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.

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.

Surgical procedures are necessary in up to 50% of trigeminal neuralgia patients. Although radiofrequency (RF) is more widely used, it is associated with high intraprocedural costs and long technical learning time. Other simpler procedures such as balloon compression (BC) require a lower training period and have significant lower costs. We evaluated the effects of BC and RF in pain control in primary trigeminal neuralgia in a randomized, double-blinded, head-to-head trial. Individuals were randomly allocated in 1 of 2 groups: BC and RF. Throughout pain, psychological and quality of life measurements were performed at baseline and after surgery. The main outcome was the worst pain in the last 24 hours (0-10) at 6 months postoperatively. After the inclusion of half of the estimated sample, a preplanned interim analysis was performed when 33 patients (62.1 ± 9.4 y.) completed the study. Pain intensity (confidence interval [CI] 95% 0.6 to 3.8, and −0.6 to 2.2, for BC and RF) did not significantly differ. Complications, interference of pain in daily life (CI 95% −0.1 to 2.3 and −0.4 to 2.3, for BC and RF), neuropathic pain symptoms (CI 95% 1.7 to 3.6 and 3.0 to 5.7, for BC and RF), mood (CI 95% 4.8 to 11.5 and 5.5 to 15.1, BC and RF, respectively), medication use, and quality of life (CI 95% 80.4 to 93.1 and 83.9 to 94.2, for BC and RF) were also not different. Radiofrequency presented more paresthetic symptoms than BC at 30 days after intervention. Based on these results, the study was halted due to futility because BC was not superior to RF.

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Introduction:The question of whether the human fetus experiences pain has received substantial attention in recent times. With the advent of high-definition 4-dimensional ultrasound (4D-US), it is possible to record fetal body and facial expressions. Objective: To determine whether human fetuses demonstrate discriminative acute behavioral responses to nociceptive input. Methods: This cross-sectional study included 5 fetuses with diaphragmatic hernia with indication of intrauterine surgery (fetoscopic endoluminal tracheal occlusion) and 8 healthy fetuses, who were scanned with 4D-US in 1 of 3 conditions: (1) acute pain group: Fetuses undergoing intrauterine surgery were assessed in the preoperative period during the anesthetic injection into the thigh; (2) control group at rest: Facial expressions at rest were recorded during scheduled ultrasound examinations; and (3) control group acoustic startle: Fetal facial expressions were recorded during acoustic stimulus (500-4000 Hz; 60-115 dB). Results: Raters blinded to the fetuses' groups scored 65 pictures of fetal facial expressions based on the presence of 12 items (facial movements). Analyses of redundancy and usefulness excluded 5 items for being of low discrimination capacity (P.0.2). The final version of the pain assessment tool consisted of a total of 7 items: brow lowering/eyes squeezed shut/deepening of the nasolabial furrow/open lips/horizontal mouth stretch/vertical mouth stretch/neck deflection. Odd ratios for a facial expression to be detected in acute pain compared with control conditions ranged from 11 (neck deflection) to 1,400 (horizontal mouth stretch). Using the seven-item final tool, we showed that 5 is the cutoff value discriminating pain from nonpainful startle and rest. Conclusions: This study inaugurates the possibility to study pain responses during the intrauterine life, which may have implications for the postoperative management of pain after intrauterine surgical interventions

BackgroundThe different phenotypic presentations of fibromyalgia (FM) have been infrequently studied and may have diagnostic and therapeutic implications. The aim of this study was to explore differences between FM patients with classical symmetric (s‐FM) presentation and FM patients with marked asymmetric (a‐FM) pain.MethodsWe performed two consecutive cross‐sectional studies on FM patients and matched healthy volunteers (HV). FM patients were divided into a‐FM (and s‐FM groups according to their score of pain intensity on each body side; patients with a difference of ≥40 mm in VAS between left and right sides were classified as a‐FM, otherwise classified as s‐FM. Participants (FM = 32; HV = 31) were assessed for clinical, cortical excitability (CE), quantitative sensory testing (QST; study 1), and intraepidermal nerve fibre density (IENFD) determinations (study 2).ResultsWhile pain intensity did not significantly differ between s‐FM and a‐FM patients, pain interference in daily activities was significantly higher in the a‐FM as compared to the s‐FM group (54.7 ± 8.9 and 37.6 ± 13.5; p < .0001). PPT was significantly lower in the more painful side of a‐FM as compared to the HV (27.7 ± 7.9 and 49.9 ± 13.0; p < .0001), while PPT in the less painful side of a‐FM was significantly higher than PPT values in the s‐FM (35.8 ± 8.3 and 27.7 ± 5.5; p = .031). S‐FM and a‐FM had significantly abnormal intracortical inhibition values on CE measurements compared to HV. There were no significant differences in IENFD between groups.ConclusionsWithin the current FM criteria, there exist different phenotypes with clinical, psychophysics, and neurophysiological findings that are not related to peripheral IENFD abnormalities.SignificanceCurrent fibromyalgia criteria may contain different phenotypes of fibromyalgia based on the lateralization of pain.

Introduction: Deep brain stimulation (DBS) is a treatment option for refractory dystonia's motor symptoms, while its non-motor symptoms (NMS) have been less systematically assessed. We aimed to describe the effects of DBS on NMS in refractory generalized inherited/idiopathic dystonia prospectively.Methods: We evaluated patients before and 1 year after DBS surgery and applied the following scales: Burke–Fahn–Marsden Rating Scale (BFMRS), NMS Scale for Parkinson's Disease (NMSS-PD), Parkinson's Disease Questionnaire-8, short-form Brief Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI), and short-form McGill Pain Questionnaire (MPQ).Results: Eleven patients (38.35 ± 11.30 years) underwent surgery, all with generalized dystonia. Motor BFMRS subscore was 64.36 ± 22.94 at baseline and 33.55 ± 17.44 1 year after DBS surgery (47.9% improvement, p = 0.003). NMSS-PD had a significant change 12 months after DBS, from 70.91 ± 59.07 to 37.18 ± 55.05 (47.5% improvement, p = 0.013). NMS changes were mainly driven by changes in the gastrointestinal (p = 0.041) and miscellaneous domains (p = 0.012). Seven patients reported chronic pain before DBS and four after it. BPI's severity and interference scores were 4.61 ± 2.84 and 4.12 ± 2.67, respectively, before surgery, and 2.79 ± 2.31 (0.00–6.25) and 1.12 ± 1.32 (0.00–3.00) after, reflecting a significant improvement (p = 0.043 and p = 0.028, respectively). NPSI score was 15.29 ± 13.94 before, while it was reduced to 2.29 ± 2.98 afterward (p = 0.028). MPQ's total score was 9.00 ± 3.32 before DBS, achieving 2.71 ± 2.93 after (p = 0.028).Conclusions: DBS improves NMS in generalized inherited/idiopathic dystonia, including chronic pain.