Postoperative pain after craniotomy is an important clinical concern because it might lead to brain hyperemia and elevated intracranial pressure. Considering the side effects of opioid, several studies have been conducted to investigate the effect of local anesthetics, especially the scalp block, on postoperative pain. However, the strength of evidence supporting this practice for postoperative pain after craniotomy was unclear and the best occasion of scalp block was also not identified. Therefore, we conducted a meta-analysis to evaluate the efficacy, safety, and the best occasion of scalp block for postoperative pain after craniotomy.PubMed, Embase, and the Cochrane Library databases from database inception to October 10, 2021 were searched for all randomized controlled trials evaluating the effect of scalp block on postoperative pain after craniotomy. Data were assessed by StataMP 16 software.A total of 12 studies were included. A random-effect model was used to analyze all data. Patients under scalp block earned fewer scores than the non-scalp block group in visual analogue scale at the very early period , early period  and intermediate period . Scalp block could also significantly prolong the time of the first request of rescue analgesia and reduce the use of additional analgesics without a significant difference in the incidence of complications. Subgroup analysis showed there was no significant difference in analgesia effect between pre-incision scalp block and post-incision scalp block in all periods.Scalp block could lead to lower pain intensity scores, more time of the first request of rescue analgesia, and fewer analgesic drugs applied in the first 12 h after craniotomy. There was no significant difference between pre-incision and post-incision scalp block in the occurrence and severity of postoperative pain. Craniotomy is an effective treatment of cerebral diseases and injuries, and postoperative pain is an important clinical concern. 86% of patients probably had the pain of somatic origin, with the involvement of soft tissues and pericranial muscles . ElevateScalp block was a common technique in craniotomy and was widely used to reduce the hemodynamic response and incisional pain during craniotomy procedure –15. AnalA meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. As our study was based on published literature data, ethical approval or patient consent was not required. Besides, only studies reporting ethical approval or patient consent were included in our meta-analysis.In this meta-analysis, 2 investigators performed a systematic literature search using keywords “scalp block” and “craniotomy” in PubMed, Embase, and the Cochrane Library databases from database inception to October 10, 2021, to identify randomized clinical trials that reported scalp block vs. non-scalp block in patients scheduled for craniotomy. To avoid omissions, the reference lists of all relevant articles were manually searched.Inclusion criteria were defined as follows: (1) Study type: only randomized controlled trials; (2) Population: patients aged >18 years; (3) Intervention: scalp block; (d) Studies that reported at least one of the following outcome measures: pain intensity measured by the visual analogue score, time of the first request of rescue analgesia, additional analgesia requirement in the first 24 h, and adverse events in the first 24 h.Exclusion criteria were designed as follows: (1) Types of articles: reviews, case reports and retrospective studies; (2) Any study using methods other than placebo and systemic analgesia in the control group; (3) Any study had scalp block in all arms.Two investigators extracted the following data from the included studies: (1) Number of patients; (2) occasion of scalp block; (3) Postoperative pain treatment modality (occasion and the dosage); (4) Pain intensity for all time points; (5) Time of the first request of rescue analgesia; (6) Additional analgesia requirement in the first 24 h; (7) adverse events in the first 24 h. Data was recorded on a dedicated data extraction form.The primary outcome was pain intensity measured by the visual analogue score within 48 h postoperative period. The interval of 0 to 100 pain intensity of VAS was rescaled to a standard interval of 0 to 10. In this study, pain level measurements were categorized into five time periods: (1) very early: < 2 h; (2) early: ≥2 h but <6 h; (3) intermediate: ≥6 h but <12 h; (4) late: ≥12 h but <24 h; (5) very late: ≥24 h but ≤48 h. When there were multiple intervention groups, all relevant experimental intervention groups or relevant control intervention groups were combined into one group. The average of their mean and standard deviation had been calculated at the same time.Subgroup analysis was conducted to evaluate efficacy in two subgroups. According to the occasion of scalp block, subgroups were classified as pre-incision scalp block and post-incision scalp block.Reviews Manager 5.4 software was used to evaluate the risk of bias in each study. Two investigators used the uniform criteria of the Cochrane collaboration for assessing the risk of bias, including selection bias, performance bias, detection bias, reporting bias, performance bias, detection bias, attrition bias, reporting bias, and other potential biases. The result of each aspect was divided into low risk, high risk, or unknown risk.I2 = 25%–50%), substantial (I2 = 50%–75%) or considerable (I2 ≥ 75%)  or the odds ratio (OR) using a 95% confidence interval (CI) separately. Standard mean difference (SMD) was used for additional analgesia requirements in first 24 h because the specific drug and route of administration varied among trials. Heterogeneity was classified as moderate (2 ≥ 75%) . Owing t2 ≥ 75%) . SubgrouA total of 225 articles from PubMed, Embase, and Cochrane Library databases were identified. 182 records were removed because of duplication or irrelevance to the study. 31 other records were excluded because they were comments (1 record), reviews (19 records), meta-analyses (5 records), and conference abstracts (6 records). The entire process of study search, selection, and inclusion are shown in Details of the included studies are shown in The summary of the meta-analysis results was in There was lower pain intensity in patients receiving scalp block at the very early period , early period  and intermediate period  than the non-scalp block group –S2. No sSix studies reported the time of the first request of rescue analgesia and there was an overall increment associated with scalp bock . Scalp block led to a notably decrease on additional analgesia requirement in first 24 h .Nausea and vomiting odds ratio in the first 24 h related to scalp block was 0.61 (95% CI = 0.23 to 1.67) as shown in According to the occasion of scalp block, patients were divided into pre-incision scalp block group and post-incision scalp block group. Pre-incision scalp block was significantly effective at the very early and early period, whereas pre-incision scalp block showed a significant reduction in pain scores at early and intermediate period after surgery –S4. TherEgger's publication bias plot was used to assess the potential risk of publication bias This meta-analysis of 12 randomized controlled trials reviewed the available evidence to evaluate the efficacy and safety of scalp block for postoperative analgesia after craniotomy. Combining all studies, we found scalp block was effective in reducing short-term pain without increasing the risk of associated complications, no matter whether it was used before or after incision.Postoperative pain after craniotomy is mainly localized in the incision and surrounding soft tissues and is less likely to be a widespread headache. The pathophysiological mechanisms of postoperative pain involve different pathways of injury perception. The effects of different analgesic techniques acted on these injury perception pathways. To block the scalp innervation and to anesthetize both the superficial layers of the scalp, local anesthetic infiltration has been accepted by many neurosurgeons, but the effect is short-lived. A study conducted by Akcil et al.  found anRescue analgesia is usually applied when the pain score is above a certain value, or the pain is unbearable. The longer time of first request of rescue analgesia  and the less usage of additional analgesics  were found in our study. The fewer additional analgesics used postoperatively, the associated side effects like gastrointestinal bleeding caused by NSAIDs or ventilation depression caused by opioids are less likely to occur.Concerns about postoperative pain management revolved around the side effects of sedation, miosis, nausea, and vomiting, which could probably mask some crucial clinical symptoms. Expect for a trial of Gazoni et al. , none ofWe conducted a subgroup analysis to figure out the advantages and disadvantages of the different occasion of scalp block and found that there was no significant difference in analgesia effect between pre-incision scalp block and post-incision scalp block. However, we found different periods of postoperative analgesia: pre-incision scalp block was effective for analgesia at very early and early periods, but post-incision scalp block was better at the early and intermediate periods. Considering the same duration of effect of scalp block, it's important to allow effective time to cover the most critical periods. When only considering the postoperative analgesic effect, performing scalp block postoperatively was recommended. However, pre-incision scalp block might also have the advantage of blunting the hemodynamic response to noxious stimuli such as cranial stapling, skin dissection, and flap stripping, which is of great importance when patients are scheduled for awake craniotomies. In general, the occasion of scalp block should be determined upon which purpose the neurosurgeons want to achieve. We believed that pre-incision scalp block should be applied when better intraoperative analgesia was needed, otherwise post-incisional scalp block was more reliable.Overall, Scalp block is a safe and reliable technique that can effectively reduce patients' pain in the first 12 h after craniotomy, and the results of our study supported its use in postoperative analgesia after craniotomy.Several limitations were objectively included in this study. First, only 12 randomized controlled studies were included in the study and no more data were available to support our conclusions. Secondly, there were also methodological differences among the included trials, such as different types and doses of local anesthetics. Thirdly, we did not focus on the relevance between the duration of craniotomy and the effect of scalp block on postoperative pain after craniotomy. We hope more trials and studies related to scalp block could be conducted in the future to support our conclusion.


Background: Frequency Rhythmic Electrical Modulated System (FREMS) is a method of transcutaneous treatment based on frequency-modulated electromagnetic neural stimulation. Its efficacy in neuropathic pain in diabetes mellitus still lacks enough research. Methods: A randomized, single-blind, sham-controlled trial in individuals with symmetric distal polyneuropathy (SDPN) as an add-on therapy compared to standard therapy with alpha-lipoic acid. Participants were randomized to FREMS and standard of care (SOC) versus SOC only. The primary outcome was a change from baseline in perceived pain assessed by visual analogue scale (VAS) after 5 days of treatment and after 8 weeks of follow-up between treatment groups. Results: After 5 days of treatment, patients in both groups felt significant reduction in pain as measured by VAS, although only FREMS treatment lasted for 8 weeks and induced a significant improvement in quality of life measured by EuroQol 5-Dimension 5-Level (EQ-5D-5L) and Clinical Global Impression of Change (CGI-C) questionnaires. There were non-significant differences observed in the instrument pain assessment. No relevant side effects were recorded during the study. Conclusions: FREMS as an addition to alpha-lipoic acid therapy occurred to be a beneficial method of treatment in individuals with SDPN and was associated with improvements in pain severity, quality of life and clinical global improvement. Diabetes mellitus (DM) is a chronic disease and a growing public health problem. It can lead to severe and progressive macro- and micro-vascular complications and results in increased mortality and decreased quality of life. One of diabetes chronic microvascular complications is a symmetric symptomatic diabetic peripheral neuropathy (DSPN). It is an important diabetic complication with a lifetime prevalence of more than 50% among people with diabetes. Among DSPN symptoms, neuropathic pain (painful DSPN) affects up to 30% of all individuals ,2. NeuroFrequency Rhythmic Electrical Modulated System (FREMS) is a method of transcutaneous treatment based on frequency-modulated electromagnetic neural stimulation. It is proposed as an innovative and valid method of treatment of various disorders beginning from sports injuries , through musculoskeletal disorders, such as radiculopathies , to peripheral neurovascular complications, such as diabetic neuropathy, vasculopathies , chronic ulcers of various etiology . FREMS efficacy in neuropathic pain in diabetes mellitus still lacks enough research.The primary endpoint of the study was the treatment’s effect on pain perception on the visual analogue scale (VAS) assessed each day in the morning. Secondary endpoints included changes in tactile sensation, temperature sensation and vibration sensation threshold on feet and changes in knee and ankle reflexes. Moreover, during the study, the patients’ quality of life was assessed by a five-level version of the EQ-5D (EQ-5D-5L). A seven-point Clinical Global Impression-Improvement scale (CGI-I) was used to track patients’ progress and treatment response over time.Patients meeting the following criteria were enrolled to the study: (1) aged 18 years old and older; (2) diagnosed with diabetes mellitus type 1 or 2; (3) symptomatic diabetic polyneuropathy affecting the lower extremities with at least one positive sensory symptom, such as pain, burning, paraesthesia or prickling; (4) without changes in neuropathy treatment during last 30 days (stable doses of pain medications or other medications prescribed for diabetic neuropathy); (5) assessed by the investigator as able to maintain compliance and cooperation for 8 weeks of the trial. Exclusion criteria were as follows: (1) lack of informed written consent to participate in the study; (2) ankle-brachial index (ABI) < 0.5 suggesting ischaemia; (3) presence of an implanted pacemaker, defibrillator or neurostimulator; (4) treatment with TENS or other electrotherapy for diabetic neuropathy during last year; (5) pregnancy; (6) any concomitant severe disease limiting compliance to study procedures or life expectancy. The study participants were asked about the presence of neuropathy symptoms, such as burning, a painful feeling of cold or hot, pins and needles, electric shocks, pricking, numbness and itching. They underwent a neurological assessment as described below. The patients screened to the study were hospitalized in the Diabetology Clinic, Institute of Rural Health in Lublin, Poland for at least 5 days of treatment. The duration of the follow-up period was planned for the next 8 weeks.The study was designed as a randomized, single-blind, sham-controlled, adjunctive therapy and single-center trial. After screening, eligible participants were randomized to the FREMS or sham-FREMS arm by drawing out of sealed white envelopes. The intervention itself lasted for 5 days and consisted of intravenous infusions of alpha-lipoic acid (600 mg q.d.) supplemented by active real FREMS therapy or an inactive procedure to mimic the active one. All the patients randomized were informed not to use any additional painkillers apart from acetaminophen while participating in the study. The patients received ten sessions of FREMS or sham-FREMS treatment spread over 5 days, each session twice daily, in accordance with the manufacturer’s recommendations for symptomatic diabetic peripheral neuropathy (DSPN). All patients underwent treatment in an isolated, quiet room, in a lying position. An Aptiva 4 device  with dedicated cables and four pairs of disposable electrodes applied to both lower extremities, were used, the screen facing away from the patient. The application of electrodes was on both legs and feet in accordance with the manufacturer’s instruction: on the tibial muscles (positioning red electrodes on the muscles and black electrodes on the tendon-muscle insertions), on the lateral surfaces of the calves , below each malleolus  and on feet (placing red electrodes on the upper sides and the black ones on soles). FREMS used sequences of biphasic (negative and positive), asymmetric and electrically balanced pulses. One session comprised of two phases: an active and a recharging one. An active phase comprised of high negative voltage spike  and extra short duration . It was followed by a recharging phase of low voltage and long duration (0.9–999 ms) pulses of variable frequency ranging 1 to 1000 Hz, mainly in the low range 1–50 Hz. Every session duration was 35 min, including the first (active) phase lasting 25 min, then the second (recharging) phase lasting 10 min. In the sham-FREMS group, participants were connected to the running apparatus with the same type of dedicated electrodes, but without energy being released. The next part of the study was a follow-up lasting 8 weeks. Every participant was given a pain assessment diary to be filled out during the 5 days of treatment and another diary for the 8 week follow-up period. The patients assessed the intensity of pain in the VAS score every day in the morning throughout the study. VAS is one of rating scales used in epidemiologic and clinical research to measure the intensity of various symptoms, e.g., pain. The pain VAS is used widely to record patients’ pain intensity, progression or to compare pain severity changes. In our research we used the simplest 0–10 VAS as a straight horizontal line with numbers from 0 (no pain) to 10 (the worst pain in a lifetime). The patients also filled out a quality-of-life questionnaire (EQ-5D-5L) thrice: at the beginning of the study, after 5 days of therapy, after 8 weeks of follow-up and a Clinical Global Improvement scale (CGI-I) twice: after 5 days of therapy and after 8 weeks of follow-up. Every patient underwent an instrumental assessment of neuropathy twice, i.e., before and after 5 days of treatment. The technician who performed the instrumental neurological assessment was still the same, she did not administer the FREMS or placebo treatment and was unaware of the treatment assignment. Moreover, to secure the blindness of the study, participants were instructed that any perceptions or their absence during sessions are possible independently of the type of treatment given. The study protocol was approved by the Ethics Committee of the Institute of Rural Health and written informed consent was obtained from all participants before enrollment. The duration of the study was planned for 8 weeks to reduce the drop-out rate and to minimize the risk and need of additional pain medications intake. According to the literature available in this field it was the minimal time to obtain significant results.Clinical data was acquired from hospital records; subjective information about neuropathy symptoms and their changes were collected from pain evaluation diaries and questionnaires filled out by patients; neuropathy assessment results were sourced from dedicated TSS  forms.The treatment’s effect on pain perception on the visual analogue scale (VAS) was assessed each day in the morning. Results from the day after the 5-day treatment period and from the last day of 8 weeks of the follow-up phase were compared with baseline. Changes in tactile sensation were assessed by the 5.07 (10 g) Semmes–Weinstein monofilament test, changes in temperature sensation were assessed by the 10-point Tip-Therm test (warm–cold), changes in vibration sensation threshold on the participants’ feet were assessed using a manual biothesiometer. Knee and ankle reflexes were checked with a neurological hammer. The instrumental assessment of neuropathy and reflexes was conducted by the same person experienced in this field for years. A ten sensitive point test protocol was used for tactile and temperature sensation, with assessment at the big toe, third and fifth toe and three  metatarsal head points on both feet, followed by two points on metatarsus and one on the heel with three examinations per point, including one random false stimulation. Foot vibration perception threshold was assessed in two points per foot: a toe’s top and the lateral ankle. The effect of treatment was assessed separately for the tactile, temperature, vibration sensation and reflexes. For each participant the authors summed up the total scores in tactile sensation, temperature sensation, vibration perception and reflexes separately before and after five days of treatment. For tactile, temperature sensation and reflexes there was one point given when a feeling or reflex was present in certain location and zero points when it was absent. In tactile and temperature sensation the maximum score was 20 (10 points on each foot). For reflexes the maximum score was 4 (2 points on each leg). The vibration perception was assessed using a manual biothesiometer and there was an average score calculated from 4 examined locations. The authors compared the total or average scores achieved after five days of treatment with the output values for each participant and flagged them as “improvement” when the total number of points for a certain feeling or reflex was higher after treatment than before. Then, the Chi-squared test was used to compare the FREMS group with the sham-FREMS group.Changes in quality of life were assessed by a five-level version of the EQ-5D (EQ-5D-5L) characterized by improved psychometric properties and validated in patients with diabetes . This mut-test for independent samples and the Mann–Whitney test were used to assess the difference between the two groups. The value of 0.05 (α = 0.05) was adopted as the critical significance level (α) for all tests. Based on the results of the analysis, the rules of test probability were adopted: p < 0.05—statistical significance, p < 0.01—strong statistical significance and p < 0.001—very strong statistical significance.Statistical analysis was conducted using Statistica v.13.0 (StatSoft) and GraphPad Prism v.9.0. MS Excel 2010 (Microsoft) was used to collect data and support statistical analyzes. In order to present the results obtained in the nominal and ordinal scale, the methods of descriptive statistics were used, i.e., the number (n) and the percentage (%). The results obtained in a quantitative scale were presented using the methods of descriptive statistics, i.e., arithmetic mean (M), median (Me), standard deviation (SD), quartile range (IQR), minimum (Min) and maximum (Max). To assess the compliance of the distribution of the examined variables with the normal distribution, the Shapiro–Wilk test was used. In the absence of a normal distribution of variables, non-parametric tests were used; while demonstrating the normal distribution of variables, parametric tests were used. The χ2 independence test was used to assess the relationship between the studied variables on the nominal and ordinal scale. A Wilcoxon pairwise test was used to evaluate the difference between the two measurements. The Student’s Out of 45 patients screened in the study, 44 were randomized . All of them had alfa-lipoic acid (600 mg q.d.) intravenous infusions given . Twenty-four patients were allocated to the FREMS group (54.5%) with additional FREMS treatment and twenty to the sham-FREMS group (45.5%) with SOC only. All participants completed the 5 days treatment phase, filled out the diaries and questionnaires provided. In the 8 weeks follow-up phase, there were 23 patients assessed in the FREMS arm and 16 in the sham-FREMS arm as they completed all necessary forms .Baseline characteristics did not significantly differ between the two treatment groups . The majp < 0.001)  a statistically significant reduction in the level of pain perception (assessed with VAS) was found on the last day of hospital stay compared to day zero (< 0.001) . In the p > 0.05) in VAS changes between the FREMS and the sham-FREMS group. The reduction in the intensity of symptoms was obtained after average 3.9 days of FREMS and after 3.2 days in the sham-FREMS group. There was also no statistically significant difference in the number of days after which a reduction in the level of pain perception was observed (p > 0.05). Nevertheless, the statistically significant effectiveness of FREMS therapy versus sham-FREMS was observed on the last day of follow-up (p < 0.05), i.e., after 8 weeks , the difference was noticeable after 8 weeks following the treatment period (p < 0.05).Moreover, the symptoms’ improvement assessed by the Clinical Global Improvement (CGI-I) rating scale was compared in two time points during the study. Despite the fact there were no statistically significant differences in the scores after the hospital treatment between the FREMS group and the sham-FREMS group  and was significant 8 weeks after its completion.https://aci.health.nsw.gov.au/__data/assets/pdf_file/0003/632847/EuroQol-5-Dimension.pdf (p < 0.01). Still, significant results in vertical VAS persisted after 8 weeks of self-observation in FREMS group compared to the time before the procedures (p < 0.01) and compared to the time after 5 weeks of treatments (p < 0.05). In sham-FREMS group there were not any significant general health improvement assessed with vertical visual analogue scale (p > 0.05) in the time points described above.The participants judged the quality of life three times during the study. The evaluation done using the EQ-5D-5L questionnaire covered the following modalities: mobility, self-care, usual activities, pain/discomfort and anxiety/depression followed by a vertical visual analogue scale (VAS) used as a quantitative measure of general health outcome reflecting the patient’s own judgment. There were not any statistically significant differences in individual variables neither between groups nor the study time points in the treatment arms. However, the study showed general health improvement in the FREMS group based on changes in the vertical visual analogue scale being a part of EQ-5D-5L questionnaires. More specifically, after 5 days of neural stimulation, a statistically significant increase in the general health outcome  was demAs a secondary endpoint, the authors paid attention to the treatment influence on tactile, temperature and vibration sensation threshold on the participants’ feet. The neurological assessment before and after 5 days of treatment did not differ significantly neither within groups nor between them.No treatment-related severe or non-severe adverse events were recorded during the study, either in the FREMS or in the placebo group.FREMS, as a method of neuropathy treatment, was based on TENS  methodology. TENS involves the use of low-voltage electric currents to treat pain. The electrical stimuli in FREMS significantly differ from those commonly used in other known electrotherapies, such as TENS. FREMS provides sequences of biphasic electrical stimuli that vary simultaneously and automatically in frequency, pulse duration and amplitude, reaching relatively high intensity (300 V) with a very short duration (10–100 μs). It is through this method that it maintains electrical balance in treated tissues . This feThis research investigated the safety and efficacy of FREMS in a randomized, single-blind, sham-controlled, adjunctive therapy and single center clinical trial. FREMS was safe and resulted in a pain reduction in patients with symptomatic diabetic polyneuropathy. The effect was significant 8 weeks after the 5 days of treatment compared with SOC only. The FREMS treatment improved the participants’ quality of life.The effect of FREMS on symptoms and signs of diabetic polyneuropathy was assessed in previous trials. However, their design and methods differ from those used in our research, which makes it difficult to compare the results. Below we summarize the most important ideas and results from the trials available so far, we hope that our paper could support the research on FREMS therapy in diabetic neuropathy.In 2005, Bosi et al. from Italy published the study of the FREMS effectiveness in the treatment of painful diabetic neuropathy in a randomized, double-blind, crossover study with 31 patients involved . CompareIn 2013, Bosi et al. published another double-blind, randomized, multicenter study of even more, i.e., three series, each of ten treatment sessions of FREMS or placebo administered within 3 weeks, 3 months apart, with an overall, relatively long follow-up of about 51 weeks . The priThe two studies carried out by Bosi et al. ,9 were pIn 2021, Crasto et al. conducted a pilot, randomized controlled trial in the United Kingdom in patients with dual neuropathic pain treatments recruited from primary and secondary care . ParticiHealth-related quality of life (HRQoL) has become an important health outcome indicator applied in many clinical trials  and focuIn our research, the applied therapies  did not show a significant improvement in mobility, self-care, usual activities nor a decrease in pain/discomfort, anxiety/depression, but FREMS therapy improved the global quality of life assessed immediately after therapy. This effect was maintained after 8 weeks in contrast to the standard of care therapy (sham-FREMS + SOC).A strength of our study was its design, which included patients randomization, single-blind masking and a placebo (sham-FREMS) arm. A limitation of the study is a quite short follow-up period. The studies assessing FREMS therapy results should last longer to improve the outcomes. Moreover, some of the participants dropped out during the study. However, although the dropout rate during the study was not negligible, it was not treatment related, as suggested by the fact that it was higher in the placebo arm than in the FREMS arm  and caused by the burden associated with study participation. What is more, our research lacked a neurological assessment after 8 weeks of follow-up. The results of the study also lack a gender distinction which may be important as DSPN is different between genders. Additionally, despite the fact that DSPN is strongly associated with glycemic control, the authors did not perform neither a blood glucose nor HbA1c tracking over the duration of the study. The research did not consider any other clinical data, such as dietary patterns, or types of anti-diabetic medications. The pain medication control was based only on the patients’ commitment of not using any additional pain medications apart from acetaminophen while participating in the study.In our study, FREMS treatments, as an add-on therapy to alpha-lipoic acid intravenous infusions, resulted in decreasing pain severity, improving patients’ quality of life and clinical global impressions. This method of therapy needs further randomized controlled studies to confirm and strengthen this and previous reports. Additionally, the cost-effectiveness studies of different treatments for diabetic neuropathy are still needed .In conclusion, the findings of the study confirm that FREMS is a safe method of alleviating pain in diabetic patients with DSPN and improves the patients’ quality of life. Currently, in the face of a still limited number of effective solutions it may turn out to be another building block in causal and symptomatic DSPN therapy. For patients who suffer from DSPN and have to deal with chronic peripheral pain, FREMS therapy may be an important complementary or alternative method of alleviating symptoms.


Adequate pain control after video-assisted thoracoscopic surgery (VATS) for lung resection is important to improve postoperative mobilisation, recovery, and to prevent pulmonary complications. So far, no consensus exists on optimal postoperative pain management after VATS anatomic lung resection. Thoracic epidural analgesia (TEA) is the reference standard for postoperative pain management following VATS. Although the analgesic effect of TEA is clear, it is associated with patient immobilisation, bladder dysfunction and hypotension which may result in delayed recovery and longer hospitalisation. These disadvantages of TEA initiated the development of unilateral regional techniques for pain management. The most frequently used techniques are continuous paravertebral block (PVB) and single-shot intercostal nerve block (ICNB). We hypothesize that using either PVB or ICNB is non-inferior to TEA regarding postoperative pain and superior regarding quality of recovery (QoR). Signifying faster postoperative mobilisation, reduced morbidity and shorter hospitalisation, these techniques may therefore reduce health care costs and improve patient satisfaction.This multi-centre randomised study is a three-arm clinical trial comparing PVB, ICNB and TEA in a 1:1:1 ratio for pain (non-inferiority) and QoR (superiority) in 450 adult patients undergoing VATS anatomic lung resection. Patients will not be eligible for inclusion in case of contraindications for TEA, PVB or ICNB, chronic opioid use or if the lung surgeon estimates a high probability that the operation will be performed by thoracotomy. Primary outcomes: (1) the proportion of pain scores ≥ 4 as assessed by the numerical rating scale (NRS) measured during postoperative days (POD) 0–2; and (2) the QoR measured with the QoR-15 questionnaire on POD 1 and 2. Secondary outcome measures are cumulative use of opioids and analgesics, postoperative complications, hospitalisation, patient satisfaction and degree of mobility.The results of this trial will impact international guidelines with respect to perioperative care optimization after anatomic lung resection performed through VATS, and will determine the most cost-effective pain strategy and may reduce variability in postoperative pain management.Trial registration The trial is registered at the Netherlands Trial Register (NTR) on February 1st, 2021 (NL9243). The NTR is no longer available since June 24th, 2022 and therefore a revised protocol has been registered at ClinicalTrials.gov on August 5th, 2022 (NCT05491239). Protocol version: version 3 (date 06-05-2022), ethical approval through an amendment .The online version contains supplementary material available at 10.1186/s12893-022-01765-y. Thoracic surgery is associated with significant postoperative pain and discomfort. Adequate pain control after video-assisted thoracoscopic surgery (VATS) for lung resection is important to improve postoperative mobilisation and recovery, and to prevent postoperative pulmonary complications. Moreover, adequate acute postoperative pain control reduces the incidence of (neuropathic) chronic pain . For an Thoracic epidural analgesia (TEA) is the usual care for postoperative pain management following VATS. The central neuraxial block by TEA produces highly effective pain relief and anaesthesiologists are experienced with this technique. Up to date, TEA is the preferred technique by the vast majority of Dutch thoracic surgeons . HoweverThe disadvantages of TEA initiated the development of unilateral regional techniques for pain management. Single-shot and continuous paravertebral, intercostal, serratus anterior and erector spinae blocks have shown to be safe and effective . A meta-Since no consensus exists on optimal postoperative pain management after VATS lung resection, different ERATS protocols lack unambiguity . Five prIn addition to pain relief, also other aspects of postoperative recovery are crucial in deciding which analgesic technique is superior. Research on pain assessment continues to be a challenge due to its subjective nature and relation to various outcomes related to recovery. Therefore, anaesthesia and pain experts strongly recommend using a validated patient related outcome measure reporting overall quality of recovery (QoR) , 17. ThuWe designed a multi-centre randomised controlled trial to determine which analgesic technique performs best in an ERATS setting regarding pain and quality of recovery. Since continuous paravertebral block and single-shot intercostal nerve block are the most popular loco-regional analgesic techniques after VATS lung resection , 21, we Postoperative pain management by using either continuous paravertebral block (PVB) or single-shot intercostal nerve block (ICNB) is non-inferior to TEA regarding pain in patients undergoing VATS anatomic lung resection. Regarding QoR, PVB and ICNB are expected to be superior to TEA as scored by the global QoR-15 questionnaire. Signifying faster postoperative mobilisation, reduced morbidity and shorter hospitalisation, these locoregional unilateral techniques may therefore reduce health care costs and improve patient satisfaction.The main objective is to compare continuous PVB, single shot multi-level ICNB and TEA as analgesic techniques in order to provide safe, effective and efficient pain control and high quality of recovery after VATS lung resection. This study will provide evidence for the optimal analgesic technique after VATS anatomic lung resection to be implemented in an ERATS protocol.This is a multi-centre randomised three-arm trial comparing continuous PVB, single-shot ICNB and TEA in a 1:1:1 ratio in patients who will undergo a VATS anatomic lung resection. We use a non-inferiority design with respect to the outcome measure ‘pain’ and a concomitant superiority design regarding ‘quality of recovery’. The SPIRIT flow diagram is shown in Fig. After informed consent, each local investigator with support of the principal investigator will enter patient data into a computerised database (Research Manager) and with an unchangeable computer generated number patients will be randomised (1:1:1) for one of the three analgesic strategies. Randomisation is done in blocks of 6, 9 and 12.All participating hospitals use the international ERATS guideline  for the As the analgesic strategies highly differ in nature (with or without percutaneous catheter) and/or postoperative care , blinding for the randomised strategy is unfeasible.Adult patients (> 18 years) referred for anatomic lung resection lobectomy or segmentectomy for either benign or malignant disease) with the intention of performing it by VATS or robot-assisted thoracoscopic surgery (RATS) are eligible for the trial. Patients should be able to provide informed consent and fill out questionnaires in Dutch language.Patients with contra-indications for TEA or PVB , sepsis and mechanical spine obstruction) or allergic reactions to local anaesthetics will be excluded. Patients chronically using opioids for reasons not related to the operation will be excluded from the study since postoperative baseline opioid requirement will be higher and TEA remains the preferred technique for these patients.In case the lung surgeon estimates the operation to be performed through a thoracotomy instead of VATS/RATS the patient will be excluded.The numerical rating scale  will be used to measure pain scores. A pain score ≥ 4 marks the clinical cut-off value for acceptable pain (NRS < 4) or not (NRS ≥ 4), since care-givers are triggered to provide additional pain medication in case of a NRS ≥ 4. The primary outcome measure for the ‘non-inferiority’ part of the study design is the proportion of NRS pain scores in rest ≥ 4, defined as the number of NRS ≥ 4 episodes divided by the total amount of NRS pain scores in rest obtained from POD 0 until POD 2. A minimum of 8 NRS pain scores will be collected  in the morning, afternoon and evening). By using the proportion of NRS pain scores ≥ 4 we do not consider absolute pain scores (which lack power and are too subjective) but instead, rely on moments of adequate and inadequate pain control which are clinically more relevant.The primary outcome for the ‘superiority’ part of the study design is QoR measured with the QoR-15 questionnaire on POD 1 and POD 2. Superiority in terms of QoR is defined as a clinically significantly higher score both at POD 1 and POD 2 or a higher score at least at POD 1 or POD 2 and the other score being at least equal (p < 0.05). The QoR-15 is a validated tool to measure overall quality of recovery and will provide a continuous variable with a minimum score of 0 and maximum score of 150, and contains the most relevant questions concerning 5 domains  of overall well-being and recovery after surgery –24.Pain scores during rest and mobilisation at baseline, in the morning, afternoon and evening on POD 0–3 and at 2–3 weeks of follow-up;Proportion of postoperative pain scores of NRS ≥ 4 during mobilisation at POD 0–3;QoR-15 pre-operatively (baseline), at POD 0, POD 3 and at 2–3 weeks of follow-up;Cumulative use of opioids and analgesics at POD 0–3 and the use of opioids at 2–3 weeks of follow-up; total opioid and non-opioid consumption as supplementary analgesic requirement during POD 0, POD 1, POD 2 and POD 3 as well as the use and dosage of opioid use at the follow-up period 2–3 weeks after the operation, when necessary the Opioid Oral Morphine Milligram Equivalent (MME) Conversion Factors table will be used;Postoperative complications until 2–3 weeks of follow-up, according to the Clavien-Dindo classification;Hospitalisation, defined as the total number of days in hospital after the surgical intervention (including readmissions within the first 30 postoperative days), the following standardised discharge criteria after surgery will be applied in all participating hospitals: normal intake of nutrition, independent mobility, absence of fever (< 38 °C), and no presence of chest tube;Patient satisfaction regarding the analgesic technique given ;Time to removal of chest drain in days;Presence of urinary catheter in days;Degree of mobility, measured each day during POD 0–3 ;Cost-effectiveness of analgesic techniques from a health care perspective .A previous pilot study performed by our group , compariThe estimated values used for the sample size regarding percentage of NRS moments in which NRS ≥ 4, are based on a single small pilot study of limited reliability. In addition, data from this pilot study showed a skewed distribution requiring non-parametric testing. Based on the Mann–Whitney U-test assuming that the actual distribution is normal and applying Dunnett’s correction to control the familywise error rate, while comparing two independent experimental groups with the same control group  we calcuWe also calculated the needed sample size to demonstrate superiority of the unilateral regional techniques regarding QoR-15 (second primary outcome). QoR-15 is well reported in the literature and a difference of 8.0 points with a standard deviation of 18 points shows a clinically relevant difference . Using tAt the preoperative outpatient clinic, during hospital admission, and at the postoperative outpatient clinic, patients will be asked to complete a number of questionnaires concerning the study end points. A detailed overview is shown in the schedule of assessments Table .Table 1SAll patients will receive paracetamol (acetaminophen) 1000 mg. In addition, NSAID will be given according to in house protocol unless contra-indications exist. All preoperative analgesics administered will be registered in the case report form (CRF).For induction and maintenance of anaesthesia in house protocols will be used with the exception of lidocaine or esketamine which will not be administered during general anaesthesia. All patients will receive 8 mg dexamethasone to reduce additional postoperative opioid requirements and aid in the prevention of postoperative nausea and vomiting. In addition, a 5HT3 receptor antagonist will be administered and additional anti-emetics based on risk factors and local protocols.The epidural catheter will be placed in the awake patient after local anaesthesia of the skin. After correct placement of the epidural catheter, a local anaesthetic  will be started and, according to in house protocols, an opioid will be added to the epidural solution. In the nursing ward, patients are allowed to mobilise under supervision when the motor function and sensibility of the extremities allows it. A provisional stop of the administration of the epidural infusion is planned after 48 h (on the second postoperative day). In case NRS pain scores are ≥ 4 despite additional pain medication, the TEA will stay in place and the epidural infusion is resumed after a bolus of 5 mL of the epidural infusion. Subsequently, NRS pain scores will be assessed daily until pain management is sufficient and the TEA can be withdrawn with a maximum of 4 days. If rescue attempts to the epidural anaesthesia fail to improve pain scores, opioids may be withdrawn from the epidural solution and oral or intravenous opioids will be supplied.After induction of general anaesthesia the patient is positioned in lateral decubitus and the relevant landmarks are identified and marked . The PVB catheter is placed under general anaesthesia at the beginning of the VATS procedure under direct thoracoscopic vision. If placement cannot be achieved at the beginning of the operation as a result of poor thoracoscopic vision (e.g. adhesions) the catheter will be placed at a later stage or at the end of surgery. It is strongly preferred to place the PVB at the beginning of the VATS procedure to benefit from the advantages of administering local anaesthetics during general anaesthesia.After introduction to the thorax and manipulation of the lung anteriorly, the sympathetic chain running parallel to the vertebral column is identified with thoracoscopy. The level of the PVB catheter placement is chosen at the intercostal space of the largest incision (mostly thoracic level 4 or 5). Under direct thoracoscopic vision, the surgeon inserts a Touhy needle at the before mentioned marked location. After feeling a “fascial pop” penetrating the intercostal ligament, loss of resistance is felt when entering the subpleural space. At the same time, the tip of the needle is observed beneath the pleural surface thoracoscopically. Injection of about 2 mL ropivacaine 7.5 mg/mL will create subpleural hydrodissection to reach the adequate paravertebral plane for placement of the catheter. The PVB catheter is subsequently placed under direct thoracoscopic vision and left next to the sympathetic chain in the paravertebral space. Next, a bolus of ropivacaine  is given through the catheter. The catheter will be fixed to the skin.Postoperatively, a ropivacaine 2 mg/mL pump for continuous infusion is given with an infusion rate of 8–14 ml/h. In case of insufficient pain control (NRS ≥ 4) a bolus of 4–5 mL is given  anaesthesia pump is available with a lockout of 20 min). No opioid additives or opioids will be administered through the paravertebral catheter. A provisional stop of the administration of local anaesthetics is planned on the second postoperative day after which removal is considered based on the effect of pain intensity, with a maximum of 4 days, comparable to the TEA group. No mobility restrictions are instructed in this group.At the end of the surgery a single shot ICNB will be placed at 9 levels (thoracic level 2 to 10) with 2-3 mL local anaesthetics per intercostal space under direct thoracoscopic vision. The injection site will be chosen just lateral from the sympathetic trunk. This group will have no analgesic catheters for continuous analgesia. No mobility restrictions are instructed in this group.If catheter placement during TEA is unsuccessful, a continuous PVB will be given during the procedure, and, if catheter placement during PVB is unsuccessful, a single shot multilevel ICNB will be used. Non-inferiority will be analysed based on intention-to-treat, as well as per-protocol analysis.If postoperatively at the recovery room the patient experiences inadequate pain control (NRS ≥ 4) and a bolus of local anaesthetic via the epidural or paravertebral catheter (if present) is insufficient, intravenous morphine will be given until a maximum dose specified by the attending anaesthesiologist. If still insufficient pain control is achieved, additional clonidine 1 μg/kg or esketamine  is injected intravenously in order to obtain adequate pain control (NRS < 4). If the above regime does not result in adequate pain control additional interventions will be administered at the discretion of the attending anaesthesiologist. All analgesic medications and interventions given will be documented and registered for the purpose of the study.The following medication will be provided to each patient: paracetamol (acetaminophen) 4 times a day 1000 mg, NSAID according to in house protocols and oxycodon 6 times a day 5 mg if needed. If this regime does not provide adequate pain control, additional opioids will be provided either orally (slow release) or intravenously by patient controlled analgesia. The latter can either be initiated in the recovery room or on the nursing ward.Consecutive patients who fulfil the inclusion criteria will be noticed during the local multidisciplinary lung oncology meeting or at the outpatient clinic. They will receive written or digital study information. At the preoperative outpatient clinic consultation, patients will have the possibility to ask questions and have additional explanation. Written informed consent must be obtained before inclusion and randomisation, that will be done by a computerised program, using Research Manager Software. Subsequently, the patient will receive the complete information about the randomised anaesthesia technique by the anaesthesiologist and will be scheduled for surgery. Patients unable or refusing to provide informed consent will be treated according to current clinical guidelines. For the SPIRIT diagram of recruitment and consent see Fig. All participating centres will have a detailed hands-on training on how to perform PVB and ICNB. This training will be held by the researchers for all participating surgeons and anaesthesiologists. During the first PVB and ICNB procedures within the study, trained personnel will attend the participating surgeon/anaesthesiologist at location until sufficient experience is reached. All VATS procedures are recorded and video’s will be controlled for distance monitoring and if there are any problems, extra visits to the participating hospitals will be planned. For TEA , all participating centres should adhere to local anaesthesia guidelines. Training by this protocol will guarantee standard execution of the interventions and high quality performance of the three different analgesic techniques.The proportion of postoperative pain scores of NRS ≥ 4 at rest will be presented as mean or median percentages with 95% confidence intervals (95-CI) depending on the distribution and the QoR-15 questionnaire scores (maximum 150 points) will be presented as means with standard deviation or medians with interquartile range depending on distribution. Consequently, comparisons for both primary outcomes will be made with student’s t-test or Mann–Whitney U-test.When both intervention groups turn out to be non-inferior to TEA regarding pain, a comparison on clinical outcome and cost-effectiveness will be done between the different intervention groups.Pain scores during rest and mobilising at baseline, the morning, afternoon and evening at POD 0–3 and at 2–3 weeks follow-up; NRS on a scale of 0–10, will be presented as means with standard deviation or median with interquartile range depending on distribution.Proportion of postoperative pain scores of NRS ≥ 4 during mobilisation at POD 0–3; will be presented as percentages with 95% confidence interval (95-CI).QoR-15 pre-operatively as baseline score, at POD 0, POD 3 and at 2–3 weeks follow-up; questionnaire scores (maximum 150 points) will be presented as means with standard deviation or median with interquartile range depending on distribution.Cumulative use of systemic opioids at POD 0–3; will be presented in the measure of milligrams (mg) using means with standard deviation or median with interquartile range depending on distribution.Postoperative complications until 2–3 weeks follow-up, according the Clavien-Dindo classification (Grade I–V); proportions with minor (grade I–II) and major (grade III–V) morbidity.Hospitalisation, defined as the total number of days in hospital after the surgical intervention (including readmissions within the first 30 days postoperatively), will be presented as means with standard deviation or median with interquartile range depending on distribution.Patient satisfaction ; evaluated as proportion of patients per category for time points t1, t2, t3 and t4 ; evaluated as proportion of patients per category for time points t1, t2, t3 and t4.The three randomisation groups will also be compared with respect to the following secondary outcome measures. Continuous variables will be described by means with SD or medians with IQR depending on distribution of data. Comparisons will be made using the student’s t-test or Mann Whitney U test respectively. In case of proportions (with 95-CI), comparisons are tested by the chi-squared test.The economic evaluation of PVB and ICNB against TEA will be performed as cost-effectiveness analysis from a health care and societal perspective in this heavily affected and mostly already specialist dependent patient population. The primary outcome for cost-effectiveness analysis is the costs per total QoR score as continuous outcome measure. Additionally, we will analyse the costs per patient with adequate pain control (defined as NRS ≤ 4). The time horizon is restricted to a follow-up of 30 days after surgery. Incremental cost-effectiveness ratios are calculated, reflecting the extra costs per score of QoR and per patient with adequate pain control. Sensitivity analyses will be performed to account for sampling variability (following bias corrected and accelerated non-parametric bootstrapping), for plausible ranges in unit costs of surgical and anaesthesiologic treatment, and for  discount rates of costs and effects. Subgroup analyses will be performed for patients treated by uniportal or multiportal VATS in order to tentatively assess differences in health care efficiency. In case all analgesic strategies turn out clinically equivalent, the study will be performed as a cost-minimization analysis.The cost analysis evaluation will include direct medical costs, out-of-pocket expenses, and indirect non-medical costs of production loss. Volume data will be gathered with clinical report forms, available hospital information systems, and the iMTA Medical Consumption Questionnaire (iMCQ) and iMTA Productivity Cost Questionnaire (iPCQ) adjusted to the study setting  in participating centres will be done to estimate real unit costs. The friction costs method will be applied to derive the costs of lost productivity. After price-indexing all costs will be expressed in Euros.The budget impact analysis (BIA) focusing on the budget of medical specialist care will be done with a planning horizon of 4 calendar years, addressing the governmental, insurer and provider perspectives. Alternative impact assessments will be made based on (1) real unit costs and (2) reimbursements. Different national implementation scenarios of unilateral regional analgesic techniques replacing TEA will be forecasted. Budget impacts will be expressed in millions of Euros.After randomisation patients will be assigned a study number and anonymous data will be registered. Data is registered and stored in Research Manager Software. Research Manager software is certified by the ‘Information Security Management System 27001’. The key to the code is safeguarded by the principal investigator.Local data management will be done by Integraal Kankercentrum Nederland (IKNL), having extensive experience with management of local data collection. Collection, storage and analysis of data will be done according to the OPtriAL data management plan.According to the risk classification, the OPtriAL has negligible risk for the study subjects. All patients, regardless of the randomisation group, will have monitoring of vital parameters and direct presence of experts in the field if required. Moreover, there will be no new medicinal intervention and all doses of applied anaesthetics are already used in daily practice.All adverse events per participant will be recorded until the end of the study and followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist.The uncertainty in the estimated values and distribution that have been used in the sample size calculations for our first primary outcome measure (proportion of NRS measurements ≥ 4) require a more solid estimation, based on a larger sample size than achieved in our pilot study. Inclusion of 50% of the number of TEA patients based on the sample size calculation to demonstrate superiority of QoR-15 (second primary outcome for superiority) will define the moment for a blinded interim analysis. At this point (inclusion of 75 patients in the TEA group), an interim analysis by our data safety monitoring board (DSMB) will establish a more precise estimate of the proportion and distribution of NRS measurements ≥ 4 for the control group (TEA). Normal or skewed distribution of the study groups will determine the use of parametric or non-parametric statistical tests, respectively. With the new estimators, the already defined clinically relevant contrasts of 17.5% for the NRS ≥ 4, 90% target power and corrected Type-1 errors of 0.0135, the DSMB will recalculate the sample size with the correct statistical tests and advise the research group whether the OPtriAL study should continue or stop the inclusion of patients after the calculated sample size of 450 patients in total.During the blinded evaluation by our DSMB, our patient recruitment will continue in order to not disrupt the complex logistics that have been set up in the multicentre setting of this national trial.Monitoring of the participating centres will be done by IKNL according to the OPtriAL monitoring plan. The sponsor location will be monitored by CTCM .All centres will be visited three times during the execution of the inclusion of study participants until finalisation of the study inclusion after a minimal period of 2 years. Remote visits are planned if needed depending on inclusion rate and queries in data management. Monitoring will take place with specific attention to informed consent, data monitoring and completeness of case report form.Large variety exists among surgeons and anaesthesiologist in applying either TEA or continuous or single-shot loco-regional analgesic techniques or even only systemic analgesia in the setting of VATS for anatomical lung resection. This variety may mainly be explained by the fact that no large randomised comparisons have been made between TEA and continuous or single-shot loco-regional analgesia in combination with a multimodal analgesic regime. Although TEA has a long history and anaesthesiologists have experience with this technique, associated patient immobilisation and indwelling urinary catheter usage may lead to prolonged hospital admission . ReducinThe results of the proposed study, which is being performed in multicentre setting within the Netherlands and Belgium, may have direct impact on national and international guidelines to optimize perioperative care for VATS anatomic lung resection. Besides determining the most effective and efficient analgesic technique, taking into account patient’s satisfaction, it will also determine the most cost-effective pain strategy and will eventually reduce variability in postoperative pain management.Additional file 1. Supplemental material.


Active stimulation included a daily session of 20-min stimulation of 1 mA HD-tACS over the left M1 for ten sessions in two weeks. The primary outcome was the change in pain intensity and quality of life, assessed using the numeric rating scale (NRS) and the fibromyalgia impact questionnaire (FIQ) at baseline and after two weeks of treatment. Secondary outcomes included other core symptoms of FM  and changes in biomarkers’ total Tau and Aβ1-42. All analyses were based on intention-to-treat for a significance level of p < 0.05. Results: Of the 38 randomized patients, 35 completed the study. After two weeks, HD-tACS induced a significant reduction in FIQ score post-treatment. However, there were no significant differences in NRS and FIQ scores compared to sham stimulation. Most adverse events were mild in severity. Nevertheless, one patient receiving HD-tACS attempted suicide during the trial. Conclusions: These results suggest that HD-tACS may effectively reduce pain, psychological distress, and symptom impacts in FM patients. However, we found no significant differences between the two groups. Future studies investigating HD-tACS in FM are warranted.Objectives: This study aimed to investigate the safety and efficacy of high-definition transcranial alternating current stimulation (HD-tACS) to the left primary motor cortex (M1) in the treatment of fibromyalgia (FM) patients. Methods: In this randomized, double-blind, sham-controlled clinical trial, patients with FM were recruited in a teaching hospital. Thirty-eight patients were randomized to active HD-tACS ( Fibromyalgia (FM) is a common debilitating condition characterized by widespread chronic pain, fatigue, sleep disturbance, impaired cognition, and anxiety and depression . For manNon-invasive brain stimulation (NIBS) techniques are potentially promising for managing chronic pain disorders, such as migraines ,9. Two pSeveral studies in FM patients suggest that tDCS over the primary motor cortex (M1) can reduce chronic pain levels ,12,13,14There are limited studies of HD-tDCS or tACS on FM ,21,22. Tclinicaltrials.gov (NTC04550598). All participants provided written informed consent before enrollment. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized controlled trials.We conducted a two-week, double-blind, randomized controlled trial at Taipei Medical University Hospital, Taipei, Taiwan. We recruited the participants from October 2020 to October 2021. The study was approved by the Institutional Review Board of Taipei Medical University (N202004140) and registered on Participants were recruited in the outpatient clinic of Taipei Medical University Hospital. Eligibility criteria were men and women at least 20 years of age with a formal diagnosis of FM made by a practicing physician according to the American College of Rheumatology 2016 FM diagnostic criteria . BaselinAn independent statistician generated a stratified random number sequence for participants. Eligible patients were blocked and randomized to either sham or active HD-tACS with allocation concealment and remained blind to their treatment condition throughout the study.HD-tACS was administered using a 4 × 1 ring electrode configuration. We targeted the left M1 by placing the anodal electrode on the C3 position in the 10/20 system for the EEG electrode positions. We set four cathodal electrodes in a radius of approximately 7.5 cm from the anode . The stimulation duration was 20 min. Alternative electrical stimulation was delivered as a monophasic square wave with a pulse width of 0.5 ms and intensity of 1 mA at 50 Hz, repeated at duty cycle with on time of 2 s and off time of 8 s . Sham HDSociodemographic information was recorded. Participants were assessed by independent evaluators blinded to treatment conditions. The study’s primary outcome was the change in pain levels, assessed via the NRS, and the change in the quality of life, evaluated by the Fibromyalgia Impact Questionnaire (FIQ). Secondary outcomes were the changes of associated symptoms from baseline to endpoint. They included assessments of anxiety  and depression , sleep quality , the pressure pain threshold (PPT), and biomarkers T-Tau and beta-amyloid 1–42 (Aβ1-42) proteins. These parameters were measured at baseline and after the final treatment.Patients were asked to rate their current overall level of pain on a scale from 0 to 10 divided at 1-point intervals, with 0 being “complete absence of pain” and 10 “the worst pain imaginable.”The FIQ assesses the impact and quality of life in patients with FM. It consists of 10 questions evaluating activities of daily living and pain and is divided into three main categories: function, overall impact, and symptoms. The maximum score is 100. A higher score indicates a more significant impact of the syndrome on the person.BAI is a 21-item questionnaire measuring the severity of anxiety. The score for each item ranges from 0 to 3, with scores of 8 to 15 indicating mild, 16 to 25 indicating moderate, and greater than 26 indicating severe anxiety.BDI-II evaluates the degree of depression and consists of 21 items measuring emotional, behavioral, and somatic symptoms. The score for each item ranges from 0 to 3, with total scores of 10 to 18 indicating mild, 19 to 29 indicating moderate, and greater than 30 indicating severe depression.PPT measures the minimum force applied to induce pain. PPTs were evaluated via delivery of direct pressure over four paired points of the body using a hand-held pressure gauge . During measurement, the patient was in a relaxed sitting position. The pressure was gradually increased at a rate of approximately 2 lb/s until the patient experienced a transition from pressure to pain or a maximum of 25 lb. We measured PPTs in the areas of the trapezius, lateral epicondyle of humerus, greater trochanter, and knees three times, and averaged the results.Τ-Tau and Aβ1-42 are biomarkers of sleep disturbance . Additiog using a refrigerated centrifuge. The plasma was then transferred to fresh 1.5-mL tubes (1 mL of plasma per tube) and stored at −80 °C. An immunomagnetic reduction (IMR) assay was used to measure the levels of T-Tau protein and Aβ1-42 in the blood. The antibodies to the Aβ1-42 and Tau conjugated on the surface of 50 nm-in-diameter Fe3O4 magnetic particles  were used. The magnetic particles can form clusters when the antibodies bind with the target protein. The alternating current susceptibility of magnetic particles can be detected  to analyze the signal of reagents. For t-tau, the reagents (MF-TAU0060) and plasma samples were mixed at a ratio of 2:1. For Aβ1-42 peptides, a 1:1 ratio of reagents (MF-AB2-0060) to plasma samples was used. After mixing, each sample for which IMR signaled was analyzed.We collected whole blood into EDTA-treated tubes. The sample was centrifugated immediately for 15 min at 2000× Adverse effects were registered using a standard form after each session. The patients reported whether they had any headache, neck pain, scalp pain, tingling, itching, burning sensation, skin redness, sleepiness, trouble concentrating, acute mood change, and other adverse effects after the stimulation. The severity of any adverse events and the degree to which they were related to the stimulation were recorded.t-test to compare the difference of measured variables between pre- and post- treatment Significance was set at p ≤ 0.05. Results were reported as mean (SD).Statistical analyses were performed using SPSS version 21 . We used a Mann–Whitney U test to compare the mean for continuous variables and a Pearson Chi-square test or Fischer exact test for categorical variables between two groups. We used paired The CONSORT flow diagram through the phases is illustrated in BAI: Beck Anxiety Inventory; BDI-II: Beck Depression Inventory Second Edition; FIQ: Fibromyalgia Impact Questionnaire; HD-tACS: high-definition transcranial alternating current stimulation; NRS: numerical rating scale; PPT: pressure pain threshold; PSQI: Pittsburgh Sleep Quality Index; Tau: Tau protein; Aβ-42: Beta-amyloid protein 42 amino acid.One participant receiving active stimulation and two receiving sham stimulation dropped out of the study. During the trial, the participant receiving active stimulation dropped out after a cardiopulmonary failure due to a suspected self-administered drug (beta-blocker) overdose. After an interview with a psychiatrist, an impulsive suicidal attempt was suspected. The patient recovered without any sequelae after management. The two participants receiving sham stimulation dropped out of the study due to physical discomfort during stimulation.t-test analysis of pre- and post-clinical profiles showed significant improvements in pain levels or quality of life in both the sham and active stimulation groups. In the sham stimulation group, we observed a decrease in pain symptoms . Similarly, in the active stimulation group, we found an improvement in FM symptoms . Self-reported depression and sleep quality symptoms also improved significantly in both groups .An independent sample non-parametric test comparing the pre-post difference, however, found no evidence of clinical superiority of active stimulation, as indicated by no significant difference in NRS and FIQ scores between the two groups .In this double-blind sham-controlled trial, we investigated the efficacy of ten 20-min stimulation sessions of HD-tACS on the left M1 in improving pain intensity and associated core symptoms of FM. In 38 FM patients, we found that both active and sham stimulation reduced overall levels of perceived pain or improved quality of life. However, there was no significant difference between active and sham stimulation on the reported pain, anxiety and depression levels, and sleep quality. In general, the protocol used in this study proved well-tolerated. Nevertheless, one patient suffered from cardiopulmonary failure after an attempted suicide.Anodal tDCS over M1 has been proposed as an effective intervention for managing clinical pain in FM . FM is cPrevious studies have suggested that HD-tDCS provides improved pain response due to its precise stimulation of cortical targets . A singlWe used tACS due to its ability to potentiate cortical excitability, which may induce more significant and longer-lasting changes than conventional methods . AdditioOur study complements previous tACS studies in the context of pain ,36,37,38Although we expected better pain improvements with the tACS compared to sham, the data did not confirm any superiority of this protocol. One possibility is the differential matching of tACS frequencies with the intrinsic properties of sensorimotor networks involved in pain regulation . It is eThe present results may suggest a significant placebo response to the application of the sham protocol, which may have omitted the actual effects of active HD-tACS. Placebo analgesic effects can be brought about by the belief and expectation of symptom improvement and have been widely observed in neuromodulation studies for chronic pain ,41. WhetCurrently, no studies have shown significant effects of tDCS on blood metabolites in FM patients. Furthermore, there is currently a lack of FM-specific biomarkers in the blood . As we pIn the present study, one patient who received active stimulation attempted suicide with a drug overdose. Although no causality was established between this protocol and the attempted suicide, this incident prompted careful consideration of the effects of neuromodulation interventions on suicidal ideation and behavior. Although it is rare, antidepressant treatments have been shown to carry an increased risk of suicidal ideation in vulnerable patients . Early aThere are several insufficiencies in the present study. First, our study contained a small sample size. A large study is suggested to confirm our findings. Second, we did not perform follow-up assessments of patient pain levels and are unable to conclude long-term results of tACS on FM pain and associated symptoms. Third, the patients enrolled in the present study were Asians. Extrapolation of our results to other ethnic groups will need further investigation. Lastly, we did not have simultaneous EEG recordings to ensure that the tACS protocol could modulate neural oscillations, nor did we use fMRI to provide information on the distribution of the tACS current in the brain as a function of anatomy. Nevertheless, future studies may perform additional computational modeling to control the interindividual variability among FM patients.We found that the FM patients showed significant improvement in pain, psychological distress, and symptom severity while receiving HD-tACS. However, no significant difference between pre- and post-treatment was noted between the patients receiving active and sham stimulation. The HD-tACS was generally well-tolerated during stimulation. Nevertheless, one patient conducted suicide unexpectedly in the present study. Caution on the potential linkage between neuromodulation and unexpected behaviors should be considered.


Effective analgesia after bariatric procedures is vital as it can reduce post-operative opioid use. This leads to less nausea which may be associated with shorter post-operative length of stay (LOS). Understanding analgesic requirements in patients with obesity is important due to the varied physiology and increased number of comorbidities.The aim of this study was to evaluate the efficacy of intraperitoneal instillation of local anesthetic (IPILA) to reduce opioid requirements in patients undergoing laparoscopic bariatric surgery.A double-blinded randomized control trial was conducted to compare intraperitoneal instillation of ropivacaine to normal saline in 104 patients undergoing bariatric surgery. The primary endpoint was pain in recovery with secondary endpoints at 1, 2, 4, 6, 24, and 48 h post-operatively. Further endpoints were post-operative analgesic use and LOS. Safety endpoints included unexpected reoperation or readmission, complications, and mortality.p = 0.04) and on movement (p = 0.02) in recovery with no difference seen at subsequent time points. Equally, IPILA was independently associated with reducing severe post-operative pain at rest and movement . There was no significant difference in LOS, opioid use, antiemetic use, morbidity, or mortality between the intervention and placebo groups.There were 54 patients in the placebo arm and 50 in the IPILA. Pain scores were significantly lower in the IPILA group both at rest (The administration of ropivacaine intraperitoneally during laparoscopic bariatric surgery reduces post-operative pain in the recovery room but does not reduce opioid use nor LOS.The online version contains supplementary material available at 10.1007/s11695-022-06086-w. Laparoscopy has greatly reduced the pain and recovery of surgery; however, optimizing post-operative pain is an ongoing goal of management. Despite improved techniques, some patients continue to experience significant post-operative pain requiring strong opioids . Post-opThe safety and efficacy of local anesthetic in perioperative care is well recognized. The primary advantages of local anesthetic agents are that they act directly on the tissue to which they are administered and they lack the systemic effects of opioids, such as nausea, sedation, and opioid-induced ventilatory impairment –7. Analgwww.anzctr.org.au. Written informed consent was obtained from all participants. Study sample size has been calculated using a standardized effect size of 0.6 using the Cohen’s d test and evidence from previous studies  were identified and recruited between November 2018 and November 2020. Patients were excluded if they had an allergy to local anesthetic, severe cardiovascular disease (congestive heart failure or ischemic heart disease), chronic renal disease (creatinine clearance < 60 mL/h), Child–Pugh score B/C, or if they declined to participate.All patients underwent their procedure with the same surgeon and anesthetist at a single institution. Laparoscopic procedures were typically carried out using a 12-mm optical entry camera port, two 12–15-mm operating ports, a 5-mm Nathanson liver retractor port, and a 5-mm assistant port. Carbon dioxide insufflation was set to a pressure of 14 mmHg. At the end of each case, a mixing cannula was used to spray a solution of either normal saline or 0.2% ropivacaine onto the diaphragm prior to the conclusion of the procedure. The amount of solution to be instilled was 0.5 mL/kg calculated based on the patient weight on the morning of the procedure to ensure safety and efficacy of the local anesthetic.2 of 40%. During the case, the patient was converted over to a combination intravenous propofol/desflurane maintenance with the view to facilitating early respiration and quicker extubation. Each patient received dexamethasone (8 mg) at the beginning of the case, unless they were diabetic on oral hypoglycaemic agents or insulin. Parecoxib (40 mg), droperidol (0.625 mg), and ondansetron (4 mg) were administered at the conclusion of the case. Paracetamol (2 g) was given on arrival in the post-anesthesia care unit (PACU) and there was as necessary (PRN) use of antiemetics and oxycodone, or fentanyl if there were allergies as required. All patients received standardized therapy on the ward which was recorded and consisted of PRN ondansetron 4 mg QID and tapentadol 50 mg PRN q3h (maximum dose 300 mg) and tramadol 50–100 mg IV/PO PRN QID. Patients were monitored in a ward-based setting with continuous saturation monitoring. A summary of anesthetic data is provided in Supplementary Table Patients were given a relaxant general anesthetic. Standardized monitoring, including 3-lead electrocardiogram, non-invasive blood pressure (NIBP), oxygen saturation, and neuromuscular monitoring, was attached. Invasive arterial monitoring was used only in the case of poorly fitting or grossly inaccurate NIBP. Patients were positioned in reverse Trendelenburg. Induction proceeded with fentanyl, ketamine, propofol, and rocuronium. An endotracheal tube was introduced once deep muscle relaxation was confirmed. The stomach was decompressed with a temporary orogastric tube. Anesthesia was maintained with oxygen/air/sevoflurane with FiOParticipants were randomized using block permutation method in a 1:1 ratio between the control and intervention arms. All individuals involved in the trial  were blinded to treatment allocation. A member of the research team who was not directly involved in any aspect of the intervention and procedure was unblinded and responsible for randomization, preparation of solutions, and collection of survey forms. The allocation sequence was implemented using sequentially numbered solution bags.Pain scores were recorded by nursing staff using a visual analogue scale (VAS) at rest and on movement in the post-operative acute care unit (PACU) and at 1, 2, 4, 6, 24, and 48 h. Pain scores at 48 h were not recorded if the patient had been discharged. The primary endpoint was post-operative pain using VAS score in recovery both at rest and upon movement. Equally, the effect of IPILA on extremes of pain (VAS > 7) in PACU was assessed. Secondary endpoints included assessment of pain scores at subsequent time points until discharge. Other secondary efficacy endpoints were post-operative analgesia and antiemetic use and LOS. Safety endpoints were unexpected reoperation or readmission, complications, and mortality.t-test or non-parametric alternative (Mann–Whitney test) and Pearson chi-square test as appropriate. Fisher’s exact test was used for safety endpoints such as reoperation or readmission, complications, and mortality due to the low number of events recorded. Uni- and multivariable linear and logistic regression analyses were performed to assess for the independent effect of IPILA on recorded post-operative pain perception. Results included unadjusted (univariable) and adjusted (multivariable) odds ratio with 95% CI estimates. Potential confounders such as surgery type, hiatus hernia repair, age, BMI, and chronic pain were controlled for in regression analyses. Data analysis was conducted using SPSS version 20  and R Statistical Programming.Continuous data for primary and secondary endpoints are summarized as medians with interquartile range or means with 95% CIs depending on their baseline normal distribution. The primary endpoint of pain scores between treatment and control groups was analyzed using Wilcoxon-rank sum test and/or chi-squared test as required. Secondary endpoints were analyzed using Student’s independent Of the 120 patients who were randomized, 104 were included in the final analysis, 54 in the placebo arm and 50 in the treatment arm  and on movement . Patients receiving IPILA had less severe pain episodes compared to placebo at rest  and on movement . The median LOS was 1.0 days in both the placebo (IQR 1.0–2.0) and IPILA groups . In addition, there were no significant differences between the groups with respect to the safety endpoints. There were no unexpected reoperations, no unplanned ICU admission, and no mortality. The only complication was a pulmonary embolus (PE) in one patient in the IPILA arm. There were five unplanned readmissions in the IPILA group and four in the placebo group, all for patients who required IV rehydration.No significant difference was seen between the IPILA and placebo groups at other post-operative time points, in post-operative analgesia intake, antiemetics use, nor mean LOS. The mean frequency of requests for opioid analgesia was 1.8 (95% CI 1.5–2.1) per hospitalization in the placebo group and 1.9 (95% CI 1.56–2.29) in the IPILA group. Mean use of antiemetics was 1.5 times per admission in the placebo group (95% CI 0.1–0.7) and 1.9 times (95% CI 0.2–0.6) in the IPILA group Supplementary file2 (DOCX 15 KB)Supplementary file3 (DOCX 15 KB)Below is the link to the electronic supplementary material.