Transcranial direct current stimulation is more effective than pregabalin in controlling nociceptive and anxiety-like behaviors in a rat fibromyalgia-like model.

OBJECTIVES: Despite the fact that fibromyalgia, a widespread disease of the musculoskeletal system, has no specific treatment, patients have shown improvement after pharmacological intervention. Pregabalin has demonstrated efficacy; however, its adverse effects may reduce treatment adherence. In this context, neuromodulatory techniques such as transcranial direct current stimulation (tDCS) may be employed as a complementary pain-relieving method. Consequently, the purpose of this study was to evaluate the effect of pregabalin and tDCS treatments on the behavioral and biomarker parameters of rats submitted to a fibromyalgia-like model. METHODS: Forty adult male Wistar rats were divided into two groups: control and reserpine. Five days after the end of the administration of reserpine (1 mg/kg/3 days) to induce a fibromyalgia-like model, rats were randomly assigned to receive either vehicle or pregabalin (30 mg/kg) along with sham or active- tDCS treatments. The evaluated behavioral parameters included mechanical allodynia by von Frey test and anxiety-like behaviors by elevated plus-maze test (time spent in opened and closed arms, number of entries in opened and closed arms, protected head-dipping, unprotected head-dipping [NPHD], grooming, rearing, fecal boluses). The biomarker analysis (brain-derived neurotrophic factor [BDNF] and tumor necrosis factor-α [TNF-α]) was performed in brainstem and cerebral cortex and in serum. RESULTS: tDCS reversed the reduction in the mechanical nociceptive threshold and the decrease in the serum BDNF levels induced by the model of fibromyalgia; however, there was no effect of pregabalin in the mechanical threshold. There were no effects of pregabalin or tDCS found in TNF-α levels. The pain model induced an increase in grooming time and a decrease in NPHD and rearing; while tDCS reversed the increase in grooming, pregabalin reversed the decrease in NPHD. CONCLUSIONS: tDCS was more effective than pregabalin in controlling nociception and anxiety-like behavior in a rat model-like fibromyalgia. Considering the translational aspect, our findings suggest that tDCS could be a potential non-pharmacological treatment for fibromyalgia.

Using Home-based, Remotely Supervised, Transcranial Direct Current Stimulation for Phantom Limb Pain.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low-amplitude direct currents to alter cortical excitability. Previous trials have established the safety and tolerability of tDCS, and its potential to mitigate symptoms. However, the effects are cumulative, making it more difficult to have adherence to the treatment since frequent visits to the clinic or outpatient center are required. Moreover, the time needed for transportation to the center and the related expenses limit the accessibility of the treatment for many participants. Following guidelines for remotely supervised transcranial direct current stimulation (RS-tDCS) implementation, we propose a protocol designed for remotely supervised and home-based participation that uses specific devices and materials modified for patient use, with real-time monitoring by researchers through an encrypted video conferencing platform. We have developed detailed instructional materials and structured training procedures to allow for self- or proxy-administration while supervised remotely in real time. This protocol has a specific design to have a series of checkpoints during training and execution of the visit. This protocol is currently in use in a large pragmatic study of RS-tDCS for phantom limb pain (PLP). In this article, we will discuss the operational challenges of conducting a home-based RS-tDCS session and show methods to enhance its efficacy with supervised sessions.

Impact of multiple-session home-based transcranial direct current stimulation (M-HB-tDCS) on eating behavior in fibromyalgia: A factorial randomized clinical trial.

BACKGROUND: Multiple-session home-based self-applied transcranial direct current stimulation (M-HB-self-applied-tDCS) has previously been found to effectively reduce chronic pain and enhance cognitive function. However, the effectiveness of this method for disordered eating behavior still needs to be studied. OBJECTIVE: This study aimed to assess whether 20 sessions of M-HB-self-applied-tDCS, administered over four weeks to either the left dorsolateral prefrontal cortex (L-DLPFC) or primary motor cortex (M1), could improve various aspects of eating behavior, anthropometric measures, and adherence. METHODS: We randomly assigned 102 fibromyalgia patients between the ages of 30 and 65 to one of four tDCS groups: L-DLPFC (anodal-(a)-tDCS, n = 34; sham-(s)-tDCS, n = 17) or M1 (a-tDCS, n = 34; s-tDCS, n = 17). Patients self-administered 20-min tDCS sessions daily with 2 mA under remote supervision following in-person training. RESULTS: Generalized linear models revealed significant effects of M-HB-self-applied-tDCS compared to s-tDCS on uncontrolled eating (UE) (Wald χ2 = 5.62; df = 1; P = 0.018; effect size, ES = 0.55), and food craving (Wald χ2 = 5.62; df = 1; P = 0.018; ES = 0.57). Regarding fibromyalgia symptoms, we found a differentiated impact of a-tDCS on M1 compared to DLPFC in reducing food cravings. Additionally, M-HB-a-tDCS significantly reduced emotional eating and waist size. In contrast, M1 stimulation was more effective in improving fibromyalgia symptoms. The global adherence rate was high, at 88.94%. CONCLUSION: These findings demonstrate that M-HB-self-applied-tDCS is a suitable approach for reducing uncontrolled and emotional eating, with greater efficacy in L-DLPFC. Furthermore, these results revealed the influence of fibromyalgia symptoms on M-HB-self-applied-tDCS's, with M1 being particularly effective in mitigating food cravings and reducing fibromyalgia symptoms.

The brief measure of preoperative emotional stress screens preoperative maladaptive psychological features and predicts postoperative opioid use: an observational study.

BACKGROUND: The Brief Measure of Preoperative Emotional Stress (B-MEPS) is a suitable screening tool for Preoperative Emotional Stress (PES). However, personalized decision-making demands practical interpretation of the refined version of B-MEPS. Thus, we propose and validate cut-off points on the B-MEPS to classify PES. Also, we assessed if the cut-off points screened preoperative maladaptive psychological features and predicted postoperative opioid use. METHODS: This observational study comprises samples of two other primary studies, with 1009 and 233 individuals, respectively. The latent class analysis derived emotional stress subgroups using B-MEPS items. We compared membership with the B-MEPS score through the Youden index. Concurrent criterion validity of the cut-off points was performed with the severity of preoperative depressive symptoms, pain catastrophizing, central sensitization, and sleep quality. Predictive criterion validity was performed with opioid use after surgery. RESULTS: We chose a model with three classes labeled mild, moderate, and severe. The Youden index points -0.1663 and 0.7614 of the B-MEPS score classify individuals, in the severe class, with a sensitivity of 85.7% (80.1%-90.3%) and specificity of 93.5% (91.5-95.1%). The cut-off points of the B-MEPS score have satisfactory concurrent and predictive criterion validity. CONCLUSIONS: These findings showed that the preoperative emotional stress index on the B-MEPS offers suitable sensitivity and specificity for discriminating the severity of preoperative psychological stress. They provide a simple tool to identify patients prone to severe PES related to maladaptive psychological features, which might influence the perception of pain and analgesic opioid use in the postoperative period.

Efficacy of Home-Based Transcranial Direct Current Stimulation Over the Primary Motor Cortex and Dorsolateral Prefrontal Cortex in the Disability Due to Pain in Fibromyalgia: A Factorial Sham-Randomized Clinical Study.

This randomized, double-blind, controlled clinical trial compared the effectiveness of home-based-(HB) active transcranial direct current stimulation (a-tDCS) over the left dorsolateral prefrontal cortex (l-DLPFC) or primary motor cortex (M1) with their respective sham-(s)-tDCS to determine whether a-tDCS would be more effective than s-tDCS in reducing pain and improving disability due to pain. The study included 102 patients with fibromyalgia aged 30 to 65 years old randomly assigned to 1 of 4 tDCS groups using a ratio of 2:1:2:1. The groups included l-DLPFC (a-tDCS, n = 34) and (s-tDCS, n = 17), or tDCS on the M1 (a-tDCS, n = 34) or (s-tDCS, n = 17). Patients self-administered 20 sessions of tDCS, with 2 mA for 20 minutes each day under remote supervision after in-person training. The Mixed Model for Repeated Measurements revealed that a-tDCS on DLPFC significantly reduced pain scores by 36.53% compared to 25.79% in s-tDCS. From baseline to the fourth week of treatment, a-tDCS on M1 reduced pain scores by 45.89% compared to 22.92% over s-tDCS. A generalized linear model showed a significant improvement in the disability scale in the groups that received a-tDCS compared to s-tDCS over M1 20.54% versus 2.49% (χ2 = 11.06, df = 1, P < .001]), while on DLPFC the improvement was 14.29% and 5.77%, with a borderline significance (χ2 = 3.19, df = 1, P = .06]), respectively. A higher reduction in serum brain-derived neurotrophic factor from baseline to treatment end was positively correlated with decreased pain scores regardless of the treatment group. The application of a-tDCS over M1 increased the heat pain threshold and the function of the descending pain inhibitory system. PERSPECTIVE: These findings provide important insights: (1) HB-tDCS has effectively reduced pain scores and improved disability due to fibromyalgia. (2) The study provides evidence that HB-a-tDCS is a viable and effective therapeutic approach. (3) HB-a-tDCS over M1 improved the function of the descending pain inhibitory system and increased the heat pain threshold. Finally, our findings also emphasize that brain-derived neurotrophic factor, as an index of neuroplasticity, may serve as a valuable marker associated with changes in clinical pain measures. TRIAL REGISTRATION: Number NCT03843203.

High-beta oscillations at EEG resting state and hyperconnectivity of pain circuitry in fibromyalgia: an exploratory cross-sectional study.

Background: Electroencephalography (EEG) has identified neural activity in specific brain regions as a potential indicator of the neural signature of chronic pain. This study compared the lagged coherence connectivity between regions of interest (ROIs) associated with the pain connectome in women with fibromyalgia (FM) and healthy women (HC). Methods: We evaluated 64 participants (49 FM and 15 HC) during resting-state EEG sessions under both eyes open (EO) and eyes closed (EC) conditions. In addition to EEG measurements, we assessed clinical and psychological symptoms and serum levels of brain-derived neurotrophic factor (BDNF). The connectivity between eight ROIs was computed across eight different EEG frequencies. Results: The FM group demonstrated increased connectivity between the left dorsolateral prefrontal cortex (DLPFC) and right anterior cingulate cortex (ACC), specifically in the beta-3 frequency band (t = 3.441, p = 0.044). When comparing the EO and EC conditions, FM patients exhibited heightened interhemispheric connectivity between insular areas (t = 3.372, p = 0.024) and between the left insula (INS) and right DLPFC (t = 3.695, p = 0.024) within the beta-3 frequency band. In the EC condition, there was a negative correlation between pain disability and connectivity in the beta-3 frequency band between the left ACC and the left primary somatosensory cortex (SI; r = -0.442, p = 0.043). In the EO condition, there was a negative correlation between central sensitization severity and lagged coherence connectivity in the alpha-2 frequency band between the right ACC and left SI (r = 0.428, p = 0.014). Moreover, in the EO-EC comparison, the lagged coherence connection between the left DLPFC and right INS, indexed by the gamma frequency band, showed a negative correlation with serum BDNF levels (r = -0.506, p = 0.012). Conclusion: These findings indicate that increased connectivity between different pain processing circuits, particularly in the beta-3 frequency band during rest, may serve as neural biomarkers for the chronic pain brain signature associated with neuroplasticity and the severity of FM symptoms.

Preemptive transcranial direct current stimulation induces analgesia, prevents chronic inflammation and fibrosis, and promotes tissue repair in a rat model of postoperative pain.

This study evaluated the effects of previous exposure to Transcranial Direct Current Stimulation (tDCS) on nociceptive, neuroinflammatory, and neurochemical parameters, in rats subjected to an incisional pain model. Forty adult male Wistar rats (60 days old; weighing âˆ¼ 250 g) were divided into five groups: 1. control (C); 2. drugs (D); 3. surgery (S); 4. surgery + sham-tDCS (SsT) and 5. surgery + tDCS (ST). Bimodal tDCS (0.5 mA) was applied for 20 min/day/8 days before the incisional model. Mechanical allodynia (von Frey) was evaluated at different time points after surgery. Cytokines and BDNF levels were evaluated in the cerebral cortex, hippocampus, brainstem, and spinal cord. Histology and activity of myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAGase) were evaluated in the surgical lesion sites in the right hind paw. The results demonstrate that the surgery procedure increased BDNF and IL-6 levels in the spinal cord levels in the hippocampus, and decreased IL-1ß and IL-6 levels in the cerebral cortex, IL-6 levels in the hippocampus, and IL-10 levels in the brainstem and hippocampus. In addition, preemptive tDCS was effective in controlling postoperative pain, increasing BDNF, IL-6, and IL-10 levels in the spinal cord and brainstem, increasing IL-1ß in the spinal cord, and decreasing IL-6 levels in the cerebral cortex and hippocampus, IL-1ß and IL-10 levels in the hippocampus. Preemptive tDCS also contributes to tissue repair, preventing chronic inflammation, and consequent fibrosis. Thus, these findings imply that preemptive methods for postoperative pain management should be considered an interesting pain management strategy, and may contribute to the development of clinical applications for tDCS in surgical situations.

Transcranial Direct Current Stimulation (tDCS) Promotes state-dependent Effects on Neuroinflammatory and Behavioral Parameters in rats Chronically Exposed to Stress and a Hyper-Palatable Diet.

Chronic stress is a common condition affecting health, often associated with unhealthy eating habits. Transcranial direct current stimulation (tDCS) has been proposed to address these issues. Thus, this research investigated the effects of tDCS on biometric, behavioral, and neurochemical parameters in chronically stressed rats fed a hyper-palatable cafeteria diet (CAFD). The study lasted 8 weeks, with CAFD exposure and/or chronic restraint stress model (CRS - 1 h/day, 5 days/week, for 7 weeks) started concurrently. tDCS or sham sessions were applied between days 42 and 49 (0.5 mA, 20 min/day). CAFD increased body weight, caloric consumption, adiposity, and liver weight. It also altered central parameters, reducing anxiety and cortical levels of IL-10 and BDNF. In turn, the CRS resulted in increased adrenals in rats with standard diet (SD), and anxiety-like and anhedonic behaviors in rats with CAFD. tDCS provided neurochemical shifts in CAFD-fed stressed rats increasing central levels of TNF-α and IL-10, while in stressed rats SD-fed induced a decrease in the adrenals weight, relative visceral adiposity, and serum NPY levels. These data demonstrated the anxiolytic effect of CAFD and anxiogenic effect of stress in CAFD-fed animals. In addition, tDCS promoted state-dependent effects on neuroinflammatory and behavioral parameters in rats chronically exposed to stress and a hyper-palatable diet. These findings provide primary evidence for additional mechanistic and preclinical studies of the tDCS technique for stress-related eating disorders, envisioning clinical applicability.

The Application of Static Magnetic Stimulation Reduces Survival of SH-SY5Y Neuroblastoma Cells.

BACKGROUND/AIM: Central nervous system cancer is still a major public health issue. The effectiveness of treatments is limited and varies depending on the severity of disease. Therefore, there is a demand for the development of novel therapies. Static magnetic stimulation (SMS) emerges as a new therapeutic option. The aim of this study was to evaluate the SMS effects on neuroblastoma cells in culture. MATERIALS AND METHODS: SH-SY5Y neuroblastoma cells were exposed to 0.3T SMS for 6, 12, 24, 36, 72 h, and 6 days. Cell viability (MTT), cell death (annexin-V/PI staining) and cell cycle (DNA content), cell proliferation (CFSE), autophagy (acridine orange), and total mitochondrial mass (MitoTracker™ Red) were analyzed to establish the cellular response to SMS. RESULTS: The viability of SH-SY5Y cells was reduced after exposure to SMS for 24 h and 6 days (p<0.05), without differences for the other times (p>0.05); however, this effect was not related to cell death or cell cycle arrest (p>0.05). In contrast, the viability of human malignant melanoma (HMV-II) cells, used as a tumoral control, was not affected. In addition, stimulated SH-SY5Y cells presented a decrease in mitochondrial mass at both exposure times and a reduction in autophagy and cell proliferation after 6 days (p<0.05). CONCLUSION: SMS application appears to be a promising adjuvant therapy for the treatment of neuroblastoma since it decreases the survival of SH-SY5Y neuroblastoma cells.

Peripheral body temperature rhythm as a marker of the severity of depression symptoms in fibromyalgia.

BACKGROUND: Circadian rhythm alterations have been reported in fibromyalgia (FM) and depression. Peripheral body temperature (PBT) is a reliable measure of the circadian system, so we compared the PBT rhythm between persons with FM and controls. We evaluated PBT correlation with depression symptoms and pain severity in women with FM. METHODS: We included 101 women aged 30-65 with FM diagnosis (FM group, n = 83) and controls (n = 18). Twenty-four-hour PBT was assessed by actigraphy. For the analysis, in the FM group, the PBT measurement was divided into four periods: morning (6 a.m.-noon), afternoon (noon-6 p.m.), evening (6 p.m.-midnight), and night (midnight-6 a.m.). According to their scores on the Hamilton Depression Rating Scale (HDRS), participants were classified as having mild or moderate to severe depression symptoms. RESULTS: There was no difference in PBT between FM and controls. Subjects with FM and moderate to severe depression symptoms showed a higher PBT (p = .003) during the evening period (p = .004). The analysis of PBT rhythm revealed an interaction between time and group according to mild or moderate to severe depression symptoms (χ2 (3) = 12.79, p < .005). The pain severity was positively correlated with PBT (ß=0.22, [CI 95%, 0.07-0.37], p = .003). CONCLUSIONS: PBT rhythm was not a sensitive measure for discriminating persons with FM from controls. In FM, PBT is related to the severity of depression symptoms and pain intensity.

Effects of Hypnotic Analgesia and Transcranial Direct Current Stimulation on Pain Tolerance and Corticospinal Excitability in Individuals with Fibromyalgia: A Cross-Over Randomized Clinical Trial.

Objective: We compare the effect of HAS, a-tDCS on the left dorsolateral prefrontal cortex (l-DLPFC), and rest-testing on pain measures [(cold pressor test (CPT) (primary outcome) and heat pain threshold]. We also compare their effects on the motor evoked potential (MEP) (primary outcome), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). Methods: This randomized, blind, crossover trial included 18 women with fibromyalgia, aged from 18 to 65 years old. They received at random and in a crossover order a-tDCS over the l-DLPFC (2mA), HAS, or a rest-testing. Results: HAS compared to a-tDCS increased the pain tolerance with a moderate effect size (ES) [Cohen's f=-0.78; (CI 95%; -1.48 to -0.12)]. While compared to rest-testing, HAS increased the CPT with a large ES [Cohen's f=-0.87; (CI 95%; -1.84 to -0.09)]. The a-tDCS compared to HAS increased the MEP amplitude with large ES [Cohen's f=-1.73 (CI 95%; -2.17 to -0.17)]. Likewise, its ES compared to rest-testing in the MEP size was large [Cohen's f=-1.03; (CI 95%; -2.06 to -0.08)]. Conclusion: These findings revealed that HAS affects contra-regulating mechanisms involved in perception and pain tolerance, while the a-tDCS increased the excitability of the corticospinal pathways. They give a subsidy to investigate their effect as approaches to counter regulate the maladaptive neuroplasticity involved in fibromyalgia. Clinical Trial Registration: www.ClinicalTrials.gov, identifier - NCT05066568.

Involvement of GABAergic, glutamatergic, opioidergic, and brain-derived neurotrophic factor systems in the trigeminal neuropathic pain process.

Trigeminal neuropathic pain (TNP) is an intense pain condition characterized by hyperalgesia and allodynia; however, its neural mechanisms are not completely understood. Its management is complex, and studies that investigate its biochemical mechanisms are important for improving clinical approaches. This study aimed to evaluate the involvement of GABAergic, glutamatergic, and opioidergic systems and brain-derived neurotrophic factor (BDNF) levels in the TNP process in rats. TNP is induced by chronic constriction injury of the infraorbital nerve (CCI-ION). Nociceptive responses were evaluated using the facial von Frey test before and after the administration of GABAergic and opioidergic agonists and glutamatergic antagonists. The rats were divided into vehicle-treated control (C), sham-surgery (SS), and CCI-ION groups, and then subdivided into the vehicle (V)-treated SS-V and CCI-ION-V groups, SS-MK801 and CCI-ION-MK801, treated with the N-methyl-d-aspartate receptor selective antagonist MK801; SS-PB and CCI-ION-PB, treated with phenobarbital; SS-BZD and CCI-ION-BZD, treated with diazepam; SS-MOR and CCI-ION-MOR, treated with morphine. BDNF levels were evaluated in the cerebral cortex, brainstem, trigeminal ganglion, infraorbital branch of the trigeminal nerve, and serum. CCI-ION induced facial mechanical hyperalgesia. Phenobarbital and morphine reversed the hyperalgesia induced by CCI-ION, and the CCI-BZD group had an increased nociceptive threshold until 60 min. CCI-ION-GLU increased the nociceptive threshold at 60 min. Cerebral cortex and brainstem BDNF levels increased in the CCI-ION and SS groups. Only the CCI group presented high levels of BDNF in the trigeminal ganglion. Our data suggest the involvement of GABAergic, glutamatergic, and opioidergic systems and peripheral BDNF in the TNP process.

The Analgesic Effect of Transcranial Direct Current Stimulation in Fibromyalgia: A Systematic Review, Meta-Analysis, and Meta-Regression of Potential Influencers of Clinical Effect.

BACKGROUND: There is tentative evidence to support the analgesic effect of transcranial direct current stimulation (tDCS) in fibromyalgia (FM), with large variability in the effect size (ES) encountered in different clinical trials. Understanding the source of the variability and exploring how it relates to the clinical results could characterize effective neuromodulation protocols and ultimately guide care in FM pain. The primary objective of this study was to determine the effect of tDCS in FM pain as compared with sham tDCS. The secondary objective was to explore the relationship of methodology, population, and intervention factors and the analgesic effect of tDCS in FM. MATERIALS AND METHODS: For the primary objective, a systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized clinical trials (RCTs) investigating tDCS as an intervention for FM pain were searched in MEDLINE, Embase, and the Web Of Science. Studies were excluded if they used cross-over designs or if they did not use tDCS as an intervention for pain or did not measure clinical pain. Analysis for the main outcome was performed using a random-effects model. Risk of bias and evidence certainty were assessed for all studies using Cochrane Risk of Bias and Grading of Recommendations Assessment, Development, and Evaluation tools. For the secondary objective, a meta-regression was conducted to explore methodology, population, and intervention factors potentially related to the ES. RESULTS: Sixteen RCTs were included. Six studies presented a high risk of bias. Significant reduction in pain scores were found for FM (standardized mean difference = 1.22, 95% CI = 0.80-1.65, p < 0.001). Subgroup analysis considering tDCS as a neural target revealed no differences between common neural sites. Meta-regression revealed that the duration of the tDCS protocol in weeks was the only factor associated with the ES, in which protocols that lasted four weeks or longer reported larger ES than shorter protocols. CONCLUSIONS: Results suggest an analgesic effect of tDCS in FM. tDCS protocols that last four weeks or more may be associated with larger ESs. Definite conclusions are inadequate given the large heterogeneity and limited quality of evidence of the included studies.

Primary somatosensory cortex and periaqueductal gray functional connectivity as a marker of the dysfunction of the descending pain modulatory system in fibromyalgia.

Background: Resting-state functional connectivity (rs-FC) may aid in understanding the link between pain-modulating brain regions and the descending pain modulatory system (DPMS) in fibromyalgia (FM). This study investigated whether the differences in rs-FC of the primary somatosensory cortex in responders and non-responders to the conditioned pain modulation test (CPM-test) are related to pain, sleep quality, central sensitization, and the impact of FM on quality of life. Methods: This cross-sectional study included 33 females with FM. rs-FC was assessed by functional magnetic resonance imaging. Change in the numerical pain scale during the CPM-test assessed the DPMS function. Subjects were classified either as non-responders (i.e., DPMS dysfunction, n = 13) or responders (n = 20) to CPM-test. A generalized linear model (GLM) and a receiver operating characteristic (ROC) curve analysis were performed to check the accuracy of the rs-FC to differentiate each group. Results: Non-responders showed a decreased rs-FC between the left somatosensory cortex (S1) and the periaqueductal gray (PAG) (P < 0.001). The GLM analysis revealed that the S1-PAG rs-FC in the left-brain hemisphere was positively correlated with a central sensitization symptom and negatively correlated with sleep quality and pain scores. ROC curve analysis showed that left S1-PAG rs-FC offers a sensitivity and specificity of 85% or higher (area under the curve, 0.78, 95% confidence interval, 0.63-0.94) to discriminate who does/does not respond to the CPM-test. Conclusions: These results support using the rs-FC patterns in the left S1-PAG as a marker for predicting CPM-test response, which may aid in treatment individualization in FM patients.

Melatonin for prevention of acute kidney injury in patients treated with intravenous polymyxin B: a double-blind, placebo-controlled randomized clinical trial.

OBJECTIVES: To evaluate the effect of melatonin versus placebo on the incidence of acute kidney injury (AKI) in patients treated with polymyxin B. METHODS: We performed a single-centre, double-blind, randomized clinical trial (NCT03725267) of 30-mg oral melatonin versus placebo for patients treated with intravenous polymyxin B. Patients aged ≥18 years receiving polymyxin B for ≤48 hours were eligible. Melatonin or placebo pills were administered until the end of polymyxin B treatment or for a maximum of 14 days. The main outcome was any level of AKI. RESULTS: Eighty-eight patients were randomized: 44 in the melatonin group and 44 in the placebo group. The study ended prematurely because of polymyxin B shortage during the COVID-19 pandemic. The patients' mean age was 63.6 ± 17.3 years, and 60.2% of the patients were men. Forty-six (52.3%, 23 in each group) patients developed AKI during the follow-up period. The incidence rate of AKI was 81.9/1000 and 77.4/1000 patients per day in melatonin and placebo groups, respectively (hazard ratio, 1.09; 95% CI, 0.61-1.94; p 0.78). Renal failure and 30-day mortality were similar between the groups. Moreover, the incidence of AKI was not different in pre-specified sub-groups. DISCUSSION: Melatonin initiated in the first 48 hours of therapy did not reduce the incidence of AKI in patients treated with polymyxin B.

Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial.

INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA). The following categories were assessed: sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Profile of Chronic Pain Scale (PCP:S), Pain Pressure Threshold (PPT), and Conditioned Pain Modulation (CPM). Blood samples were collected to analyze BDNF serum levels. RESULTS: At baseline, no significant difference was found regarding all measurements. VAS pain was significantly reduced in the LDN + tDCS (p = 0.010), LDN + tDCS Sham (p = 0.001), and placebo+tDCS Sham (p = 0.009) groups. In the PCP:S, the LDN+tDCS group showed reduced pain frequency and intensity (p = 0.001), effect of pain on activities (p = 0.014) and emotions (p = 0.008). Depressive symptoms reduced after all active interventions (p > 0.001). CONCLUSION: Combined LDN+tDCS has possible benefits in reducing pain frequency and intensity; however, a placebo effect was observed in pain using VAS, and further studies should be performed to analyze the possible association.

Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial

Abstract Introduction Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. Objective The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. Methods This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA). The following categories were assessed: sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Profile of Chronic Pain Scale (PCP:S), Pain Pressure Threshold (PPT), and Conditioned Pain Modulation (CPM). Blood samples were collected to analyze BDNF serum levels. Results At baseline, no significant difference was found regarding all measurements. VAS pain was significantly reduced in the LDN + tDCS (p = 0.010), LDN + tDCS Sham (p= 0.001), and placebo+tDCS Sham (p= 0.009) groups. In the PCP:S, the LDN+tDCS group showed reduced pain frequency and intensity (p= 0.001), effect of pain on activities (p= 0.014) and emotions (p= 0.008). Depressive symptoms reduced after all active interventions (p > 0.001). Conclusion Combined LDN+tDCS has possible benefits in reducing pain frequency and intensity; however, a placebo effect was observed in pain using VAS, and further studies should be performed to analyze the possible association.