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Introduction. Fibromyalgia syndrome (FMS) is a pain disorder with an estimated prevalence of 1–5%. It is associated with a variety of somatic and psychological disorders. Its exact pathogenesis is still unclear but is involved with neural oversensitization and decreased conditioned pain modulation (CPM), combined with cognitive dysfunction, memory impairment, and altered information processing. Connectivity between brain areas involved in pain processing, alertness, and cognition is increased in the syndrome, making its pharmacologic therapy complex. Only three drugs, pregabalin, duloxetine, and milnacipran are currently FDA-approved for FM treatment, but many other agents have been tested over the years, with varying efficacy. Areas Covered. The purpose of this review is to summarize current clinical experience with different pharmacologic treatments used for fibromyalgia and introduce future perspectives in developing therapies. Expert Opinion. Future insights into the fields of cannabinoid and opioid research, as well as an integrative approach towards the incorporation of genetics and functional imaging combined with additional fields of research relevant towards the study of complex CNS disorders, are likely to lead to new developments of novel tailor-made treatments for FMS patients.

Fibromyalgia is a chronic pain syndrome with unsatisfactory response to current treatments. Physical trauma, including traumatic brain Injury (TBI) is among the etiological triggers. Hyperbaric Oxygen therapy (HBOT) is an intervention that combines 100% oxygen with elevated atmospheric pressure. HBOT has been applied as a neuro-modulatory treatment in central nervous system–related conditions. The current study investigated the utility of HBOT for TBI–related fibromyalgia. Fibromyalgia patients with a history of TBI were randomized to either HBOT or pharmacological intervention. HBOT protocol comprised 60 daily sessions, breathing 100% oxygen by mask at 2 absolute atmospheres (ATA) for 90 minutes. Pharmacological treatment included Pregabalin or Duloxetine. The primary outcome was subjective pain intensity on visual analogue scale (VAS); Secondary endpoints included questionnaires assessing fibromyalgia symptoms as well as Tc-99m-ECD SPECT brain imaging. Pain threshold and conditioned pain modulation (CPM) were also assessed. Results demonstrated a significant group-by-time interaction in pain intensity post-HBOT compared to the medication group (p = 0.001), with a large net effect size (d = -0.95) in pain intensity reduction following HBOT compared to medications. Fibromyalgia related symptoms and pain questionnaires demonstrated significant improvements induced by HBOT as well as improvements in quality of life and increase in pain thresholds and CPM. SPECT demonstrated significant group-by-time interactions between HBOT and medication groups in the left frontal and the right temporal cortex. In conclusion, HBOT can improve pain symptoms, quality of life, emotional and social function of patients suffering from FMS triggered by TBI. The beneficial clinical effect is correlated with increased brain activity in frontal and parietal regions, associated with executive function and emotional processing.

Fibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the quality of life of 2-4% of the population, with 9:1 female-to-male incidence ratio. FMS is an important representative example of central nervous system sensitization and is associated with abnormal brain activity. Key symptoms include chronic widespread pain, allodynia and diffuse tenderness, along with fatigue and sleep disturbance. The syndrome is still elusive and refractory. The goal of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on symptoms and brain activity in FMS. A prospective, active control, crossover clinical trial. Patients were randomly assigned to treated and crossover groups: The treated group patients were evaluated at baseline and after HBOT. Patients in the crossover-control group were evaluated three times: baseline, after a control period of no treatment, and after HBOT. Evaluations consisted of physical examination, including tender point count and pain threshold, extensive evaluation of quality of life, and single photon emission computed tomography (SPECT) imaging for evaluation of brain activity. The HBOT protocol comprised 40 sessions, 5 days/week, 90 minutes, 100% oxygen at 2ATA. Sixty female patients were included, aged 21-67 years and diagnosed with FMS at least 2 years earlier. HBOT in both groups led to significant amelioration of all FMS symptoms, with significant improvement in life quality. Analysis of SPECT imaging revealed rectification of the abnormal brain activity: decrease of the hyperactivity mainly in the posterior region and elevation of the reduced activity mainly in frontal areas. No improvement in any of the parameters was observed following the control period. The study provides evidence that HBOT can improve the symptoms and life quality of FMS patients. Moreover, it shows that HBOT can induce neuroplasticity and significantly rectify abnormal brain activity in pain related areas of FMS patients. ClinicalTrials.gov NCT01827683.

Background Acute Kidney Injury (AKI) complicates a substantial part of patients with COVID-19. Direct viral penetration of renal cells through the Angiotensin Converting Enzyme 2 receptor, and indirect damage by the aberrant inflammatory response characteristic of COVID-19 are likely mechanisms. Nevertheless, other common respiratory viruses such as Influenza and Respiratory Syncytial Virus (RSV) are also associated with AKI. Methods We retrospectively compared the incidence, risk factors and outcomes of AKI among patients who were admitted to a tertiary hospital because of infection with COVID-19, influenza (A + B) or RSV. Results We collected data of 2593 patients hospitalized with COVID-19, 2041 patients with influenza and 429 with RSV. Patients affected by RSV were older, had more comorbidities and presented with higher rates of AKI at admission and within 7 days (11.7% vs. 13.3% vs. 18% for COVID-19, influenza and RSV, respectively p =  0.001). Nevertheless, patients hospitalized with COVID-19 had higher mortality (18% with COVID-19 vs. 8.6% and 13.5% for influenza and RSV, respectively P <  0.001) and higher need of mechanical ventilation (12.4% vs. 6.5% vs.8.2% for COVID-19, influenza and RSV, respectively, P =  0.002). High ferritin levels and low oxygen saturation were independent risk factors for severe AKI only in the COVID-19 group. AKI in the first 48 h of admission and in the first 7 days of hospitalization were strong independent risk factors for adverse outcome in all groups. Conclusion Despite many reports of direct kidney injury by SARS-COV-2, AKI was less in patients with COVID-19 compared to influenza and RSV patients. AKI was a prognostic marker for adverse outcome across all viruses. Graphical abstract

Background Fibromyalgia (FM), involving somatic, cognitive, and affective domains is often regarded as a hallmark central sensitization syndrome. Despite limited current therapeutic options, emerging understanding of its neural underpinnings offers the potential of applying novel neuromodulation strategies. Specifically, limbic dysregulation underlying abnormalities in pain modulation and somatic-affective processing, has been shown to play a key role in FM. Here, we assessed the long-term efficacy of targeted limbic self-neuromodulation for improving clinical disease burden in FM. Methods Forty-seven patients with FM participated in a double-blind, randomized, dual-control study employing a novel specialized neurofeedback probe representing amygdala activity. Patients underwent 10 sessions of either genuine neurofeedback training (NFT = 21), or sham neurofeedback training (NFS = 13), or treatment as usual (TAU = 13). Disease severity and symptom burden were assessed using the Symptom Severity Score (SSS), along with other questionnaires administered before and after treatment. A clinical follow-up was performed 10–12 months post-intervention. Results NFT led to a significant immediate and long-term reduction in the SSS (F (2,40)  = 7.32, p  = 0.00, ηp2 = 0.27) and the Fibromyalgia Impact Questionnaire (FIQ) (F (2,40)  = 9.85, p  = 0.00, ηp2 = 0.33), alongside multidomain short- and long-term clinical benefits. NFS resulted in a long-term reduction in pain but did not affect other disease measures or overall disease burden. The TAU group showed no clinical improvements. Conclusions Our findings support the intimate involvement of limbic brain areas in the pathophysiology of FM and suggest that targeted neuromodulation offers a novel, mechanism-based approach for managing multidomain symptoms in FM. Trial registration This study was preregistered with the National Institutes of Health (NIH). Registration number: NCT02146495. Name of trial registry: Targeted Limbic Self-modulation as a Potential Treatment for Patients Suffering From Fibromyalgia  https://clinicaltrials.gov/study/NCT02146495 .

Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by disruptions in pain processing within the central nervous system. It exhibits a high prevalence among patients with a history of traumatic experiences, notably childhood sexual abuse (CSA). This study compared the efficacy of hyperbaric oxygen therapy (HBOT) to the current pharmacological standard of care for individuals suffering from CSA-related FMS. Forty-eight participants diagnosed with FMS and a history of CSA were randomly assigned to either the HBOT group (60 sessions of 100% oxygen at 2 ATA for 90 min, with air breaks every 5 min) or the medication (MED) group (FDA-approved medications, Pregabalin and Duloxetine). The primary endpoint was the Fibromyalgia impact questionnaire (FIQ) score, while secondary endpoints encompassed emotional status and daily functioning questionnaires, as well as pain thresholds and conditioned pain modulation tests. Brain activity was evaluated through single photon emission computed tomography (SPECT). Results revealed a significant group-by-time interaction for the FIQ score favoring HBOT over MED (p < 0.001), with a large effect size (Cohen's d = − 1.27). Similar findings were observed in emotional symptoms and functional measures. SPECT imaging demonstrated an increase in activity in pre-frontal and temporal brain areas, which correlated with symptoms improvement. In conclusion, HBOT exhibited superior benefits over medications in terms of physical, functional, and emotional improvements among FMS patients with a history of CSA. This associated with increased activity in pre-frontal and temporal brain areas, highlighting the neuroplasticity effect of HBOT.

Background Tetrahydrocannabinol (THC) has shown efficacy in alleviating chronic pain, particularly in disorders characterized by central sensitization. Offset analgesia (OA) and conditioned pain modulation (CPM) are key biomarkers used to evaluate central pain modulation. This study aimed to compare the effects of THC on OA and CPM in fibromyalgia syndrome (FMS), a prototypical condition of central sensitization. Methods In a randomized, double-blind, placebo-controlled crossover design, 23 FMS patients participated in two experimental sessions. Each session included the McGill Pain Questionnaire, visual analogue scale (VAS) assessments, and evaluations of OA and CPM, conducted both before and after sublingual administration of either THC (0.2 mg/kg) or placebo. Results THC significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo ( P  = 0.01 and P  = 0.02, respectively). THC also significantly enhanced OA relative to baseline and placebo ( P  = 0.04 and P  = 0.008), while no effect was observed on CPM ( P  = 0.27). Notably, baseline OA magnitude significantly predicted THC-induced pain relief (R² = 0.404, P  = 0.003), whereas CPM did not show a significant association ( P  = 0.121). Conclusions This is the first study to evaluate THC’s distinct effects on central pain modulation using both OA and CPM. THC selectively enhanced OA without influencing CPM, highlighting differential neural mechanisms underlying these paradigms. Furthermore, OA predicted treatment response, suggesting its potential as a biomarker for personalized cannabinoid-based therapies in FMS and other central sensitization disorders. Trial registration The study was prospectively registered on ClinicalTrials.gov (ID: NCT05644054) at 1.1.2023. Further details can be found at: https://clinicaltrials.gov/study/NCT05644054?locStr=Israel&country=Israel&cond=fibromyalgi215a%20&intr=THC&aggFilters=status:not%20rec&rank=1 .

Catecholamine infusion elicits an increase in clotting factors and this increase has been attributed to stimulation of β2-adrenorecptors (β2AR). Accordingly, we tested the hypothesis that inhalation of a short-acting selective β2AR agonist can induce a procoagulant state in healthy individuals. We recruited 23 healthy volunteers (nine females; mean age: 26±0.8 years; body mass index: 24.7±0.5 kg/m2) and randomly allocated them into two groups, the β2AR arm (seventeen subjects) and the saline arm (six subjects). Hemodynamics, plasma norepinephrine concentration, and procoagulant, anticoagulant, and fibrinolytic profiles of each participant were determined using specific assays before and after inhalation of either 2 mL nebulized normal saline or a mixture of 1 mL saline and 1 mL of salbutamol (5 mg salbutamol sulfate), a selective β2AR agonist, which were delivered by a nebulizer over ten minutes. Saline inhalation had no effect on the procoagulant, anticoagulant and fibrinolytic profiles of the six healthy volunteer in the study's saline arm. Salbutamol inhalation caused (a) a significant increase in the activity or levels of the procoagulant factors; FVIII increased by 11±3% (p = 0.04), von Willebrand factor increased by 7±1% (p = 0.03), and (b) a significant decrease in the activated partial prothrombin time from 27.4±0.4 seconds to 25.5 ±0.5 seconds (p<0.001) in the 17 volunteers in the study's β2AR arm. D-dimer and prothrombin fragments F1+2 were elevated by 200 ±90% and 505.0 ±300.0%, respectively. In addition, the activity of the anticoagulant protein C pathway (demonstrated by the protein C Global assay) decreased from 1.0±0.08 to 0.82±0.06 (p<0.001). Although plasma levels of tissue plasminogen activator decreased, all other indices of the fibrinolytic system did not change following salbutamol inhalation. We found that a single inhalation of salbutamol, a short-acting β2AR agonist, activates the clotting system without affecting the fibrinolytic system. This induction of a procoagulant state in healthy subjects warrants further investigation in patients treated with these agents.

Our understanding of chronic pain has evolved significantly, shifting from a focus on peripheral damage to recognizing the central mechanisms underlying pain perception. This perspective article explores the concept of nociplastic pain, a term introduced by the International Association for the Study of Pain (IASP) in 2017, which describes pain arising from altered pain modulation within the central nervous system, without clear evidence of tissue damage or inflammation. The historical progression from fibrositis to fibromyalgia, and now to nociplastic pain, underscores the complexity of chronic pain syndromes and the need for a multidisciplinary approach to management. Nociplastic pain is characterized by central sensitization, leading to heightened pain sensitivity and often accompanied by comorbidities such as fatigue, sleep disturbances, and cognitive difficulties. Advances in neuroimaging have revealed altered connectivity within key brain networks, such as the default mode and salience networks, in patients with nociplastic pain, providing insights into the neural underpinnings of this condition. The article also addresses controversies surrounding the role of small fiber neuropathy and autonomic dysfunction in nociplastic pain, highlighting the ongoing debates in the field. The practical importance of recognizing nociplastic pain across various medical disciplines—including primary care, orthopedics, neurology, psychiatry, and rheumatology—is emphasized, with recommendations for integrating this knowledge into clinical practice. Emerging therapies, such as neurofeedback, hyperbaric oxygen therapy, and neuromodulation, offer new avenues for treatment, particularly for patients who do not respond to conventional approaches. The article calls for continued research into the mechanisms of nociplastic pain, the development of reliable diagnostic tools, and the exploration of novel therapeutic strategies to improve patient outcomes. The recognition and management of nociplastic pain are crucial for advancing the care of patients with chronic pain, necessitating interdisciplinary collaboration and a patient-centered approach.

Objective. The association between Fibromyalgia Syndrome (FMS) and childhood maltreatment and adversity has frequently been proposed but limited data exists regarding the transcultural nature of this association. Methods. 75 Israeli FMS patients and 23 Rheumatoid Arthritis (RA) patients were compared. Childhood maltreatment was assessed by the Childhood Trauma Questionnaire (CTQ) and potential depressive and anxiety disorders were assessed by the Patient Health Questionnaire-4. FMS severity was assessed by the Widespread Pain Index (WPI), the Symptom Severity Score (SSS), and the FIQ. PTSD was diagnosed according to the DSM IV. RA severity was assessed by the RA Disease Activity Index. Health status was assessed by the SF-36. Results. Similar to reports in other countries, high levels of self-reported childhood adversity were reported by Israeli FMS patients. PTSD was significantly more common among FMS patients compared with RA patients, as well as childhood emotional abuse and physical and emotional neglect. Levels of depression and anxiety were significantly higher among FMS patients. Conclusion. The study demonstrated the cross cultural association between FMS and childhood maltreatment, including neglect, emotional abuse, and PTSD. Significant differences were demonstrated between FMS patients and patients suffering from RA, a model of an inflammatory chronic rheumatic disease.