2026-04-01
David Josefsson, Louise Danielsson, Max Jakobsson
BackgroundA range of studies have shown that psychological and lifestyle factors are associated with musculoskeletal pain. The factors also correlate with persistent systemic inflammation. Since systemic inflammation is also present in numerous conditions involving musculoskeletal pain, it is of interest to examine whether systemic inflammation mediates the relationship between psychological and lifestyle factors and musculoskeletal pain.MethodsA systematic review was conducted according to the PRISMA guidelines. The PubMed, Scopus and PsycINFO databases were searched for studies examining systemic inflammation as a mediating factor between psychological and/or lifestyle factors and musculoskeletal pain. Studies were grouped into three themes of influencing factors; sleep disturbances, obesity and psychological factors. A risk of bias assessment tool for mediation studies was used to assess methodological quality. A narrative synthesis of outcomes was performed.ResultsTwenty-one articles were included in the review. Evidence derived primarily from moderate-quality studies suggested small but significant mediating effects of systemic inflammation on the relationship between sleep disturbance and musculoskeletal pain, as well as between obesity and osteoarthritis. In contrast, no consistent mediating effects were observed for psychological factors. However, findings from studies of low to moderate quality indicated potential interaction effects, suggesting that psychological factors may lead to pain in the presence of systemic inflammation.ConclusionSystemic inflammation may represent a biological pathway linking sleep disturbances and obesity to musculoskeletal pain, likely operating alongside other mediating factors. For psychological factors, systemic inflammation appears to act as an interacting variable rather than a direct mediator of pain. Given the reliance on cross-sectional data in current research, longitudinal studies are essential to confirm these causal mechanisms and to evaluate the clinical significance of targeting systemic inflammation in pain management.
DOI: 10.3389/fpain.2026.17557442026-03-31
Roaa Shaban
Pain in non-verbal children with neurocognitive impairment (NCI) remains a complex and frequently under-recognized clinical challenge. Accurate pain assessment is essential for effective management, and is often hindered by non-verbal presentation, developmental adaptability, and the influence of sedation or illness. In response to these challenges, several observational tools have been developed to identify pain-related behaviors in non-verbal children. Among the most widely used tools is the Face, Legs, Activity, Cry, and Consolability (FLACC) scale, which was originally validated in young children and later adapted for use in children with communication barriers. Its revised version included additional behavioral descriptors tailored to children with cognitive impairments (CI). Similarly, the Non-Communicating Children's Pain (NCCP) Checklist was specifically developed for children with CI and provides a structured assessment across multiple behavioral domains. These tools have shown strong clinical utility and reliability, particularly in postoperative and critical care settings. Although both FLACC and the NCCP Checklists have proven effective, the latter is more designed to children with significant CI, suggesting a broader set of pain indicators. However, both tools require trained observers and clinical familiarity for optimal use. This review explores the strengths and limitations of these and other pain assessment tools, emphasizing the need for individualized approaches and validated instruments to ensure accurate pain recognition and treatment in pediatric populations, particularly those with NCI, including cases where critical illness further limits communication.
DOI: 10.3389/fpain.2026.17516042026-03-30
Giovanni Iolascon, Antimo Moretti
Sarcopenia and pain are two highly prevalent conditions in aging populations, each exerting profound effects on mobility, independence, and quality of life. Emerging evidence demonstrates that these conditions are not merely coincidental but are closely interconnected through shared biological, mechanical, and neurophysiological pathways. Pain reduces physical activity, accelerates muscle wasting, and fosters functional decline, while sarcopenia increases vulnerability to painful syndromes such as osteoarthritis, fragility fractures, and low back pain. This bidirectional relationship is further amplified by chronic low-grade inflammation (“inflammaging”), mitochondrial dysfunction, and central sensitization, creating a vicious cycle of musculoskeletal fragility and disability. Despite robust epidemiological data, current diagnostic frameworks for sarcopenia fail to integrate pain dimensions, risking misclassification and underestimation of disease burden. Novel screening approaches that combine anthropometric measures with validated pain assessments may improve case finding and clinical management. This narrative review synthesizes epidemiological insights, mechanistic links, and diagnostic challenges, and advocates for integrated strategies that simultaneously target muscle health and pain management. Recognizing pain as both a determinant and consequence of sarcopenia is essential to advancing prevention, rehabilitation, and multidisciplinary care in older adults.
DOI: 10.3389/fpain.2026.17599432026-03-27
Hashim Talib Hashim, Mostafa A. Khalifa, Aya Ahmed Shimal, Marafi Jammaa Ahmed, Mohamed H. Elbadawi, Khadeeja Ali Hamzah, Abdulhadi M. A. Mahgoub, Alaa R. AL-Ihribat, Salem Waleed Salem Mohamed, Fathima Raahima Riyas Mohamed, Elian Khalafalla, Amna Kamil, Anzah Imtiaz Wagga, Ahmed Mohamed Shahin, Abdelrhman H. Mohammed
BackgroundOngoing research aims to identify the most effective sedative for procedural sedation. This meta-analysis compares dexmedetomidine with midazolam-fentanyl in surgical patients.MethodsWe conducted a search through MEDLINE, EMBASE and CENTERAL to find randomized controlled trials (RCTs) comparing dexmedetomidine and midazolam-fentanyl. Data on participant characteristics, intervention details, and outcomes were extracted, focusing on intraoperative hemodynamic parameters, respiratory safety, and adverse events. Sedative efficacy and recovery profiles were also evaluated and assessed descriptively across included studies. Data were analyzed using RevMan 5.4, applying random effects models for significant heterogeneity (I2 > 50%). Studies with fewer than three data points per group were excluded, and sensitivity analyses were performed.ResultsWe include 4 RCTs with 259 patients. Dexmedetomidine significantly lowered mean arterial pressure (MAP) by −6.42 mmHg (95% CI: −8.24 to −2.21, p < 0.001). Initially, heart rate differences were not significant, but after excluding an outlier, dexmedetomidine reduced heart rates by 6.71 bpm (95% CI: −10.74 to −2.68, p = 0.001). Respiratory rate and oxygen saturation showed no significant differences between groups, and adverse events were comparable.ConclusionDexmedetomidine offers superior blood pressure control compared to midazolam-fentanyl, with similar safety profiles for respiratory parameters. Further research is needed to assess long-term outcomes such as postoperative delirium and residual sedation.
DOI: 10.3389/fpain.2026.16644602026-03-27
Paul A. Glare, Charles Brooker, Andrew D. Weiss, Daniel J. Costa, Sofia Casbolt, Llewellyn Casbolt
IntroductionCurrent pharmacotherapy options for neuropathic pain (NPP) are limited. RM191A is a novel copper-amino acid complex that mimics superoxide dismutase and has anecdotal evidence for fast-onset analgesia. The aim of this pilot randomized clinical trial (RCT) was to evaluate the safety and efficacy of a topical gel containing RM191A compared with placebo in adults with moderate-to-severe chronic peripheral NPP.Materials and methodsThis single-site study was conducted at an Australian pain clinic. Eligible patients were randomized to receive either active or placebo gel, applied four times daily to the painful site for 3 days, followed by a 4-day washout and crossover to the other gel. Co-primary outcomes were changes in the Numerical Pain Rating Scale (NPRS) scores for average pain from baseline to Days 1 and 3. Secondary outcomes included safety/tolerability and neuropathic pain characteristics.ResultsTwenty-seven participants (14 males, 13 females, mean age 67 ± 15 years) were screened, with 25 proceeding to randomization and 24 completing both treatment periods. No first-order (p = 0.816) or second-order carryover effects (p = 0.322) were detected. The Day 1 coprimary outcome was not significant (p = 0.323), but there was a trend toward one-sided statistical significance for the Day 3 coprimary outcome (p = 0.073). The mean reduction in NPRS Average Pain by Day 3 was significant for the active gel (–0.9 ± 1.6, p = 0.012) but not the placebo (–0.2 ± 1.7, p = 0.485). Post hoc analysis revealed the superiority of the active gel in participants with Douleur Neuropathique 4 (DN4) scores ≥4 (n = 15, p = 0.047). The number needed to treat (NNT) for 50% pain reduction by Day 3 was 8 (95% CI: greater than 3.9). The active gel was more effective against burning pain, paroxysmal pain, and paraesthesia/dysesthesia than other types of NPP. There were no serious adverse events, while four (16%) participants reported mild skin irritation.DiscussionThis small pilot RCT found that 3 days of RM191A gel modestly reduced chronic peripheral neuropathic pain. The NNT of 8 compares favorably with topical lidocaine (14.5) and is similar to duloxetine (7.4) and gabapentinoids (8.9). Larger, longer studies in well-defined neuropathic pain populations are warranted.Clinical Trial RegistrationANZCTRN 12617000206325. https://www.anzctr.org.au/
DOI: 10.3389/fpain.2026.17728992026-03-26
Lauren E. Penz, Andrew W. Nelson, F. Clay Smither, Jonathan M. Hagedorn
IntroductionThis case describes the application of spinal cord stimulation for the treatment of phantom limb pain in a patient with a left transhumeral amputation. Treatment of pain involving a high frequency spinal cord stimulator allowed the patient to utilize his myoelectric prosthesis and improve his overall function.Clinical findingsSevere, phantom limb pain with associated involuntary muscle contractions prevented the patient from wearing a prosthesis for more than three hours per day. He also had difficulty using his myoelectric prosthesis to use his left upper extremity for functional tasks.Therapeutic interventionA high frequency spinal cord stimulator was placed at the level of the cervical spine. The patient had improvement in pain and overall function. He was also able to tolerate wearing his prosthesis longer each day.ConclusionHigh frequency spinal cord stimulation may be an effective treatment option for individuals with phantom limb pain. Treatment of phantom limb pain may decrease barriers to prosthesis use and improve overall function.
DOI: 10.3389/fpain.2026.17516942026-03-23
Licia Lugli, Elisabetta Garetti, Maria Federica Roversi, Arianna Bianchini, Riccardo Cuoghi Costantini, Isotta Guidotti, Michele De Novellis, Eugenio Spaggiari, Paola Lago, Alberto Berardi
BackgroundTherapeutic hypothermia (TH) is the standard treatment for moderate to severe hypoxic–ischemic encephalopathy (HIE), yet pain assessment during TH remains challenging. This study compares two validated pain scales in asphyxiated newborns undergoing TH and receiving fentanyl analgesia.MethodsTwenty term infants with HIE treated with TH were enrolled. Pain was assessed using EDIN and N-PASS, while sedation was monitored using the N-PASS sedation subscale.ResultsN-PASS pain and sedation scores significantly decreased by day 3, whereas EDIN scores showed no significant temporal change. Effective analgesia significantly increased over time, either when defined based on EDIN (OR 3.12, p = 0.002) and on N-PASS (OR 3.06, p = 0.007), while N-PASS sedation did not show a time-dependent association. No scale showed a significant association with fentanyl dosage. A moderate positive correlation was found between EDIN and N-PASS pain scores (r = 0.409, p < 0.001). Sedation targets were achieved in only 40%–50% of assessments, with early undersedation and later oversedation observed.ConclusionsEDIN and N-PASS pain scores demonstrate moderate concordance, but capture different dimensions of neonatal pain during TH. N-PASS appears more sensitive to temporal changes, likely due to its combined behavioral and physiological components, whereas EDIN may be affected by hypothermia-related behavioral suppression.
DOI: 10.3389/fpain.2026.17836112026-03-18
Danlin Zhu, Han Zhenkai
Given the rapid expansion of AI applications across multiple dimensions of cancer pain management, there is an urgent need to synthesize current evidence and clarify future directions to guide clinical and research practice. Cancer pain remains one of the most central and challenging issues in pain medicine. Its pathogenesis is multifaceted, involving tumor invasion, treatment-related injury, and diverse biopsychosocial factors; assessment is difficult, treatment decisions involve numerous variables, and long-term management is resource-intensive. Epidemiological data indicate that approximately half of all patients with cancer experience moderate-to-severe pain during the disease course, with the burden markedly higher in advanced stages. The rapid advancement of AI in medicine has spurred growing interest in its potential contributions to cancer pain assessment, analgesic decision-making, remote follow-up, and interventional planning. This mini-review, organized from a clinical care-pathway perspective, summarizes recent applications of AI in cancer pain assessment, opioid management, remote monitoring, and interventional or longitudinal care. We further discuss methodological and real-world challenges, emphasizing how AI may ultimately contribute to an integrated, longitudinal management framework for cancer pain.
DOI: 10.3389/fpain.2026.17529582026-03-18
Raymundo Salcedo, Reihaneh Moghadam, Sahar Saneifard, Alexander Zhou, Vafi Salmasi
IntroductionClinical trials for neuropathic pain often employ strict exclusion criteria that may limit the generalizability of their findings to real-world clinical populations. This study systematically analyzed the nature, prevalence, and reporting quality of exclusion criteria in neuropathic pain trials.MethodsWe conducted a systematic review of studies published from 2012 to 2022 to analyze exclusion criteria from clinical trials studying treatments for neuropathic pain. We extracted data on the number, type, and frequency of exclusion criteria used. We also analyzed patient flow metrics, including screening, eligibility, enrollment, and completion rates, identified key missing information, and performed correlations between different exclusion criteria to establish patterns in exclusion criteria use.ResultsWe included 161primary clinical trial publications of neuropathic pain interventions in our analysis. Most trials examined medication-based interventions and were placebo/sham controlled. The median number of exclusion criteria per study was 5 (IQR 4–7)). Medical comorbidities (86.4%), age restrictions (71.0%), and minimum pain score requirements (71.6%) were used most often as exclusion criteria. Psychological comorbidities were excluded in 56.8% of trials, despite being common in chronic pain populations. Only 36.4% of trials reported the number of patients screened, and 43.8% reported eligibility numbers, highlighting significant gaps in transparent reporting. Among trials that did report patient flow metrics, the mean eligibility rate was 67.9% of screened patients, while the mean enrollment rate was 60.9% of screened patients. We observed moderate correlations between certain exclusion criteria, particularly between minimum pain duration and score requirements (r = 0.56), and weak correlation between the presence of other painful conditions and patients on other treatments (r = 0.40).ConclusionsOur findings demonstrate that neuropathic pain trials frequently employ multiple exclusion criteria that may significantly limit their generalizability to clinical practice. The high prevalence of psychological comorbidity exclusions is particularly concerning given their common co-occurrence with chronic pain. Additionally, inconsistent reporting of patient flow metrics hampers the assessment of how exclusion criteria affect trial recruitment and generalizability. We recommend standardization of exclusion criteria reporting and careful consideration of whether strict exclusions truly serve trial objectives.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD42023387885, identifier CRD42023387885.
DOI: 10.3389/fpain.2026.1716686