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Objective To compare the analgesic effects of stimulation of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep (d) repetitive (r) transcranial magnetic stimulation (TMS) in patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-arm parallel study. Methods Participants were randomly allocated into the active PSI-rTMS, ACC-rTMS, sham-PSI-rTMS, or sham-ACC-rTMS arms. Stimulations were performed for 12 weeks, and a comprehensive clinical and pain assessment, psychophysics, and cortical excitability measurements were performed at baseline and during treatment. The main outcome of the study was pain intensity (numeric rating scale [NRS]) after the last stimulation session. Results Ninety-eight patients (age 55.02 ± 12.13 years) completed the study. NRS score was not significantly different between groups at the end of the study. Active rTMS treatments had no significant effects on pain interference with daily activities, pain dimensions, neuropathic pain symptoms, mood, medication use, cortical excitability measurements, or quality of life. Heat pain threshold was significantly increased after treatment in the PSI-dTMS group from baseline (1.58, 95% confidence interval [CI] 0.09-3.06]) compared to sham-dTMS (−1.02, 95% CI −2.10 to 0.04, p = 0.014), and ACC-dTMS caused a significant decrease in anxiety scores (−2.96, 95% CI −4.1 to −1.7]) compared to sham-dTMS (−0.78, 95% CI −1.9 to 0.3; p = 0.018). Conclusions ACC-and PSI-dTMS were not different from sham-dTMS for pain relief in CNP despite a significant antinociceptive effect after insular stimulation and anxiolytic effects of ACC-dTMS. These results showed that the different dimensions of pain can be modulated in humans noninvasively by directly stimulating deeper SNC cortical structures without necessarily affecting clinical pain per se. ClinicalTrials.gov identifier: NCT01932905.

SummaryBackground and Objectives Although low socioeconomic status has been considered a contraindication to peritoneal dialysis (PD), no published data clearly link it to poor outcomes. The goal of this study was assessing the effect of income on survival in the Brazilian Peritoneal Dialysis Multicenter Study.Design, setting, participants, & measurements Incident PD patients enrolled in this prospective cohort from December 2004 to October 2007 were divided according to monthly family income. The median age was 59 years, 54% were women, 60% Caucasians, 41% diabetics, and 24% had cardiovascular disease. Most of them were in continuous ambulatory PD, had not received predialysis care, had Ͻ4 school years, and had a family income of Ͻ5 minimum wage (80%). Survival analysis was performed using the Kaplan-Meier method and the Cox proportional hazards model adjusting the results for age, gender, educational status, predialysis care, first therapy, PD modality, calendar year, and comorbidities.Results There were no differences in technique (log rank test 2 ϭ 4.36) and patient (log rank test 2 ϭ 2.92) survival between the groups. In the multivariate analysis, low family income remained not associated either to worse technique survival (hazard ratio [HR] ϭ 1.29; 95% confidence interval [CI] ϭ 0.91 to 1.84) or to patient survival (HR ϭ 1.40; 95% CI ϭ 0.99 to 1.99).Conclusions According to these results, economic status is not independently associated with outcomes in this large cohort and should not be considered a barrier for PD indication.

Typical and atypical antipsychotic drugs have been shown to have different clinical, biochemical, and behavioral profiles. It is well described that impairment of metabolism, especially in the mitochondria, leads to oxidative stress and neuronal death and has been implicated in the pathogenesis of a number of diseases in the brain. Considering that some effects of chronic use of antipsychotic drugs are still not well known and that succinate dehydrogenase (SDH) and cytochrome oxidase (COX) are crucial enzymes of mitochondria, in this work, we evaluated the activities of these enzymes in rat brain after haloperidol, clozapine, olanzapine, or aripiprazole chronic administration. Adult male Wistar rats received daily injections of haloperidol (1.5 mg/kg), clozapine (25 mg/kg), olanzapine (2.5, 5, or 10 mg/kg), or aripiprazole (2, 10 or 20 mg/kg) for 28 days. We verified that COX was not altered by any drug tested. Moreover, our results demonstrated that the atypical antipsychotic olanzapine inhibited SDH in the cerebellum and aripiprazole increased the enzyme in the prefrontal cortex. We also observed that haloperidol inhibited SDH in the striatum and hippocampus, whereas clozapine inhibited the enzyme only in the striatum. These results showed that antipsychotic drugs altered SDH activity but not COX. In this context, haloperidol, olanzapine, and clozapine may impair energy metabolism in some brain areas.

Central post-stroke pain affects up to 12% of stroke survivors and is notoriously refractory to treatment. However, stroke patients often suffer from other types of pain of non- neuropathic nature (musculoskeletal, inflammatory, complex regional) and no head-to-head comparison of their respective clinical and somatosensory profiles has been performed so far. We compared 39 patients with definite central neuropathic post-stroke pain with two matched- control groups: 32 patients with exclusively non-neuropathic pain developed after stroke and 31 stroke patients not complaining of pain. Patients underwent deep phenotyping via a comprehensive assessment including clinical exam, questionnaires and quantitative sensory testing to dissect central post-stroke pain from chronic pain in general and stroke. While central post-stroke pain was mostly located in the face and limbs, non-neuropathic pain was predominantly axial and located in neck, shoulders and knees (p<0.05). Neuropathic Pain Symptom Inventory clusters burning (82.1%, n=32, p<0.001), tingling (66.7%, n= 26, p<0.001) and evoked by cold (64.1%, n=25, p<0.001) occurred more frequently in central post-stroke pain. Hyperpathia, thermal and mechanical allodynia also occurred more commonly in this group (p<0.001), which also presented higher levels of deafferentation (p<0.012) with more asymmetric cold and warm detection thresholds compared to controls. In particular, cold hypoesthesia (considered when the threshold of the affected side was less than 41% of the contralateral threshold) odds ratio was 12 (95%CI: 3.8-41.6) for neuropathic pain. Additionally, cold detection threshold/ warm detection threshold ratio correlated with the presence of neuropathic pain (ρ=-0.4, p< 0.001). Correlations were found between specific neuropathic pain symptom clusters and quantitative sensory testing: paroxysmal pain with cold (ρ=-0.4; p=0.008) and heat pain thresholds (ρ=0.5; p=0.003), burning pain with mechanical detection (ρ= -0.4; p=0.015) and mechanical pain thresholds (ρ=-0.4, p<0.013), evoked pain with mechanical pain threshold (ρ= -0.3; p=0.047). Logistic regression showed that the combination of cold hypoesthesia on quantitative sensory testing, the Neuropathic Pain Symptom Inventory, and the allodynia intensity on bedside examination explained 77% of the occurrence of neuropathic pain. These findings provide insights into the clinical-psychophysics relationships in central post-stroke pain and may assist more precise distinction of neuropathic from non-neuropathic post-stroke pain in clinical practice and in future trials.

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Background: Central neuropathic pain (CNP) is often refractory to available therapeutic strategies and there are few evidence-based treatment options. Many patients with neuropathic pain are not diagnosed or treated properly. Thus, consensus-based recommendations, adapted to the available drugs in the country, are necessary to guide clinical decisions. Objective: To develop recommendations for the treatment of CNP in Brazil. Methods: Systematic review, meta-analysis, and specialists opinions considering efficacy, adverse events profile, cost, and drug availability in public health. Results: Forty-four studies on CNP treatment were found, 20 were included in the qualitative analysis, and 15 in the quantitative analysis. Medications were classified as first-, second-, and third-line treatment based on systematic review, meta-analysis, and expert opinion. As first-line treatment, gabapentin, duloxetine, and tricyclic antidepressants were included. As second-line, venlafaxine, pregabalin for CND secondary to spinal cord injury, lamotrigine for CNP after stroke, and, in association with first-line drugs, weak opioids, in particular tramadol. For refractory patients, strong opioids (methadone and oxycodone), cannabidiol/delta-9-tetrahydrocannabinol, were classified as third-line of treatment, in combination with first or second-line drugs and, for central nervous system (CNS) in multiple sclerosis, dronabinol. Conclusions: Studies that address the treatment of CNS are scarce and heterogeneous, and a significant part of the recommendations is based on experts opinions. The CNP approach must be individualized, taking into account the availability of medication, the profile of adverse effects, including addiction risk, and patients' comorbidities.

Poststroke pain (PSP) is a heterogeneous term encompassing both central neuropathic (ie, central poststroke pain [CPSP]) and nonneuropathic poststroke pain (CNNP) syndromes. Central poststroke pain is classically related to damage in the lateral brainstem, posterior thalamus, and parietoinsular areas, whereas the role of white matter connecting these structures is frequently ignored. In addition, the relationship between stroke topography and CNNP is not completely understood. In this study, we address these issues comparing stroke location in a CPSP group of 35 patients with 2 control groups: 27 patients with CNNP and 27 patients with stroke without pain. Brain MRI images were analyzed by 2 complementary approaches: an exploratory analysis using voxel-wise lesion symptom mapping, to detect significant voxels damaged in CPSP across the whole brain, and a hypothesis-driven, region of interest-based analysis, to replicate previously reported sites involved in CPSP. Odds ratio maps were also calculated to demonstrate the risk for CPSP in each damaged voxel. Our exploratory analysis showed that, besides known thalamic and parietoinsular areas, significant voxels carrying a high risk for CPSP were located in the white matter encompassing thalamoinsular connections (one-tailed threshold Z . 3.96, corrected P value ,0.05, odds ratio 5 39.7). These results show that the interruption of thalamocortical white matter connections is an important component of CPSP, which is in contrast with findings from nonneuropathic PSP and from strokes without pain. These data can aid in the selection of patients at risk to develop CPSP who could be candidates to pre-emptive or therapeutic interventions.