Codesign and system integration should be treated as a single, interacting design requirement in moving digital youth pain health solutions towards equitable, sustained, embedded care.
Introduction:Neurodevelopmental disorders (NDDs) affect up to 15% of children in the United States and are associated with co-occurring health challenges such as chronic pain, which can negatively affect development and quality of life. Increased risk of chronic pain in children with NDDs remains poorly understood; this study aimed to estimate chronic pain prevalence among children with NDDs and explore whether this association differs by sex. Methods:We conducted a cross-sectional analysis of children participating in the 2022 to 2023 National Survey of Children's Health (age 3-17 years, n = 84,117). Neurodevelopmental disorders included attention deficit and hyperactivity disorder, autism, intellectual disability, speech disorder, Tourette syndrome, learning disability, and developmental delay. Chronic pain was defined as frequent or persistent pain in the past 12 months. Weighted multivariable logistic regression estimated associations between NDDs and chronic pain, adjusting for sociodemographic and health covariates. Results:Overall, 18.7% (95% confidence interval: 18.2%-19.2%) of children had an NDD. Chronic pain prevalence was higher among children with NDDs than among those without (10.3% vs 5.2%, P < 0.001). After adjustment, children with any NDD (aOR 1.9 [1.7-2.2]) had increased odds of chronic pain. Tourette syndrome showed the greatest odds (aOR = 3.2 [1.7-6.2]). Sex did not alter the association between NDDs and chronic pain (P = 0.79). Conclusion:Neurodevelopmental disorders affect 1 in 6 U.S. children and are associated with almost double the odds of chronic pain. This increased odds emphasizes the need for improved chronic pain recognition and management among children with NDDs. Future research should examine chronic pain in youth with NDDs, to improve assessment, management, and understanding of pain mechanisms.
Abstract Introduction: Tetrodotoxin-resistant voltage-sensitive sodium channel subtypes 1.8 and 1.9 play a key role on “silent” (mechano-insensitive) nociceptors activation during sinusoidal electrical stimulation. Therefore, we hypothesized that an UVB–induced sensitization of this particular nociceptor class can be revealed by such electrical stimulation pattern. Objectives: We set out to study ultraviolet-B (UV-B)-induced sensitization of C-nociceptors using heat and mechanical stimulation, but also transduction independent slow depolarizing electrical pulses. Methods: Single fibre recordings of pig saphenous nerve were performed after UV-B irradiation with 3-fold minimum erythemal doses. Results: A total 45 C fibers were recorded from UV-B inflamed skin and discharge patterns compared with nonirradiated control units (n = 134). We did not observe a sensitization to heat or mechanical stimulation in mechanosensitive nociceptors, but some of the “silent” nociceptors were sensitized to mechanical stimulation. The most drastic changes were found for electrical activation thresholds that increased about 3-fold in tactile “C-touch” fibers, but that were reduced in silent nociceptors up to a factor of 5. The threshold to 1-Hz stimulation was also increased 2-fold in “polymodal” nociceptors, although not significantly. Conclusion: Potentially, the combination of desensitized C-touch and polymodal nociceptors with sensitized silent nociceptors might be based on high expression of depolarization-resistant Na V 1.8 sodium channels in silent nociceptors. Functionally, sensitized silent nociceptors appear to be the primary candidate to underlie hyperalgesia in acute UV-B inflammation.
Abstract Introduction: Two-pore domain potassium channels regulate neuronal excitability by generating background potassium currents that stabilize the resting membrane potential. Although several two-pore domain potassium channels have been implicated in pain signaling, the physiological role of tandem pore domain halotane-inhibited K+ channel (THIK2) remains largely unknown despite its high expression in human and mouse nociceptive dorsal root ganglion (DRG) neurons. Objective: This study aimed to determine the cellular distribution of THIK2 in sensory neurons and to investigate its contribution to neuronal excitability and nociceptive processing under physiological and inflammatory conditions. Methods: We combined molecular analyses, electrophysiological recordings, and behavioral approaches. THIK1 and THIK2 expression patterns were mapped in mouse DRGs. Whole-cell electrophysiology was used to assess membrane excitability in sensory neurons from wild-type and THIK2 −/− knockout mice. Behavioral tests evaluated thermal sensitivity under naive and inflammatory conditions. Results: We provide the first comprehensive characterization of THIK1 and THIK2 expression in mouse DRG. THIK2 deletion increased neuronal firing during sustained stimulation, indicating a loss of tonic inhibitory control of membrane excitability, particularly in nonpeptidergic IB4-positive C-fiber neurons. Behaviorally, THIK2 −/− mice displayed marked thermal hypersensitivity at baseline and during inflammation, consistent with enhanced sensory neuron hyperexcitability. Conclusion: THIK2 channels act as key regulators preventing pathological hyperexcitability in nociceptive sensory neurons. Their loss leads to increased neuronal firing and enhanced thermal sensitivity, identifying THIK2 as a promising therapeutic target for chronic inflammatory pain.
Introduction:Fibromyalgia is a heterogeneous chronic condition characterized by variability in pain, psychological distress, central sensitization, and functional impairment. Cross-sectional studies have identified reproducible symptom phenotypes; however, their longitudinal stability remains incompletely understood. Objectives:This study aimed to evaluate the longitudinal stability of data-driven fibromyalgia phenotypes across repeated clinical assessments in a large, harmonized, multi-institutional cohort. Methods:We analyzed longitudinal data from 821 adults with fibromyalgia recruited from 2 academic medical centers. Standardized assessments included the Revised Fibromyalgia Impact Questionnaire, Beck Depression Inventory, Central Sensitization Inventory, McGill Pain Questionnaire, and selected SF-36 functional domains. Unsupervised clustering was performed at baseline to derive symptom phenotypes, which were ordered by overall severity. Using baseline-derived model parameters, phenotype membership was assigned at subsequent visits. Phenotype transitions were examined between visit 1 and visit 2 (n = 191) and across visits 1 to 3 (n = 72) using transition matrices and alluvial visualizations. Results:Two clinically interpretable fibromyalgia phenotypes were identified at baseline, representing lower-severity/preserved function and higher-severity/global impairment profiles. Across 6-month follow-up intervals, most participants remained within their baseline phenotype (61.9% from visit 1→2 and 64.8% from visit 2→3). Transitions occurred in a minority of individuals and were primarily between adjacent severity phenotypes. Among participants with 3 or more visits, phenotype membership remained stable across repeated assessments. Conclusion:Data-driven fibromyalgia phenotypes demonstrate substantial longitudinal stability, supporting their validity as enduring clinical constructs rather than transient symptom states. These findings support phenotype-based stratification for longitudinal research and precision treatment approaches in fibromyalgia. Longitudinal analysis shows that fibromyalgia symptom phenotypes are largely stable over time, with infrequent transitions occurring mainly between adjacent severity groups.
Introduction/Objectives:Temporomandibular disorders (TMD) are associated with multiple comorbidities; however, specific comorbidities may be differentially associated with painful and nonpainful TMD. We describe the prevalence of TMD symptoms, quantified associated comorbidities, and identified associated factors of painful TMD symptoms in a large database. Methods:Data were extracted from BigMouth repository (January 2014-May 2025) for adults with responses to TMD-related items of "pain upon chewing/talking/jaw use" (used to classify patients into self-reported "painful" vs "nonpainful TMD symptoms"), "jaw popping/clicking," and "jaw locking." Associations between painful TMD and comorbidities were calculated with χ2 tests and prevalence ratios (PRs). Logistic regression identified factors associated with painful TMD symptoms. Results:Of 259,768 patients (46.5 ± 17.8 years old, 51.4% women), common symptoms were tooth grinding (21.3%), headaches (23.3%), pain on chewing (9.5%), temporomandibular joint noises (21.6%), and jaw locking (3.1%). Compared with those with nonpainful TMD, those with self-reported painful TMD symptoms had significantly higher prevalence of headaches (38.8% vs 16.1%, PR = 2.41, 95% confidence interval [CI] 2.36-2.46), arthritis (19.4% vs 16.1%, PR = 1.20, 95% CI 1.15-1.26), depression (34.7% vs 18.1%, PR = 1.91, 95% CI 1.84-1.98), anxiety (29.9% vs 21.8%, PR = 1.37, 95% CI 1.31-1.43), sleep apnea (17.7% vs 9.1%, PR = 1.95, 95% CI 1.86-2.05), and gastrointestinal issues (16.4% vs 9.8%, PR = 1.67, 95% CI 1.58-1.77, all P's < 0.001). Each additional somatic comorbidity more than doubled the odds of having painful TMD (P = 0.010, odds ratio = 2.67, 95% CI 1.26-5.63); age and sex were not associated. Conclusion:Painful TMD is strongly associated with psychological and somatic comorbidities. Accumulation of somatic comorbidities increases TMD risk, highlighting the need of integrated medical-dental approaches to TMD care.
Introduction:Epidural steroid injections (ESIs) are commonly used for lumbosacral radicular pain, but clinical outcomes remain variable. Objective:This study aimed to identify predictive factors and determine short-term patient-reported outcomes in an understudied Southeast Asian population. Methods:A retrospective study involving 198 patients with chronic lumbosacral radicular pain undergoing lumbar ESI was conducted. Treatment success was defined as a ≥30% reduction in the Brief Pain Inventory worst pain score at 4-week follow-up. At follow-up, 167 patients had complete data and were categorized as responders (n = 83) or nonresponders (n = 84). Multivariable binary logistic regression was performed using observed complete-case data to identify factors associated with treatment success. Results:The observed 4-week response rate was 49.7%. In multivariable analysis, previous spine surgery was associated with lower odds of treatment success (adjusted odds ratio [aOR] 0.30, 95% confidence interval [CI] 0.11-0.80, P = 0.016), whereas unilateral transforaminal ESI (TFESI) was associated with higher odds of response compared with bilateral TFESI (aOR 3.16, 95% CI 1.23-8.13, P = 0.017). Baseline current pain intensity showed a negative direction of association but did not reach statistical significance (aOR 0.86, 95% CI 0.73-1.02, P = 0.086). Specific MRI findings were not significantly associated with clinical outcomes. Conclusion:Clinical history and treatment context were more informative than MRI findings for estimating short-term lumbar ESI response. Prior spine surgery was associated with poorer response, whereas unilateral TFESI was associated with higher odds of short-term treatment success.
Introduction:Autonomous sensory meridian response (ASMR) is a cross-sensory phenomenon experienced by an estimated 20% of the population and characterised by a calming, pleasurable tingling sensation triggered by audio-visual or tactile stimuli. Prior work suggests that ASMR experiencers show heightened pain sensitivity but similar pain tolerance to nonexperiencers, and emerging evidence points to possible analgesic effects. Objectives:This study sought to replicate and extend these findings using a larger sample, pain threshold as an index of pain perception, and sex as a variable. Methods:Male and female ASMR experiencers (N = 20) and controls (N = 20) completed algometer testing at baseline, during an ASMR-inducing video, and during a control video. Pain thresholds and visual analogue pain ratings were collected, and participants reported whether they experienced ASMR tingling in each condition. Results:ASMR experiencers reported higher pain ratings than controls (P = 0.017) but showed comparable pain thresholds (P = 0.963). Among ASMR experiencers, experiencing tingles was associated with increased pain threshold (P = 0.012). Women overall exhibited lower thresholds (P = 0.001) and showed no condition-related changes, whereas men demonstrated increased thresholds during both videos (P = 0.009, P = 0.007), suggesting a distraction-related buffering effect for men. Descriptively, male ASMR experiencers mirrored this pattern, while female ASMR experiencers showed elevated thresholds only during the ASMR video. Conclusion:These findings indicate that ASMR may modulate pain perception and that sex differences influence pain-related responses. They highlight ASMR's potential as an analgesic mechanism and underscore the importance of incorporating sex as a factor in future ASMR pain research.
Introduction:Neuropathic pain after cervical spinal cord injury (SCI) is common and difficult to manage. Objectives:To evaluate whether intraoperative nitrous oxide (N2O) influences acute postoperative pain and long-term neuropathic pain after cervical SCI surgery. Methods:This single-center, randomized study enrolled adults (≥20 yr) undergoing emergency surgery for traumatic cervical SCI (American Spinal Injury Association Impairment Scale C or D). Patients were randomly assigned to receive intraoperative N2O or Air. The primary outcome was resting pain intensity on postoperative day 1 (D1), measured using the Numeric Rating Scale (NRS). Secondary outcomes included global pain and neuropathic pain assessments up to 6 months (6M) after surgery. Results:Of 80 randomized patients, 59 were analyzed (mean [SD] age 70.34 [12.07] years; 46 [78%] male). Baseline characteristics were similar between groups (Air, n = 29; N2O, n = 30). The primary outcome was higher in the N2O group, indicating no acute analgesic effect (NRS on D1: 3.27 [2.69] vs 5.10 [3.06]; P = 0.021). By contrast, at 6M, resting NRS was lower in the N2O group (1.72 [2.64] vs 0.53 [1.25]; P = 0.030), and numbness-related symptoms also improved. No serious adverse events occurred. Conclusion:Intraoperative N2O did not reduce acute postoperative pain after cervical SCI surgery. However, exploratory secondary analyses suggested a potential reduction in chronic neuropathic pain at 6 months, supporting the hypothesis that early perioperative modulation of central sensitization may influence pain chronification after SCI.
Introduction:Erythromelalgia is a descriptive term for burning pain and erythema in distal extremities, often worsened by heat and improved by cold. Inherited erythromelalgia has been primarily linked to gain-of-function variants in SCN9A, encoding voltage-gated sodium channel NaV1.7. However, approximately 65% to 85% of patients with erythromelalgia do not have pathogenic SCN9A variants. Objectives:The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia. Methods:With IRB approval and informed consent, probands and families with erythromelalgia underwent next-generation sequencing. A list of genes of interest was produced based on Mendelian inheritance models. Selected gene candidates were assessed using the Sequence Kernel Association Test-Optimal (SKAT-O). Results:Sixty-two probands with erythromelalgia and their relatives were included in Mendelian analysis, which identified variants in PR domain zinc finger protein 12 (PRDM12) and dihydropyrimidinase-like protein 2 (DPYSL2). In a targeted 12-gene rare-variant set analysis using SKAT-O, zinc finger homeobox protein 2 (ZFHX2) showed evidence of association (P = 6.9 × 10-4), surpassing Bonferroni correction for 12 tests (α = 4.17 × 10-3), whereas KIF1B showed only a nominal association signal (P = 0.03) that did not survive multiple-testing correction. Conclusion:Genes associated with both increased and decreased pain sensitivity are of considerable interest for elucidating pain mechanisms and analgesic development. As rare variants in PRDM12 and DPYSL2 were identified in a pediatric erythromelalgia cohort and a gene-based rare-variant association signal for ZFHX2 was identified, replication and functional validation are needed.
Abstract Introduction: Pain from medical procedures can have negative effects on children and adolescents (eg, healthcare avoidance), and is often not adequately prevented and treated. Best practices emphasize the important role of caregivers in procedural pain management. Objectives: To investigate caregivers' perceptions, knowledge, and behaviours related to their children's procedural pain management and to describe the barriers perceived by caregivers encountered during the management of their child's procedural pain. Methods: This was a cross-sectional online survey of caregivers with children aged 0 to 17 years. Statistical analysis of closed-ended responses and inductive content analysis of open-ended responses were completed. Results: Among 104 caregivers (56.7% female, average child age = 8.9 years), 93% were present during their child's recent painful procedure, 62% reported participating in pain management, and 66% perceived their child's recent procedural pain was well-managed. The most used pain management strategies reported were psychological (eg, 59% used deep breathing). Caregivers reported seeking information about pain management from electronic sources (37%) and/or healthcare providers (35%), and 70% reported being satisfied with the information available to them. Caregivers reported their own lack of knowledge, their child's emotions, communication breakdowns, and healthcare professional attitudes as barriers to helping with pain management. Conclusions: Caregivers are often present during their children's painful procedures, but many reported not being involved in pain management. Despite significant progress in procedural pain management, there remain knowledge gaps among caregivers and barriers to their active engagement. Addressing these may help to improve pediatric procedural pain management implementation.
Abstract Introduction: Adolescence is a period of drastic biopsychosocial change that affects the trajectory of health into adulthood. Cross-sectional studies have reported that older youth typically exhibit lower experimental pain sensitivity than younger youth, but only one study thus far has directly examined this longitudinally. The factors contributing to changes in pain sensitivity remain unclear, but sex hormones, which dramatically fluctuate during adolescence, could play a key role. Objectives: This longitudinal study aimed to examine changes in experimental pain sensitivity/modulation and their relationship to changes in sex hormone levels. Methods: Healthy girls (n = 35, 9–16 years old) completed quantitative sensory testing (QST) at baseline and 1-year follow-up including thermal/pressure pain threshold; heat/cold pain intensity; cold pain tolerance; mechanical temporal summation; offset analgesia; and heat/pressure conditioned pain modulation. Serum blood samples were analyzed for total testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), and androstenedione (A4). Pain measures that significantly differed from baseline to follow-up were dependent variables in bootstrapped linear regression models with sex hormones as individual predictors in separate models. Additional regressions included baseline age and changes in pubertal stage and menstrual phase as covariates. Results: Cold pain threshold (CPT) increased over 1 year (baseline = 11.93°C, follow-up = 15.72°C, P = 0.012). Increased ΔDHT predicted increased ΔCPT after controlling baseline age, Δpubertal stage, and Δmenstrual phase ( ΔR 2 = 0.294, ΔF 1,18 = 9.49, P = 0.006, β = 0.583), but no other relationships between ΔQST measures and Δsex hormones were significant. Conclusion: These findings suggest that during puberty, changes in sex hormone levels may have minor contributions to changes in experimental pain sensitivity in healthy girls.
Abstract Introduction: Whiplash-associated disorder grade II (WADII) is characterised by persistent pain in the absence of frank nerve injury, yet its molecular mechanisms remain unclear. Objectives: To identify molecular signatures of 2 recovery groups characterised by persistent moderate/severe and minimal symptoms in WADII using RNA-sequencing of blood samples 6 months postinjury. Methods: We performed bulk transcriptional analyses on blood samples collected from the primary cohort of individuals with WADII 6 months postinjury (n = 15/recovery group). Findings were replicated through meta-analyses using an independent cohort of chronic WAD. Blood cellular composition was estimated via deconvolution analyses across both cohorts. Results: Although there were no differentially expressed genes between recovery groups, we identified sex-specific gene expression signatures of recovery. In the primary WADII cohort, HLA-DQA1, HEBP1, and NECTIN2 showed lower expression in females with moderate/severe symptoms compared with minimal symptoms. SLC12A1 and MXRA7 showed lower expression in males with moderate/severe pain, whereas HLA-G was upregulated. Gene expression meta-analysis in females identified 6 differentially expressed genes, including replication of lower HLA-DQA1 expression from the primary cohort. There were no differentially expressed genes in the meta-analyses in males or between recovery groups. Deconvolution analyses revealed diverging trends between sexes for blood cell types and whiplash symptom severity scores. Ligand–receptor pair analyses further suggested distinct sex-specific recovery trajectories. Conclusion: Transcriptional profiling revealed sex-specific molecular blood signatures associated with persistent whiplash symptoms 6 months postinjury. Future research is needed to further characterise sex-specific mechanisms after whiplash injury to improve prognosis and targeted management strategies.
Research supports the efficacy of music-based interventions (MBIs) for pain management, but understanding of their underlying mechanisms is lagging. This scoping review aims to map existing mechanism-focused MBI research, identify knowledge gaps, and highlight the strengths and weaknesses of this body of research. Studies were eligible if they tested a mechanism, moderator, or predictor of the effects of MBIs on clinical or experimental pain and were published in English in a peer-reviewed journal. Following the Joanna Briggs Institute scoping review methodology, we searched MEDLINE, Embase, PsycINFO, PubMed, and Scopus from inception through February 2026. Two reviewers completed screening and data extraction, with discrepancies resolved by a third reviewer. From 663 records screened, 57 studies were included. Most studies employed experimental pain models with healthy volunteers. All but 4 studies examined the mechanisms of music audio recordings; the remaining studies examined active music-making. We identified convergent evidence for several candidate mechanisms, including positive emotional valence, cognitive agency, and sensorimotor synchronization. Evidence from neuroimaging studies point to the impact of music on early stages of pain processing as well as on higher-order cognitive and affective interpretation of pain. Finally, preliminary evidence suggests that music may restore default mode network connectivity involved in self-referential thoughts. Across studies, several methodological limitations constrained inferences. Future research should (1) employ rigorous designs that distinguish between competing mechanistic models and, when feasible, incorporate causal manipulations to test hypothesized mechanisms and (2) examine whether music influences pain processing differently in populations with vs without clinical pain.
Objective:To assess the efficacy and clinical implementation of virtual reality (VR) paired with nitrous oxide for procedural pain management during botulinum toxin (BoNT) injections in children with developmental disabilities. Methods:A randomized, crossover study was conducted with 31 children with developmental disabilities receiving BoNT injections with nitrous oxide (median age = 10 years, range = 5-17 years; 16 males). Child life specialists facilitated VR during one BoNT appointment and standard of care distraction (eg, music, tablet) at another. Primary outcomes included pain experience assessed using the Faces Pain Scale-Revised, anxiety, and nitrous oxide concentrations. Secondary outcomes assessed clinical implementation by side effects, preferences, and acceptability. Results:Children, parents, and child life specialists reported significantly lower pain scores, and nitrous oxide concentrations were reduced in the VR condition compared with standard of care. Virtual reality paired with nitrous oxide was used throughout the procedure for most children (n = 23; 74.2%). Eight children discontinued VR during the procedure (preference [n = 3], mild side effects [n = 5]). The procedure duration did not differ between conditions, and parents reported greater satisfaction with their experience when VR was used. Conclusion:On average, when VR was used, pain levels were lower while also using lower nitrous oxide concentrations. Implementation of VR into the clinical context, paired with nitrous oxide, appeared beneficial and clinically efficient. Virtual reality in combination with nitrous oxide may provide synergistic effects for procedural sedation resulting in improved patient experiences. Further research is warranted to explore potential effect modifiers for a personalized medicine approach.
Introduction:Chronic pain exhibits significant interindividual variability, partly because of genetic factors. The dopaminergic system is implicated in pain modulation. Objectives:This study investigated the association between single-nucleotide polymorphisms (SNPs) in dopamine pathway genes and chronic pain susceptibility in a Japanese population. Methods:A case-control study compared 191 patients with chronic pain with 282 healthy controls in Japan. Genotype data from previous whole-genome studies were analyzed for SNPs within or flanking 8 candidate genes (tyrosine hydroxylase, solute carrier family 6 member 3 [SLC6A3], dopamine D1-D5 receptor genes, and catechol-O-methyltransferase), including the gene body and ±30 kb flanking regions. Association analyses used Pearson chi-squared tests and modified Poisson regression with Bonferroni correction. Results:After quality control, 184 SNPs were analyzed. A significant association was identified between the rs2963257 SNP flanking the SLC6A3 gene and chronic pain (genotypic P = 0.00026). This remained significant after Bonferroni correction. Analysis using a dominant model for the A allele (GA + AA vs GG) also showed a significant association (prevalence ratio = 2.11, 95% confidence interval = 1.23-3.61, P = 0.0017), indicating individuals carrying at least one A allele had a significantly higher prevalence of chronic pain vs those with the GG genotype. No other SNPs showed a significant association after multiple comparison correction. Conclusions:The SLC6A3 rs2963257 polymorphism is associated with chronic pain susceptibility in the Japanese population. Specifically, the A allele appears to increase susceptibility under a dominant model, suggesting the GG genotype may have a protective effect against chronic pain.
Introduction:Paracetamol (PCM) is extensively administered in clinical settings to alleviate mild to moderate pain and/or decrease fever. However, noncompliance with prescribed dosages can lead to severe and irreversible liver damage from PCM overdose. Although N-acetylcysteine (NAC) serves as the standard antidote for PCM toxicity, no commercially available combination of PCM and NAC has been marketed to mitigate its toxic effects. Objectives: This study aims to evaluate both the antinociceptive and hepatoprotective effects of the PCM and NAC combination in a murine model. Methods:Male and female C57Bl6/J mice were assigned to 4 groups. Group A received oral PCM exclusively, administered every 6 hours (4 doses within 24 hours), whereas groups B-D were administered PCM alone, a combination of PCM/L-NAC (N-acetyl-l-cysteine), or PCM/D-NAC (N-acetyl-d-cysteine) every 4 hours (6 doses within 24 hours). Results:Both PCM/L-NAC and PCM/D-NAC combinations yielded superior analgesia compared with the standard regimen. Furthermore, L-NAC administration mitigated the increase of glutamate pyruvate transaminase, a key hepatic marker associated with PCM hepatotoxicity. In addition, a protective effect from D-NAC in conjunction with PCM on glutathione levels was suggested. Our findings suggest that NAC enhances the analgesic properties of PCM while concurrently reducing its hepatotoxic potential in mice. Moreover, data indicate that L-NAC may represent a more effective candidate than D-NAC for this purpose, particularly regarding hepatoprotection. Conclusion:This study presents novel insights into the synergistic effects of the PCM/NAC combination on pain relief and hepatic safeguarding, warranting consideration for the development of novel therapeutic strategies targeting pain and fever management in patients.
Introduction:Complex regional pain syndrome (CRPS) is a disabling condition relying in part on the production of pain-supporting autoantibodies. The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling system regulates the adaptive system of immunity and is targeted to control autoimmune diseases. Objectives:To evaluate the hypothesis that JAK-STAT inhibition could reduce the behavioral, cellular, and biochemical correlates of CRPS in a well-characterized murine tibia fracture model. Methods:Tofacitinib was used to inhibit JAK-STAT activity. Mechanical sensitization and hindlimb unweighting were used to follow nociceptive changes. Assays of regional lymph node hypertrophy, germinal center formation, and autoantibody production probed activation of adaptive immunity while single cell mass cytometry (CyTOF) identified specific cell sets sensitive to tofacitinib in this model. Results:Tofacitinib reduced hindlimb allodynia and unweighting in male and female mice after tibial fracture. Subsequent experiments focused on male mice showed reduced autoantibody binding to keratin 16, histone 3.2, GFAP, and NMDAR2B in fracture animals treated with tofacitinib. The enhanced deposition of IgM in the skin of fracture limb hind paws was also eliminated by tofacitinib. Correspondingly, tofacitinib reduced lymph node hypertrophy and germinal center formation. Mass cytometry demonstrated that CD4+ and CD8+ T lymphocytes in regional lymph nodes show tofacitinib-sensitive changes in the activation of key immune signaling systems after fracture including BCL6, IkB, pCREB, and pS6. Conversely, enhanced production of the innate immune mediators IL-1β and IL-6 were not suppressed by tofacitinib. Conclusions:We conclude that tofacitinib reduces the regional nociceptive changes found in a murine model of CRPS possibly through inhibition of autoantibody production.
Introduction:Nonspecific chronic low back pain (cLBP) frequently accompanies psychiatric comorbidities, including anxiety, depression, insomnia, and substance use disorders (SUDs), which worsen patient outcomes. However, research characterizing the prevalence and temporal risk of these comorbidities using large-scale, age-stratified data remains limited. Objectives: This study evaluated the prevalence of anxiety, depression, insomnia, and SUDs after cLBP diagnosis and the population's vulnerability to these conditions. Methods:We performed a retrospective cohort study using the TriNetX network, analyzing deidentified electronic health records from over 150 million patients. Individuals with cLBP from 2014 to 2023 were categorized into age groups (0-25, 26-49, and 50+ years) based on neurodevelopmental milestones and cLBP epidemiology. Annual point prevalence of anxiety, depression, insomnia, and SUDs was calculated for each group. Competing risk analysis determined the 10-year cumulative incidence of each outcome after cLBP diagnosis. Results:Among 1,045,921 individuals with cLBP, all psychiatric comorbidities rose in prevalence across age groups from 2014 to 2023. By 2023, anxiety prevalence reached 30.8% (0-25), 39.0% (26-49), and 33.0% (50+); depression prevalence was 20.9%, 28.7%, and 27.1%, respectively. Insomnia prevalence increased from 6.9% (0-25) to 13.6% (26-49) and 20.1% (50+). SUD substantially increased from 0 to 25 (7.73%) to 26 to 49 (27.7%) and 50+ (23.2%) groups. For all groups, females showed higher anxiety, depression, and insomnia rates, whereas SUDs were more common in males. Ten-year competing risk cumulative incidence showed that anxiety had the highest risk across all groups: 30.5% (0-25), 27.3% (26-49), 20.5% (50+). Conclusion:Individuals with cLBP face a rising and substantial burden of psychiatric comorbidities, with age- and sex-specific increasing patterns. Screening and interventions should be tailored by age to improve outcomes for this high-risk population.
Commentary on: Habermann MB, Christian MB. Uncontrollability of experimental pain decreases pain intensity and relief pleasantness ratings in a between- group design. PAIN Rep 2026;11:e1448.
