage of treatment. We collected extensive required phenotyping on all 805 randomized BEST Trial participants, and additional optional phenotyping on 510 (63.4%) participants.Conclusions The BEST Trial successfully enrolled a racially and geographically diverse sample of chronic low back pain patients and completed rich phenotypic assessments to inform our primary goal of identifying in whom different treatments show optimal response. We demonstrated the feasibility of collecting extensive phenotypic assessments in a multi-site clinical trial of cLBP.Clinical trial registration number The Biomarkers for Evaluating Spine Treatments (BEST) Trial is registered on ClinicalTrials.gov. Registration number: NCT05396014 (https://clinicaltrials.gov/study/NCT05396014).

The gut microbiota plays crucial roles in the development and functions of the central nervous system (CNS) as well as in modulation of neurobehavior in heath and disease. The gut brush border enzyme intestinal alkaline phosphatase (IAP) is an important positive regulator of gut microbial homeostasis. In mice, IAP is encoded by Akp3 gene, which is specifically expressed in the duodenum of the small intestine. IAP deficiency alters gut bacterial composition and gut barrier function. Decreased IAP activity has been observed in aging, gut inflammatory diseases, and metabolic disorders. We hypothesized that this enzyme could also play an important role in modulating neurobehavior. We performed deep sequencing of gut bacterial 16S rRNA and found that IAP deficiency changed gut microbiota composition at various taxonomic levels. Using targeted metabolomic analysis, we also found that IAP deficiency resulted in changes of gut bacteria-derived metabolites in serum and brain metabolism. Neurobehavioral analyses revealed that Akp3-/- (IAP knockout) mice had decreased basal nociception thresholds, increased anxiety-like behavior, and reduced locomotor activity. Furthermore, Akp3-/- mice had more pronounced brain microglial phagocytic activity, together with an increase in the activated microglia population. Fecal microbiota transplantation from wildtype to Akp3-/- mice partially improved neurobehavior and reduced brain microglial phagocytic activity in Akp3-/- mice. This study demonstrates that deficiency of the endogenous gut-derived host factor IAP induces behavioral phenotype changes (nociception; motor activity, and anxiety) and affects brain microglia activity. Changes in the gut microbiota induced by knocking down Akp3 contribute to behavioral changes, which is probably mediated by microglia activity modulated by the gut bacteria-derived metabolites.

This study aims to examine the modulatory effects of transcutaneous auricular vagus nerve stimulation (taVNS) on Chronic low back pain (cLBP). 70 cLBP patients were recruited and randomized into taVNS or transcutaneous greater auricular nerve stimulation (tGANS) group. Both interventions were administered by participants themselves after initial training (five times/week for four weeks). Magnetic resonance imaging (MRI) data were collected at baseline and after 4-week interventions. Seed-based static and dynamic functional connectivity (sFC and dFC) were performed to investigate the modulation effects on descending pain modulation system and reward network using the periaqueductal gray (PAG) and ventral tegmental area (VTA) as seeds. 51 patients (taVNS: n ​= ​25; tGANS: n ​= ​26) completed the study. Within-group comparisons showed a significant improvement in pain-related outcomes for both groups. Between-group comparisons revealed no significant differences. FC analysis showed that both taVNS and tGANS can increase the PAG - postcentral gyrus sFC. The taVNS is associated with increased PAG - amygdala and PAG - paracentral gyrus and decreased PAG - medial frontal cortex sFCs compared to tGANS. The present study suggest that both taVNS and tGANS can alleviate cLBP through distinct yet overlapping pathways. Our findings underscore the potential of auricular nerve stimulation as a telehealth solution for cLBP and other chronic pain conditions.

Purpose of Review This narrative review describes the management of patients experiencing alcohol use disorder (AUD) and co-occurring chronic pain (CP). An overview of the epidemiology and pathophysiology of both conditions is provided, including the potential overlapping mechanisms in the central nervous system (CNS). Pharmacological and nonpharmacological treatment approaches for both conditions are discussed, including mechanisms of action and the potential for adverse effects. Additionally, social and psychological factors influencing both conditions are reviewed. The need for additional research on the underlying mechanisms of comorbidity and the development of personalized treatment strategies for both disorders are highlighted. Recent Findings The prevalence of chronic excessive alcohol use is relatively high among adult patients with CP conditions, and the prevalence of CP is increased in patients with AUD. Much evidence suggests that the mechanisms underlying AUD and the processes involved in the dysregulation of pain signaling potentially intersect. There is overlap in some nonpharmacological treatments that are used for treating both AUD and CP, specifically those that involve cognitive and behavioral interventions. Several classes of prescribed pain medications can interact with alcohol, including anti-inflammatory agents, muscle relaxants, and opioid analgesics; these therapies can be harmful to patients with AUD. Extra caution should be exercised in prescribing them to patients with AUD. Summary AUD and CP are two disabling conditions that frequently co-occur. Research is needed to understand the overlaps in pathophysiology and provide better treatment to patients living with both conditions.

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a "normal" operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos-expressing neurons and selective activation of GABAergic interneurons significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More important, restoring a "normal" range of neural dynamics through attenuation of pain-induced S1 synchronization alleviated pain-like behavior. These results suggest that spontaneous pain pushed the S1 regional network into a synchronized state, whereas reversal of this synchronization alleviated pain.

The reduced antidepressant and antihyperalgesic effects of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine during maintenance treatment has been reported, but little is known about the molecular mechanism of this phenomenon. In three comorbid pain and depression animal models (genetic predisposition, chronic social stress, arthritis), we showed that the fluoxetine's antidepressant and antihyperalgesic effects were reduced during the maintenance treatment. Fluoxetine exposure induced upregulation of the 5-hydroxytryptamine 1A (5-HT1A) auto-receptor and indoleamine 2,3 dioxygenase 1 (IDO1, a rate-limiting enzyme of tryptophan metabolism) in the brainstem dorsal raphe nucleus (DRN), which shifted the tryptophan metabolism away from the 5-HT biosynthesis. Mechanistically, IDO1 upregulation was downstream to fluoxetine-induced 5-HT1A receptor expression because 1) antagonism of the 5-HT1A receptor with WAY100635 or 5-HT1A receptor knockout blocked the IDO1 upregulation, and 2) inhibition of IDO1 activity did not block the 5-HT1A receptor upregulation following fluoxetine exposure. Importantly, inhibition of either the 5-HT1A receptor or IDO1 activity sustained the fluoxetine's antidepressant and antihyperalgesic effects, indicating that 5-HT1A-mediated IDO1 upregulation in the brainstem DRN contributed to the reduced antidepressant and antihyperalgesic effects of fluoxetine. These results suggest a new strategy to improving the therapeutic efficacy of SSRI during maintenance treatment.

Surgical pain is associated with delirium in patients, and acupuncture can treat pain. However, whether electroacupuncture can attenuate the surgical pain-associated delirium via the gut–brain axis remains unknown. Leveraging a mouse model of foot incision-induced surgical pain and delirium-like behavior, we found that electroacupuncture stimulation at specific acupoints (e.g., DU20+KI1) attenuated both surgical pain and delirium-like behavior in mice. Mechanistically, mice with incision-induced surgical pain and delirium-like behavior showed gut microbiota imbalance, microglia activation in the spinal cord, somatosensory cortex, and hippocampus, as well as an enhanced dendritic spine elimination in cortex revealed by two-photon imaging. The electroacupuncture regimen that alleviated surgical pain and delirium-like behavior in mice also effectively restored the gut microbiota balance, prevented the microglia activation, and reversed the dendritic spine elimination. These data demonstrated a potentially important gut–brain interactive mechanism underlying the surgical pain-induced delirium in mice. Pending further studies, these findings revealed a possible therapeutic approach in preventing and/or treating postoperative delirium by using perioperative electroacupuncture stimulation in patients.

BACKGROUND:Sacroiliac joint (SIJ) pain is a common etiology of chronic lower back pain. Treatment of persistent sacroiliac joint pain may entail intraarticular steroid injections and lateral branch radiofrequency neurotomy.OBJECTIVES:This study evaluates the efficacy of SIJ intervention treatments by comparing intraarticular steroid injections with lateral branch radiofrequency neurotomy.STUDY DESIGN:Retrospective cohort study.SETTING:We reviewed electronic medical records of patients with SIJ pain at Massachusetts General Hospital from 2006  through 2016 and identified 354 patients who received 930 SIJ intraarticular  injections and 19 patients who received 41 SIJ lateral branch radiofrequency neurotomies.METHODS:The Numeric Rating Scale (NRS) score for pain and the Eastern Cooperative Oncology Group (ECOG) Performance Status were measured prior to intervention and on follow-up. A mixed effects model was used to evaluate the duration of treatment effect.RESULTS:Patients who received an SIJ intraarticular steroid injection reported lower pain scores following treatment with a mean (standard deviation) NRS reduction from 6.77 (2.25) to 2.72 (2.81). SIJ lateral branch radiofrequency neurotomy resulted in NRS reduction from 5.96 (2.39) to 3.54 (3.14). A linear mixed model analysis suggests SIJ intraarticular steroid injections provided an estimated mean (CI 95%) of 38 (30-46.3) days of pain relief. Lateral branch radiofrequency neurotomy provided 82 (39.4-124.8) days of pain relief. The mean preprocedure ECOG score was 1.22 for both interventions and trended toward improvement with a post SIJ intraarticular injection score of 1.05 and SIJ lateral branch radiofrequency neurotomy score of 1.03.LIMITATIONS:There was variable follow-up reporting among patients. The small size of the lateral branch radiofrequency cohort limited intergroup comparisons.CONCLUSION:Both SIJ intraarticular steroid injections and SIJ lateral branch radiofrequency neurotomy demonstrated significant pain relief for patients with SIJ pain. SIJ lateral branch radiofrequency neurotomy provided a longer duration of pain relief (82 days) versus SIJ intraarticular steroid injection (38 days).

Background: We examined whether the effect of true electroacupuncture on pain and functionality in chronic pain participants can be differentiated from that of medication (gabapentin) by analyzing quantitative sensory testing (QST). Methods: We recruited chronic back and neck pain participants who received six sessions (twice weekly) of true electroacupuncture versus sham electroacupuncture or 3 weeks of gabapentin versus placebo treatment. QST profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after three sessions (visit 4) or six sessions (visit 7) of acupuncture or 3 weeks of gabapentin or placebo. Results: A total of 50 participants were analyzed. We found no differences in QST profile changes (p = 0.892), pain reduction (p = 0.222), or functionality (p = 0.254) between the four groups. A major limitation of this pilot study was the limited number of study participants in each group. Conclusion: This pilot study suggests that a large-scale clinical study with an adequate sample size would be warranted to compare acupuncture and medication therapy for chronic pain management. Trial registration number: NCT01678586 (ClinicalTrials.gov).

BACKGROUND: The incremental dose of opioids used in chronic pain management often leads to a reduced opioid analgesic effect, opioid misuse, and addiction. Central dopamine (DA) dysfunction contributes to the chronicity of pain and a decreased opioid analgesic effect. Methylphenidate (MPH/Ritalin) enhances central DA function by inhibiting DA reuptake. In this study, we used a rat model of chronic pain to examine whether combination of MPH with morphine (MOR) would improve the MOR analgesic effect under a chronic pain condition. METHODS: Tibiotarsal joint Complete Freund’s Adjuvant (CFA) injection in rats was utilized to induce chronic nociception. The analgesic effect of low-dose MPH (0.25 mg/kg), low-dose MOR (2.5 mg/kg), and their combination was examined in CFA rats. Nociceptive behavior was assessed by von Frey test. Conditioned place preference (CPP) and open field tests (OFTs) were used to examine the rewarding behavior and locomotor activity in rats, respectively. RESULTS: Our findings are as follows: (1) in CFA rats with chronic pain, 2.5 mg/kg of MOR had less analgesic effect than 10 mg/kg of MOR at 28 days after injury (95% confidence intervals [CIs] for difference of means of von Frey threshold in gram: −11.9 [−6.5 to −17.3]); (2) in the 1-hour time window of 30–90 minutes after injection, the combination of MPH (0.25 mg/kg) with MOR (2.5 mg/kg) increased synergistically and prolonged the analgesic effect in CFA rats as compared with MPH or MOR alone (P = .01 for MPH by MOR interaction, and 95% CIs for difference of means of von Frey threshold in gram: 3.3 [1.37–6.12] for the combination versus MPH and 3.2 [1.35–5.74] for the combination versus MOR); (3) at the low dose (0.25 mg/kg), MPH did not increase locomotor activity (MOR + MPH versus MOR, P = .13) nor significantly enhanced MOR reward behavior (MOR + MPH versus MOR, P = .63) in CFA rats. CONCLUSIONS: Our data suggest that a combination therapy using low-dose MPH and MOR may produce a MOR-sparing effect in chronic pain management.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with many systemic comorbidities, including sensory dysfunctions. A growing body of literature explored patients' unusually intense reactions to innocuous sensory stimuli but very little is known about ASD patients' response to noxious stimuli such as pain. Patients with ASD are thought to have low sensitivity to pain, but currently, there is no clear consensus on pain responsivity/sensitivity/expression in patients with ASD. Pain is likely a significant source of suffering for patients with ASD, but limited literature suggest that it may be underdiagnosed and undertreated, due to patients' potentially abnormal reaction to pain/pain expression, and their limited social communication skills. In this article, we first discuss the abnormalities in pain sensitivity and expression, two key obstacles in pain management for patients with autism. Next, we explore currently available tools in pain diagnosis for patients with autism. The third, we discuss pain management in autism patient with an emphasis on the perioperative setting where literature is most abundant. Last, we call for further research and offer suggestions for implementing better pain assessment and management protocols based on our understanding of this unique population.

Objective. To determine the relationship between opioid dose change, pain severity, and function in patients with chronic pain. Design. Retrospective cohort study. Setting. Community interdisciplinary pain management practice. Subjects. A total of 778 patients with chronic pain prescribed opioids for three or more consecutive months between April 1, 2013, and March 1, 2015. Methods. Changes in opioid dose, pain severity rating, modified Roland Morris Disability Questionnaire score, and opioid risk data were extracted from medical records and analyzed for associations. Results. Two hundred forty-three subjects (31.2%) had an overall dose decrease, 223 (28.7%) had a dose increase, and 312 (40.1%) had no significant change in dose (<20% change). There was a weak negative correlation between change in opioid dose and change in pain severity (r = -0.08, P = 0.04) but no association between change in disability scores and dose change (N = 526, P = 0.13). There was a weak positive correlation between change in pain severity rating and change in disability scores (r = 0.16, P < 0.001). Conclusions. The results suggest that escalating opioid doses may not necessarily result in clinically significant improvement of pain or disability. Similarly, significant opioid dose reductions may not necessarily result in worsened pain or disability. This exploratory investigation raised questions of possible subgroups of patients who might demonstrate improvement of pain and disability with opioid dose adjustments, and further research should prospectively explore this potential, given the limitations inherent in retrospective analyses. Prescribers should still consider reduction of opioid doses as recommended by current guidelines, in an effort to mitigate the potential risks associated with high-dose treatment.

INTRODUCTION:Infants can experience pain similar to adults, and improperly controlled pain stimuli could have a long-term adverse impact on their cognitive and neurological function development. The biggest challenge of achieving good infant pain control is obtaining objective pain assessment when direct communication is lacking. For years, computer scientists have developed many different facial expression-centred machine learning (ML) methods for automatic infant pain assessment. Many of these ML algorithms showed rather satisfactory performance and have demonstrated good potential to be further enhanced for implementation in real-world clinical settings. To date, there is no prior research that has systematically summarised and compared the performance of these ML algorithms. Our proposed meta-analysis will provide the first comprehensive evidence on this topic to guide further ML algorithm development and clinical implementation.METHODS AND ANALYSIS:We will search four major public electronic medical and computer science databases including Web of Science, PubMed, Embase and IEEE Xplore Digital Library from January 2008 to present. All the articles will be imported into the Covidence platform for study eligibility screening and inclusion. Study-level extracted data will be stored in the Systematic Review Data Repository online platform. The primary outcome will be the prediction accuracy of the ML model. The secondary outcomes will be model utility measures including generalisability, interpretability and computational efficiency. All extracted outcome data will be imported into RevMan V.5.2.1 software and R V3.3.2 for analysis. Risk of bias will be summarised using the latest Prediction Model Study Risk of Bias Assessment Tool.ETHICS AND DISSEMINATION:This systematic review and meta-analysis will only use study-level data from public databases, thus formal ethical approval is not required. The results will be disseminated in the form of an official publication in a peer-reviewed journal and/or presentation at relevant conferences.PROSPERO REGISTRATION NUMBER:CRD42019118784.