Low energy pulsed electromagnetic signals (PEMS) therapy, in the field of bioelectronics, has been suggested as a promising analgesic therapy with special interest in treating conditions with poor response to pharmacotherapy. This study evaluated the effectiveness of PEMS therapy on the treatment of chronic low back pain patients with a neuropathic component. A group of 64 individuals with such condition was allocated to a 2-week treatment period (10 twenty-minute sessions on consecutive days) with an active PEMS therapy device or an inactive device in random order. The pain was assessed on a visual analog scale, and the functional status was assessed using the SF-12 questionnaire. The visual analog scale scores were lower after treatment than at baseline but only in the group treated with the active device. According to the DN4 score, neuropathic pain decreased in both experimental groups with respect to baseline, but this was only significant for the group treated with the active device. Similarly, an improvement in the SF-12 and Medical Outcomes Study (MOS) sleep scale components was reported. The study demonstrated that low-energy PEMS therapy was efficient in reducing pain and improving function in chronic low back pain patients with a neuropathic component. Low back pain is a health problem characterized by high prevalence in the general population, particularly in Western societies, with significant economic and social repercussions. Low back pain is one of the major reasons for medical treatment seeking and is one of the most challenging chronic pain disorders to treat . In addiCompared to inflammatory pain, neuropathic pain has a greater impact on sleep disturbances, anxiety, and reduction in quality of life and functional capacity ,17,18,19Within the field of bioelectronics, the use of electromagnetic signals has had a notable increase in the past decade in acute and chronic rehabilitation treatments, and it provides a noninvasive, safe, and accurate method to stimulate therapeutic targets depending on the tissue, functional or structural location, and the type or mechanism of pain or disease ,26,27. I®, Biotronic Advance Develop®, Granada, Spain), with a monopolar capacitive dielectric PEMS transmission. According to all the above mentioned, the present study aimed to evaluate the analgesic efficacy of PEMS therapy in patients with chronic non-specific low back pain associated with a neuropathic component using a noninvasive bioelectronic device , 1 month post-treatment, and 3-month follow-up. This study was designed to assess the effect of PEMS therapy on pain and disability in patients with non-specific low back pain complaints. The trial was conducted at the Virgen de las Nieves Hospital, Granada, Spain. All procedures were in accordance with the local research ethics committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The trial protocol was approved by the institutional ethics committee before recruitment, screening, and data collection. At the initial phase (Visit 0), the protocol was explained to the potential participants, and they were asked to sign the informed consent. Informed consent and clinical history were obtained from all individual participants included in the study.Patients diagnosed with non-specific chronic low back pain associated with a neuropathic component, referred to the Pain Treatment Unit of the Virgen de las Nieves Hospital in Granada (Spain), were recruited for study participation. Various inclusion and exclusion criteria shown in  were useThere are few previous studies in the literature demonstrating statistically significant differences in the efficacy of the treatment. Given these conditions, the present research has been developed as a pilot study of a total of 60 patients; including the relevant cases of neuropathic pain that were considered interesting for the study. Such sample size has been determined considering the time of application of the sessions and the limited time available to complete the study (3 months).Once the eligibility of the participants according to the inclusion and exclusion criteria was verified and they signed an informed consent to participate in the study, they were sequentially and randomly assigned to either the intervention group (treated with the active device) or the control group (treated with the inactive/sham device) at the time of enrollment. The assignment was performed using a computer-generated sequence guarded and created by a person belonging to the research support staff of the FIBAO , who was outside the research group, through a computerized system of simple randomization 1:1 (M.A.S. 2.1 @ Glaxo Wellcome). The used software generates a sequence of numbers randomized and assigned to each patient (in order of inclusion into the study) to the corresponding group.®, Biotronic AD®, Granada, Spain) at the painful area in twenty-minute sessions every day (visit 1–10), except the weekends, for 2 weeks in active mode. In contrast, subjects assigned to the control group, underwent all procedures similarly to the treatment arm, except that the device remained in inactive mode during the session. Participants in the intervention group received PEMS therapy with a pulsed emission of 840 kHz low intensity and pulses of the order of nanoseconds, with a pulse/pause ratio of 500 μs and an average work cycle as applied energy of 45%, and the emissions were modulated and processed digitally. The PEMS therapy application was dynamic, with a continuous rotation and translational movement on the dorsolumbar spine, making focused energy deposits in the areas involved in the painful process. Five milliliters of almond oil were used to improve gliding along with the 20-min application of PEMS [Patients allocated to the intervention group were locally exposed to a therapy based on the administration of low energy PEMS, via noninvasive transcutaneous and dielectric capacitive monopolar transmission to the target tissues, using a bioelectronic device , i.e., without selecting any pain program. Therefore, no electromagnetic signal energy was transmitted when the device was turned on. Sham devices were externally identical to the active devices, and they were also connected to the current, allowing the pilots to light up, mimicking the intervention device. No vibration, heat, or other tactile stimuli was generated by any of these devices. Therefore, neither the patient nor the person managing the device was aware of whether the subject was receiving electromagnetic waves.All patients followed the usual pharmacological treatment for their painful condition , according to the established guidelines that follow international recommendations see . They diAll subjects with at least one intervention of PEMS were included in the safety population. Patients were followed up throughout the study, and all local tissue effects and adverse events were recorded.The intensity of self-reported pain was measured using a visual analog scale (VAS). The VAS is a single-item continuous scale comprising a 10-cm in-length horizontal line anchored by two verbal descriptors, one for each symptom extreme, “no pain at all” (score of 0) and “worst imaginable pain” (score of 10). The pain VAS is administered as a paper and pencil measure, and it is self-completed by the respondent and takes 1 min to complete. The respondents were asked to place a line perpendicular to the VAS line at the point that represents their pain intensity. Subjects rated their pain intensity in the VAS once a day for the five days preceding each visit in the morning upon rising and recorded it in a diary. Then distance in cm from the endpoint of the VAS labeled as “no pain at all” to the patient’s mark was measured with a ruler and the score of the subject’s pain was determined, so it was used as a numerical index of pain severity. Two VAS scores were calculated, the maximum VAS as the highest daily pain intensity measure collected during the last 5 days prior to each visit, and the baseline VAS, which was calculated as the average daily pain intensity measures collected during the last 5 days prior to each visit.At baseline (visit 0), one month after finishing the treatment , and after a three-month follow-up , participants completed a battery of instruments to measure the biopsychosocial sequelae often associated with chronic low back pain. At visit 0, a clinical evaluation was performed in which the clinical anamnesis was conducted  along with protocol explanation. Then, one month after the patients finished the treatment sessions (visit 11), they underwent a medical examination, and records, surveys, and health scales and questionnaires were provided again. Administrative staff set up an appointment for the next medical assessment, in consultation after 3 months (visit 12) for a similar evaluation. Different medical professionals conducted the initial and final assessment of the treatment in consultation with patients.Neuropathic pain was assessed by using the DN4 questionnaire, a validated and clinician-administered questionnaire developed by the French Neuropathic Pain Group. The DN4 includes four questions consisting of sensory descriptors and signs related to bedside sensory examination and was deliberately reduced to a minimum number of simple and presumably discriminant items requiring yes or no responses, also simplifying its scoring. The DN4 was developed to differentiate neuropathic and nociceptive pain and consists of 7 items related to symptoms and 3 items related to the clinical examination . QuestioQuality and quantity of sleep were assessed using the Medical outcomes study (MOS) sleep scale , a subscHealth-related life quality was assessed using the version of the SF-12 Health Survey questionnaire ,42 adaptp < 0.05). All statistical analyses were performed using the statistical software SPSS Statistics version 24.0 for Windows .Demographic and clinical characteristics of patients allocated at each group were described as mean and standard deviation for continuous variables and absolute and relative frequencies for categorical variables. Differences in continuous variables between the two experimental groups at any visit were analyzed by the independent group student’s t test for unpaired samples or Mann–Whitney test. Categorical variables were compared for differences between the two experimental groups using the χ2 test. The validity conditions of the test have been considered (number of cells with expected frequency less than 5 not higher than 55–30%). Comparisons between the values obtained at each visit and the values obtained at the baseline visit for each experimental group were performed. For these comparisons, the McNemar test for paired data for categorical variables with two levels and the two-factor generalized linear mixed model Manova analysis of repeated measures for ordinal variables were used. Means and standard errors were used as descriptive parameters for interaction factors. For each factor, the Mauchly sphericity test  and the Levene test  have been performed. Where a significant result was disclosed, a post-hoc comparison between visits (for each device) and between devices (at each visit) with nonparametric test of Wilcoxon-Mann–Whitney was also performed. The Mauchly sphericity test and the Levene test have been performed in each of them to contrast the hypotheses of equality of variances between the differences in the levels of the visit factor and between the levels of the device factor, respectively. The Wilcoxon and Mann–Whitney nonparametric test was used to analyze the differences between visits for each treatment and between treatments at each visit. To address the issue of potential confounders, univariate analyses were performed to assess the potential effects of age, sex, and baseline pain VAS score on change in pain intensity. The χ2 analysis was used to assess the relationship between sex and change in pain severity. Pearson correlation analyses were performed to assess the relationships for age and pretreatment pain score versus change in pain severity. A statistically significant difference was considered when the significance level was less than 5% (n = 39) or sham treatment (n = 38) (Seventy-seven subjects were randomly assigned to receive either PEMS ((n = 38) . A totalThe study was then performed finally with full data from 65 individuals, 34 in treatment group and 31 in control group . SociodeOnly the treated group had improved VAS pain scores at one and three months after finishing sessions . In the Average total scores obtained using the DN4 questionnaire are presented in The average scores obtained in the MOS–sleep questionaries are shown in At baseline, the two SF-12 components were similar in both experimental groups. PCS  improved in treated individuals, but in the control group was even worse than at baseline. As expected, the treated group reported a higher score than the control group in subsequent visits. In contrast, no differences were found using the MCS  .®, Biotronic Advance Develops®, Granada, Spain), via noninvasive transcutaneous to transmit electromagnetic signals through a dielectric, capacitive monopolar transmission. Pain intensity describes how much a patient is in pain [The current randomized trial was designed to evaluate the clinical improvement in a cohort of patients with non-specific chronic low back pain associated with a neuropathic component after treatment with PEMS by using a bioelectronic therapeutic device  is also an important pain severity component. The SF-12 instrument was used to evaluate the increase in the quality of life perceived by the patients. This SF-12 is subdivided into two separate health constructs: the physical component summary score (PCS) and the mental component summary score (MCS). As the SF-12 is a reduced version of the MOS, it does not contain sleep behavior items. The MOS–Sleep scale, a face valid index of sleep disturbance with adequate established reliability with objective sleep measures, was also administered to evaluate the effects on sleep quality and quantity.Health-related quality of life instruments have been widely recommended as an outcome measurement for patients with low back pain ,56, and,Regarding the evaluation of the recovery of function, the authors use specific scales depending on the musculoskeletal diseases. Several scoring systems are frequently used in the clinical environment to measure the disability related to the low back condition. Up to date, studies investigating the effect of PEMS therapies on back pain did not evaluate the health-related quality of life by using the SF-12 questionnaire. However, the SF-12 tool was developed as an abbreviated version of the SF-36, containing a subset of 12 identical questions embedded in the SF-36 eight constructs . In thisLastly, no significant differences in the demographic information and the physical examination provided before the trial, including gender, age, studies, civil status, or economic activity, were found between the two experimental groups. In addition, no significant differences between the two experimental groups in terms of the values of VAS, DN4, SF-12, MOS sleep scale score were found at baseline. Thus, the extent of pain and disability and the quality of life due to low back pain and the physical characteristics of the subjects in the PEMS-treated group and the sham group were similar at baseline. Importantly, neither group showed side or abnormal effects throughout the trial. Although PEMS is safe, its safety needs to be furtherly evaluated for its use in long-term treatment, because a 2-weeks treatment with a three-month follow-up shows only medium-term results. Additional investigations and clinical trial studies are needed.Notwithstanding, it is worth noting some limitations that might have influenced the results of our study. VAS has some disadvantages. In particular, it seems to be more difficult to understand than other measurement methods and hence, more susceptible to misinterpretations or “zero-values.” However, this is particularly true in elderly patients and when respondents are given good instructions and the limitations are borne in mind, the VAS is still a valuable instrument to assess pain intensity and changes due to therapy. Likewise, SF-12 summary component scores could be an oversimplification of the information collected by the individual dimensions because they are calculated from the original 8 dimensions. However, summary components can be interpreted together with the profile provided by the 8 dimensions to avoid possible errors in interpreting the results. The use of SF-12 in conjunction with a disability scale has been recommendable because each tool measures unique aspects of disability and health-related quality of life. However, there is some overlap between both instruments, particularly concerning physical-function assessment. Regarding the MOS sleep scale, the lack of a cut-off score undermines its utility as a clinical tool. Nevertheless, the MOS scale may be more useful in studies where the focus is general health status assessment, but information on sleep parameters is of interest. This study also has several strengths: it is a randomized double-blind placebo-controlled treatment study; all the patients, outcome assessors, and the statistician were blinded to the group assignment, the sample size was large enough, and compliance was high.In the present study, PEMS therapy decreased the pain intensity in patients with chronic low-back pain with a neuropathic component. The results of this study may provide important health and economic benefits because of the high prevalence and the low therapeutic control of this condition. The major benefit in pain and disability control found in this study, compared with others performed with PEMS treatment, is mainly based on the use of a bioelectronic device that allows a dielectric, capacitive, and monopolar transmission, ensuring the bioavailability of the signal with therapeutic value in the target tissues, in the absence of side effects. Although the most effective pattern and mode of application of PEMS remain controversial, its application according to the new forms of noninvasive transmission offered by medical bioelectronics represents an important advance, and this type of technique can be postulated as one of the first-choice therapies in the management of low back pain with a neuropathic component. Despite the promising results obtained in this study, we should bear in mind and consider that this is a pilot trial. New studies with a larger number of patients and with more extended follow-up periods are needed to optimize the protocols for this type of treatment with PEMS and to corroborate the results obtained in the present research.


Persistent back/and or leg pain is a common outcome after spinal surgery (otherwise known as failed back surgery syndrome [FBSS]). Studies have shown that spinal cord stimulation (SCS) at 10 kHz provides effective analgesia in FBSS patients with both back and leg pain symptoms and in those with predominant back pain. This study is the first to evaluate the therapy in FBSS patients with predominant leg pain.The safety and efficacy of 10 kHz SCS was evaluated in an uncontrolled, open‐label, prospective study of FBSS patients with predominant leg pain in the Netherlands. Follow‐ups were performed at 1, 3, 6, and 12 months post implantation.Sixty out of 68 patients (88%) experienced sufficient pain relief during a stimulation trial. Of these, 58 proceeded to permanent implantation of a 10 kHz SCS system. After 12 months of treatment, 80% of patients experienced ≥ 50% reduction in baseline leg pain, and a similar proportion (76%) experienced ≥ 50% reduction in baseline back pain. At least two‐thirds of patients were also leg pain and back pain remitters . The therapy was also associated with a general improvement in patients’ quality of life, as measured by secondary outcomes including disability, perception of health improvement, mental well‐being, and satisfaction. A positive impact on opioid consumption was also observed.Consistent with previous findings, 10 kHz SCS for the treatment of FBSS patients with predominant radicular symptoms is safe and effective and is associated with improved quality of life. Low back pain is a common health complaint that has risen in prevalence during recent decades.Traditional spinal cord stimulation (SCS) is a minimally invasive therapy that has been widely used in recent decades to treat FBSS. During traditional SCS, low‐frequency (up to 200 Hz) electrical pulses delivered to the spinal cord elicit paresthesia over the painful area to mask the sensation of pain. Two randomized controlled trials (RCTs) have confirmed the analgesic efficacy of the therapy in FBSS patients with predominant leg pain. North and colleagues randomized patients to either reoperation or traditional SCS.Various European bodies have assessed the evidence base for SCS in FBSS. The European Federation of Neurological Societies (EFNS) review concluded that the therapy is efficacious in this population with grade B supporting evidence.Ten kilohertz SCS, an alternative paresthesia‐free SCS paradigm, has emerged to address the concerns with paresthesia coverage and lack of effective pain relief in significant proportion of patients. In an RCT, 10 kHz SCS demonstrated clinical benefit in patients with both back and leg pain. The SENZA‐RCT mainly comprised FBSS patients (87%) with baseline back pain and leg pain of at least 5 cm on the visual analog scale (VAS).This prospective, multicenter, open‐label study was conducted in five sites throughout the Netherlands. Non‐WMO  research and local ethics committee approvals were obtained at each participating site as required. The study was performed in accordance with ISO 14155‐2011; Data Protection Directive 95/46/EC; recommendations guiding physicians in biomedical research involving humans adopted by the 18th World Medical Assembly, Helsinki, Finland (1964 and later revisions); and local laws and regulations.Patients aged 18 years or over who had provided written informed consent were screened for enrolment according to the following key eligibility criteria: diagnosed with FBSS refractory to conservative therapy and minimally invasive pain procedures for at least 3 months and indicated for SCS as per Dutch SCS guidelines, average leg pain intensity ≥ 5 cm measured on the VAS, and back pain intensity ≤ average leg pain intensity on the VAS ; impression of change in health evaluated using the Global Impression of Change (GIC) questionnaires for clinicians and patients; catastrophic thinking related to pain measured using the Pain Catastrophizing Scale (PCS); emotional mood status measured on the Hospital Anxiety and Depression Scale (HADS); and patient satisfaction. Medication usage and change in opioid dose following treatment were not the endpoints of the study but were collected and reported for all patients on opioids during the study.Descriptive statistics were used to summarize data collected during the study. Continuous variables were summarized using the number of observations (patients), mean, standard error of the mean (SEM), minimum, median, and maximum. Categorical variables were summarized using counts and percentages. As this was a noncomparative study, the sample size was computed to reach a prespecified precision of 60% to 65% for the responder rate at 12 months, and calculated using the confidence interval formula, based on the Clopper–Pearson method. Analysis of effectiveness‐related endpoints was conducted on patients who completed each study visit. All analyses were carried out in Microsoft Excel.Between April 2015 and September 2017, 70 patients were enrolled in the study Figure . The lasAll 70 enrolled patients underwent a temporary stimulation trial; however, two patients experienced an adverse event during the trial phase and were excluded. Of the 68 remaining patients that completed the trial, 60 (88%) experienced a reduction of at least 50% in baseline leg pain. A further two patients were excluded after the trial phase: one due to an adverse event and one due to physician decision. In total, 58 patients proceeded to receive a permanent implant.Mean leg pain VAS score (±SD) decreased from 7.7 ± 2.4 cm at baseline to 1.2 ± 2.0 cm at the end of the trial, an average reduction of 84%. A high level of leg pain relief was sustained for 12 months, with average decreases in baseline VAS score of 76%, 70%, 58%, and 75% at 1, 3, 6, and 12 months, respectively Figure .Likewise, a high level of back pain relief was experienced during the trial phase and maintained out to 12 months Figure . Mean baN = 40/50) were responders to therapy for leg pain  reported response for back pain  and 80% (N = 40/50) of patients were leg pain and back pain remitters, respectively  reduced their ODI score sufficiently to reclassify them from severely disabled or crippled to moderately or minimally disabled.Functional outcomes on the ODI are shown in Figure Patients were classified at baseline and 12 months according to their daily intake of oral morphine equivalent  occurred during the study at any point. A total of six serious adverse events (SAEs) were reported during the 12‐month study period in five patients. All SAEs were resolved.Failed back surgery syndrome is a complex and challenging pathology to treat. 10 kHz SCS is a minimally invasive intervention that provides paresthesia‐free pain relief. The therapy is used to treat a variety of chronic pain etiologies associated with trunk and/or limb pain.To our knowledge, this is the first study to evaluate 10 kHz SCS in FBSS patients with predominant radicular symptoms Table . Among oOur 12‐month pain relief outcomes are consistent with previous studies of the therapy that included FBSS patients with other pain patterns. The SENZA‐RCT enrolled patients with both leg pain and back pain ≥ 5 cm on the VAS.In the prospective, single‐arm SENZA‐EU study of 10 kHz SCS in predominant back pain, the majority of implanted patients had a history of spinal surgery (79%).Stauss and colleagues also evaluated 10 kHz SCS in a large, retrospective, real‐world study of chronic back and leg pain patients.Among chronic pain patients, pain relief is a critical measure of therapy effectiveness. However, the impact of a therapy on patients’ lives beyond pain relief is also an important consideration. After 12 months of 10 kHz SCS, patients in the current study reduced their level of disability and reported a perceived improvement in health. Furthermore, a third of the patients that took opioids at some point during the study reduced or eliminated their intake. Previous studies of 10 kHz SCS in FBSS patients have documented similar benefits.In the SENZA‐RCT, 70% of the 10 kHz SCS group reduced their ODI classification at 12 months, while quality of life in the cohort increased across various scales.Some of the wider benefits of 10 kHz SCS in our cohort are further reflected in their improved mental well‐being. Average anxiety and depression scores both decreased on the HADS scale, and pain catastrophizing reduced on the PCS. These outcomes may be important because affective aspects such as depression, anxiety, and catastrophizing are often associated with elevated levels of pain and disability in chronic pain patients.Although not evaluated in our study, another important benefit of 10 kHz SCS is the absence of uncomfortable stimulation arising from postural changes, enabling patients to carry out routine daily activities with a high level of comfort. Around 95% of 10 kHz SCS patients in the SENZA‐RCT reported driving and sleeping with stimulation switched on.Overall, the present study showed promising outcomes in this group of Dutch FBSS patients with predominant radicular symptoms. To our knowledge, this study is the first to evaluate 10 kHz SCS in this patient group. However, our study lacked a control group and randomization, which could lead to selection bias in the patient population. Moreover, the study enrolled patients with predominant leg pain, and the patients also had back pain albeit with comparatively less intensity. The study could not isolate the patients who had only leg pain because the majority of FBSS patients have back pain along with leg pain with varying intensity. However, in all subjects, leg pain was the predominant complaint following back surgery. Consequently, our results should be interpreted within this context.Failed back surgery syndrome is a complex pathology that leaves patients with chronic back and/or radicular pain that is often refractory to conventional treatment. The present study prospectively evaluated 10 kHz SCS in FBSS patients with predominant leg pain and found the treatment to be safe and effective. The findings demonstrate that 10 kHz SCS may be a useful therapeutic option to treat the diverse range of back and leg pain symptoms experienced by FBSS patients.J.K.W. is a consultant for Nevro Corp. A.R., A.S., D.C., J.S., P.R., and V.M. are employees of Nevro Corp. Rest of the authors have no conflicts to disclose.


The incidence rates of adverse events secondary to any operation are a well-known problem in any surgical field. One outstanding example of such adverse events is postoperative pain. Thus, the incidence of acute postoperative pain following any surgical procedure and its treatment are central issues for every surgeon. In the times of Enhanced Recovery After Surgery (ERAS) programs, acute pain therapy became an increasingly well investigated and accepted aspect in almost all surgical subspecialties. However, if it comes to the reduction of postoperative complications, in the actual context of postoperative pain, surgeons tend to focus on the operative process rather than on the perioperative procedures. Undoubtedly, postoperative pain became an important factor with regard to the quality of surgical care: both, the extent and the quality of the surgical procedure and the extent and the quality of the analgesic technique are decisive issues for a successful pain management. There is growing evidence that supports the role of acute pain therapy in reducing postoperative morbidity, and it has been demonstrated that high pain scores postoperatively may contribute to a complicated postoperative course. This overview comprises the current knowledge on the role of acute pain therapy with regard to the occurrence of postoperative complications. Most of the knowledge is derived from studies that primarily focus on the type and quality of postoperative pain therapy in relation to specific surgical procedures and only secondary on complications. As far as existent, data that report on the recovery period after surgery, on the rehabilitation status, on perioperative morbidity, on the development of chronic pain after surgery, and on possible solutions of the latter problem with the institution of transitional pain services will be presented. The incidence rates of adverse events secondary to any operation are a well-known problem in any surgical field. In the realm of general surgery, these incidences range from 3% to 53% , 2], , . In the It is therefore a key question: which is the hen, and which is the egg?Is postoperative pain an indicator for a (developing) complication, which means that management of the complication will automatically lead to a simultaneous decline in pain severity, or is postoperative pain, itself, a complication on its own, which inversely means, that management of the postoperative pain will reduce the level of complications?There is growing evidence that supports the role of acute pain therapy in reducing postoperative morbidity . At the This overview shall comprise the current knowledge on the role of acute pain therapy with regard to the occurrence of postoperative complications. Most of the knowledge is derived from studies that primarily focus on type and quality of postoperative pain therapy in relation to specific surgical procedures and only secondary on complications. As far as existent, data that report on the recovery period after surgery, on the rehabilitation status, on perioperative morbidity, on the development of chronic pain after surgery, and on possible solutions of the latter problem with the institution of transitional pain services will be presented.The quality of postoperative recovery is commonly measured by either objective parameters such as length of recovery room or hospital stay or subjective parameters such as postoperative nausea and vomiting (PONV). In order to improve this aspect, an Australian group established a scoring system, referred to as the “Quality of Recovery-40 (QOR-40)” , to evalLooking at the effect of regional analgesia in breast cancer surgery, it was also reported that the use of a single shot of PVB prior to surgery reduces recovery time from analgesia and the incidence of PONV . A retroAnother technique for regional analgesia during breast surgery was implemented with the pectoral nerves (PECS) types 1 and 2 blocks. Their application, together with general analgesia, leads to improved analgesia and a decreased incidence of PONV and a shorter hospital stay .Looking at the effect of systemic analgesia in breast cancer surgery, a literature review reports on intravenous injection of clonidine , which rIn summary the data available in breast cancer surgery demonstrate that regional analgesia, including PVB and local anesthetic infiltration, is associated with higher QoR-40 score and reduced PONV incidence and earlier discharge compared to an opioid-based analgesia .It is assumed that an effective pain treatment will facilitate and promote early postoperative rehabilitation with all benefits from better physiotherapy to early discharge and return to work. Unfortunately, only few data are available .A randomized controlled trial reporting on knee surgery found that epidural analgesia (EA) and peripheral nerve blocks (PNB) were a combination of methods that, compared with intravenous patient controlled analgesia (PCA), improved knee flexion and reduced the length of rehabilitation . The samOne randomized, double-blind, placebo-controlled trial on patients undergoing hip fracture surgery was not able to demonstrate improvement in recovery of physical independence for the EA patients . One yeaBesides a systemic and/or catheter-bound regional acute pain therapy, the concept of a local pain therapy was established throughout the past years. Such a localized pain therapy may be performed in a single-shot technique with long-lasting local anesthetics in small laparoscopy incisions either immediately pre- or postoperatively. A good alternative, however, at present that is less known, is a continuous postoperative wound infiltration via small catheters that will be inserted into the wound at the end of the operation. Long-acting local anesthetics may be administered with a primary bolus of 5–10 mL with a subsequent continuous infusion flow rate of 5–10 mL/h by way of self-emptying elastomeric pump systems. Ideal incisions for this technique are medium-sized incisions in conventional hernia surgery, Pfannenstiel incisions, or incisions for breast surgery.A recent meta-analysis reports on a comparison of postoperative epidural analgesia with a catheter-bound continuous wound infiltration . The ava–A continuous wound infiltration leads to a significantly lower ratio of postoperative hypotension.–Complications such as abscess formation, bleeding, ileus, nausea and vomiting, urinary tract infection, wound infection, and itching were equal in both analgesic techniques.–In the epidural analgesia group, the postoperative pain score was significantly lower at rest and at mobilization compared to the group of patients with continuous wound infiltration.Another meta-analysis focused on the position of the postoperatively administered wound catheter: preperitoneal vs. subcutaneous . Twenty-Two clear statements were reported:–There is an indirect advantage for the preperitoneal catheter position, as the reported postoperative pain control was similar to the group of patients with epidural analgesia.–Postoperative mobilization, patient satisfaction, hypotension as side effect, and analgetic consumption was less in the group of patients with a preperitoneal catheter position.In essence, the available data are only able to give a hint toward an improvement in the early postoperative rehabilitation, thus, leading to an avoidance of typical complications in this time period. No conclusive or long-term data exist.Without specific data on each surgical subspecialty, perioperative morbidity is the single most prominent problem in possible existing postoperative adverse events. Perioperative morbidity comprises problems with respiratory, coagulatory, intestinal, and hormonal stress-induced function disorders.A recently published study on the association between postoperative pain and 30-day postoperative complications highlights the problem . ConsecuThe results of this study reflect a common knowledge: postoperative pain impairs both physical mobilization and pulmonary mobilization, i.e. coughing, thus leading to a higher risk of respiratory complications. A delayed removal of urinary catheters secondary to pain-related delayed mobilization may increase the incidence of urinary tract infections. Finally, a delayed intestinal function may be secondary to postoperative pain and/or adverse effects of analgesia. The authors conclude that their findings support the hypothesis of a causal relationship between postoperative pain and complications after surgery, leading to the advice that personalized analgesia in modern perioperative care is a central issue.Within the past two decades, it is has become evident that EA is able to reduce a good amount of the above-mentioned postoperative problems. The effects of different anesthetic and postoperative analgesic techniques on perioperative complications were evaluated in a systematic review . A clearAnother meta-analysis focused on the protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic surgery . CoverinThe same group published a systematic review and meta-analysis of randomized controlled trials 6 years later in order to elicit the impact of epidural analgesia on mortality and morbidity after surgery . In 10 oAgain, looking upon the effect of a combination of general anesthesia and EA, a retrospective cohort study on patients with intermediate and high-risk noncardiac surgery found that EA was associated with a statistical significant reduction in the 30-day-mortality . HoweverA quite recent study investigated patients undergoing any type of colectomy with or without EA using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) to assess any association between EA (versus non-EA) and complications after colectomy. Patients, 4.176, with EA were matched 1:4 via propensity score to 16.704 non-EA patients undergoing colectomy . The priPutting together the available information on the role of EA, there is undoubtedly a favorable effect on the postoperative outcome, even if this effect may be restricted to major surgery performed on intermediate or high-risk patients.The possible advantages of regional analgesic techniques have to be balanced to the inherent risk of such techniques if looking upon postoperative complications. There are two excellent surveys which allow for a reasonable opinion: A National Audit Project of the Royal College of Anaesthetists entailed a 2-week national census, which identified 707.455 central neural blockades performed over 1 year in the UK National Health Service . All majQuite similar numbers were derived from a prospective analysis of 18.925 postoperative patients receiving patient-controlled EA, intravenous PCA, continuous brachial plexus block, and continuous femoral/sciatic nerve block in a German University Hospital . EpiduraIn summary, neurological damage and even more permanent damage is extremely rare after regional analgesic techniques. These rather rare complications should not counterweigh the advantages of such techniques with regard to the option of reducing postoperative complications.More than 10 years of research undoubtedly demonstrate high incidences of persistent, chronic pain (CP) that resides after many surgical procedures . One larA prerequisite for the detection of patients at risk for the development of CP after surgery is a strict pain assessment and assessment of pain-related functional interferences in the early postoperative phase. If pain (and its consequences) is not assessed, and/or – perhaps even more important – if assessment is not embedded in a setting of standardized clinical pathways, which triggers well-defined analgesic techniques, deficits of pain management will remain undetected.per se is a devastating symptom, and treatment still remains difficult and often unsuccessful . T. T45]. TThe latter findings exemplify three important aspects:per se with more efficient analgesic approaches. Here, regional anesthesia techniques have been more favorable than drugs (e.g. opioids) . T. T53]. Topioids) . A systeopioids) . Three c–It remains unclear whether a perioperative intravenous lidocaine administration offers an advantage compared to placebo or no treatment with regard to postoperative pain score in the early postoperative phase, to gastrointestinal recovery, to postoperative nausea, and to opioid consumption.–The quality of evidence was limited by the inconsistency, the inaccuracy, and the quality of currently available trials.–There is no sufficient evidence as to the optimal intravenous lidocaine dosage and duration of administration in comparison to epidural analgesia.Specific preventative treatment options might be given perioperatively; however, here, only ketamine seems to be effective in preventing (some aspects of) CP after surgery .There is a very interesting and new approach to prevent CP after surgery by a multidisciplinary team in the hospital as well as after discharge (see below); this service has been introduced punctually in some countries in single hospitals, and the first results are promising , 57]..57].Many studies suggest that chronic pain after surgery is multifactorial (see above). Thus, prevention and treatment might only work using a multidisciplinary approach. Furthermore, prevention and treatment might need to continue for a while after the patient has left the hospital. In order to decrease CP after surgery effectively and sustainably, a comprehensive, multi-disciplinary and inter-sectoral working facility dedicated to prevent and treat CP after surgery was proposed , 57] an an57] anidentify patients with an increased risk for developing chronic post-surgical pain,provide adequate pain medication for patients (including rather a reduction of opioids than a continuation), andoffer psychological and/or physiotherapeutic treatment to provide support where negative aspects limit recovery and functioning , 59], , .The first results indicate an impressive reduction in opioid use after surgery by such a multidisciplinary approach . Such anto provide patients with instructions to maximize the use of nonopioid analgesics;the minimum number of opioid tablets to prescribe after each procedure is 0, depending on procedure and patient characteristics;the maximum number of opioid tablets to prescribe varies by procedure, but should not exceed 20 tablets.Together, for in and outpatient surgeries, appropriate use of analgesics together with, e.g. after inpatient major procedures with a high risk of prolonged and chronic pain after surgery, a multidisciplinary preventative approach, ideally by having a “transitional pain service” in place, would be of great advantage. However, future effort needs to be taken to show the medical as well as socioeconomic benefits of such a service to appeal hospitals and politics to invest in this.Click here for additional data file.


Introduction: Spinal Cord Stimulation (SCS) is a last-resort treatment for patients with intractable chronic pain in whom pharmacological and other treatments have failed. Conventional tonic SCS is accompanied by tingling sensations. More recent stimulation protocols like burst SCS are not sensed by the patient while providing similar levels of pain relief. It has been previously reported that conventional tonic SCS can attenuate sensory-discriminative processing in several brain areas, but that burst SCS might have additional effects on the medial, motivational-affective pain system. In this explorative study we assessed the influence of attention on the somatosensory evoked brain responses under conventional tonic SCS as well as burst SCS regime.Methods: Twelve chronic pain patients with an implanted SCS device had 2-weeks evaluation periods with three different SCS settings . At the end of each period, an electro-encephalography (EEG) measurement was done, at which patients received transcutaneous electrical pulses at the tibial nerve to induce somatosensory evoked potentials (SEP). SEP data was acquired while patients were attending the applied pulses and while they were mind wandering. The effects of attention as well as SCS regimes on the SEP were analyzed by comparing amplitudes of early and late latencies at the vertex as well as brain activity at full cortical maps.Results: Pain relief obtained by the various SCS settings varied largely among patients. Early SEP responses were not significantly affected by attention nor SCS settings . However, late SEP responses (P300) were reduced with tonic and burst SCS: conventional tonic SCS reduced P300 brain activity in the unattended condition, while burst SCS reduced P300 brain activity in both attended and unattended conditions.Conclusion: Burst spinal cord stimulation for the treatment of chronic pain seems to reduce cortical attention that is or can be directed to somatosensory stimuli to a larger extent than conventional spinal cord stimulation treatment. This is a first step in understanding why in selected chronic pain patients burst SCS is more effective than tonic SCS and how neuroimaging could assist in personalizing SCS treatment. Spinal Cord Stimulation (SCS) is a last-resort treatment for patients with intractable neuropathic pain in whom pharmacological and other treatments have failed. SCS is based on electrical stimulation of the nerve fibers in the spinal cord dorsal column (A-beta fibers) by an implanted electrode that is connected to an implanted pulse generator. Pain reduction occurs in the body area corresponding to the stimulated spinal segments. Conventional tonic SCS  is accompanied by tingling sensations (paresthesia). More recently developed stimulation protocols like burst stimulation  and other high-frequency stimulations (up to 10 kHz) are paresthesia-free while providing similar levels of pain relief  study in five patients who were trialing SCS, showed that compared with conventional tonic SCS, burst SCS led to increased synchronized alpha activity in the cingulate cortex and dorsolateral prefrontal cortex as well as behaviorally decreased attention to the pain. It was suggested that the analgesic effects of burst SCS are obtained by modulating both the lateral discriminatory and medial affective/attentional pain pathways . After aOne of the consequences of these findings reported by De Ridder et al. is that if reduction of cortical attention to pain is one of the working mechanisms of burst stimulation, burst might not only cause alterations in resting state activity, but also influences the capacity for attending and processing peripheral somatosensory input. In the present explorative study, we assessed the influence of attention on somatosensory evoked brain responses under conventional tonic SCS as well as burst SCS regime.It has been previously reported that conventional tonic SCS can attenuate the somatosensory processing in SI, SII and the cingulate cortex e.g., , 14–18].–18.14–18www.trialregister.nl, NTR 4479).Twelve chronic pain patients , on average 57 years old, all with Failed Back Surgery Syndrome (FBSS) and pain in their low back as well as one or two legs participated in this study. Those 12 patients also participated in the larger Burst evaluation study described in a previous publication . The BurAll 12 participating patients had three EEG recording sessions between August 2014 and March 2015 . Ten patAll patients evaluated three different SCS settings, each for 2 weeks: conventional tonic SCS, burst SCS and sham SCS . ParticiElectroencephalography (EEG) measurements were conducted during three sessions: at visits 2, 3 and 4 . EEG datPatients sat comfortably in an armchair in an electrically and sound-shielded room. They received transcutaneous electrical stimulation to induce Somatosensory Evoked Potentials (SEP). Stimulation was applied to the tibial nerve at the ankle of their affected leg in order to study the evoked potentials in several cortical areas . Square Non-painful electrical stimulation of the tibial nerve evokes the first positive EEG activity after about 40 ms (P40) in the primary somatosensory cortex. This activation is generally measured at the vertex . P40 actEach patient had three EEG recording sessions, one session with each of the three SCS regimes. During each session the spinal cord stimulator was still active with the same setting and intensity as it had been for the 2 weeks prior to the EEG recording. At each EEG session, a resting state EEG recording and two SEP recordings were made. Throughout the entire recording session the patients were asked to relax and keep their eyes open looking at a fixation cross. During one of the SEP recordings patients had to pay attention to the stimuli that were applied to their tibial nerve. They were asked to silently count them and afterwards report the number to the researcher. During the other SEP recording patients were asked to mind wander and not pay attention to the stimuli. The order in which stimuli had to be attended or not attended, was counterbalanced over the sessions and over the patients.http://neuroimage.usc.edu/brainstorm/) . Cardiac and blinking artifacts were also detected using the ECG and EOG signals and corrected using the Signal-Space Projection approach . All thenstorm/)  followinnstorm/) . Data waParticipants head model was estimated using the Symmetric Boundary Element Method from the open-source software OpenMEEG: Scalp 1.0000 1082V | Skull 0.0125 642V | Brain 1.0000 642V) , 30. We Approximately 200 SEP epochs from −200 to 500 ms were averaged per participant, with time = 0 ms being the time of delivery of the electrical stimulation at the tibial nerve. Each epoch was DC offset corrected  and the stimulation artifact  was cut. Source data was Z-scored with respect to the baseline  and individual cortical maps were smoothed using a circularly symmetric Gaussian surface kernel with a full width half maximum size of 10 mm . In ordet-test, 1,000 permutations, p < 0.05, cluster alpha 0.05)  were evaluated on the different SEP amplitudes at latencies of interest at the vertex  using two sided non parametric Wilcoxon signed rank tests and a two-way analysis of variance (ANOVA) test, including SCS regime  and participants attention condition . In addition, whole brain source differences between conditions were estimated correcting for multiple comparisons using a non-parametric cluster based permutation test (paired ha 0.05) .Clinically, the 12 participants responded differently to the three spinal cord stimulation regimes they evaluated. The amount of pain relief by the three different SCS regimes varied largely for the individual patients. The average VAS scores for pain were 46 (range: 17–79) for burst SCS, 61 (range: 17–90) for tonic SCS, and 53 (range: 21–72) for sham SCS . Six patAll participants could clearly feel and count the applied stimuli at their tibial nerve in all three SCS conditions. Average stimulation amplitude was 27 mA (range: 10–75 mA). The individual's stimulation amplitude was stable over the three EEG recording sessions (<10% variation for each subject) and so was the perceived intensity of the applied stimuli, which was non-painful but clearly sensed by all participants. All participants were therefore able to focus on the applied stimuli and could count them correctly, with an average accuracy of 98% for all three SCS conditions. Since none of the participants perceived the stimuli as painful in either of the three conditions, all reported that they were capable of shifting their attention away from the stimuli during the trials in which they were asked to mind wander.Neither attention nor SCS setting had a statistically significant effect on the amplitudes of the early SEP latencies . Which corresponds with the similar intensity scores that were reported for the applied stimuli by the participants during all three SCS settings.Sham SCS was intended to have no therapeutic effect. Attending the electrical stimuli applied at the tibial nerve during sham SCS caused no statistically significant differences in P300 amplitude as when the stimuli were not attended . CompariWhen the participants were asked to mind wander during tonic SCS and did not attend the applied stimuli, the P300 amplitude decreased substantially in comparison to the attended condition . The rigDuring burst SCS, paying attention to the applied stimuli or not attending them did not change the P300 amplitude of the SEP .When the applied stimuli were attended by the participants, only the burst SCS regime reduced the P300 amplitude as compared with sham SCS . When thp < 0.03) during burst SCS in comparison to sham SCS , somatosensory, mid cingulate, and left and right insular cortices .Attention can modulate the amplitude of the P300 in chronic pain patients treated with spinal cord stimulation. When patients either silently counted the applied electrical stimuli or were mind wandering, this modulated the SEP amplitude of the P300, but not the evoked potentials at earlier latencies and neither the perceived intensity of the applied stimuli.Previous findings by De Ridder et al.  and De RDuring sham SCS, attending or not attending the peripherally applied stimuli only caused a small difference in P300 amplitudes, indicating that even while the patients were mind wandering, somatosensory stimuli were still processed to almost the same amount as if they were attended. Attending the applied stimuli while receiving tonic SCS showed a P300 amplitude similar to the sham conditions. However, when the stimuli were not attended, the amplitude decreased substantially. During burst SCS, not attending the stimuli caused an even lower P300 than not attending them during tonic SCS. Attending the stimuli during burst SCS however, did not cause an increase in the P300 amplitude, indicating that burst SCS might affect the attention that could be directed to the applied somatosensory stimuli.The 12 participants in this study are not healthy subjects, but chronic pain patients who have been suffering neuropathic pain for years and are treated with analgesic medication and SCS therapy. SEP amplitudes and latencies in chronic pain patients vary from healthy subjects, as amplitudes have been reported larger and certain latencies to be delayed . TherefoBesides SCS therapy, most of the patients were also using analgesic medication. Although high dose opioids can induce an increase in low frequency (delta band) brain activity and a decrease in amplitude of potentials evoked by painful stimuli, opioids have been reported to not influence the amplitudes of the non-painful SEPs . ParacetIn our study, the participants had their spinal cord stimulator for at least half a year, so all of them were familiar with tonic SCS and the paresthesia it caused. This means we have a different population than De Ridder et al. reported on , 13. TheFor each participant the amplitude and the perceived intensity of the applied tibial nerve stimuli did not vary during the three study conditions. However, the effects of the three SCS regimes  on their own ongoing pain varied largely over the participants, as did their preference for specific SCS settings. Preference was also influenced by other aspects than pain reduction, like the presence or absence of paresthesia . The numTo make sure that the participants actively attended the applied electrical stimuli at their tibial nerve, we asked them to silently count the stimuli and report the number at the end of the measurement. To avoid them just remembering the number of applied stimuli from previous measurements, we randomly varied the number of stimuli of every SEP recording. Since the patients reported the correct numbers in all attention conditions, it is very likely they were indeed counting and paying attention. In the mind wandering condition, we can never be completely certain that patients were indeed not counting or otherwise attending the stimuli when we asked them not to do so. However, the differences in P300 amplitude between the attended and unattended stimuli in the sham and tonic SCS conditions suggest that patients were again compliant and were not attending the stimuli during these recordings.Tonic SCS is accompanied by paresthesia, generally by the patients described as constant tingling sensations. When we applied electrical stimuli to the tibial nerve, these electrical stimuli and the paresthesia are concurrent sensations that need to be processed by the brain, in addition to the patient's ongoing pain. When the patients were asked to not attend the applied stimuli under tonic SCS, it led to a decreased P300 amplitude and reduced activity in somatosensory and motor cortices , which dOther studies have found that conventional tonic SCS inhibits the early SEP latencies that are generated in the primary somatosensory cortex , 38. OneOne other study also reported reduced late SEP (P300) amplitudes in response to non-painful tibial nerve stimulation during tonic SCS as compared with no SCS . In thatPolácek et al.  applied Our EEG study is an explorative study, with a small number of participants to search for potential differences in effects and working mechanisms between tonic and burst spinal cord stimulation. In addition we compared burst and tonic SCS with sham SCS. Only 12 chronic pain patients with an implanted SCS device participated in our study that was underpowered. Interpreting the statistical results has to be done carefully, but since the effects of tonic and burst SCS happen in those 12 patients regardless of the effect of SCS on their pain, our results are interesting to further test in an properly powered study.A major limitation of our present study, however, is that sham SCS might not have been real sham stimulation for every participant and some patients might have actually received sufficient energy to perceive therapeutic effects. Two patients reported their lowest pain scores under sham SCS regime. The therapeutic range of burst SCS is still unknown and this range might vary to a great extent per patient, similar to how the therapeutic range of conventional tonic SCS varies per patient and is among others dependent on the individual's anatomy of the spinal cord and the position of the electrode lead in the epidural space , 43. HowBurst stimulation is one of the relatively new developments in spinal cord stimulation regimes. Several aspects of the working mechanisms of burst stimulation and other new paresthesia-free regimes are still unknown and require further research, as they seem to affect different or additional cortical areas than tonic SCS. The present study showed that burst SCS reduced the P300 amplitude of the somatosensory evoked potential. A similar reduction was also obtained during tonic SCS when patients were instructed to not attend peripherally applied pulses. Which suggests that burst SCS reduced the capacity for attention directed to somatosensory stimuli.Our findings support the hypothesis posed by De Ridder and Vanneste  that burThe data and code supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Twente Ethics Committee, Enschede, the Netherlands. The patients/participants provided their written informed consent to participate in this study.The conception was originated from CdV and ML. Data collection was done by MT-C and CdV. Data analysis and interpretation was performed by GN and CdV. The first draft was written by GN and CdV and further input was provided by ML and MT-C. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


By domains, improvement was observed in musculoskeletal , fluctuation-related , nocturnal , discoloration and/or edema/swelling  and radicular pain . A total of 21 adverse events in 11 patients (22%) were reported, five being severe, but not related to safinamide. Conclusion: Safinamide is well tolerated and improves pain in PD patients at 6 months. Future studies are necessary to analyze the possible beneficial effect of safinamide on pain in PD patients.Background and objective: Pain is a frequent and disabling symptom in Parkinson’s disease (PD) patients. Our aim was to analyze the effectiveness of safinamide on pain in PD patients from the SAFINONMOTOR (an open-label study of the effectiveness of SAFInamide on NON-MOTOR symptoms in Parkinson´s disease patients) study. Material and Methods: SAFINONMOTOR is a prospective open-label single-arm study conducted in five centers from Spain. In this analysis, a secondary objective of the study, the score in the KPPS  at V1 (baseline) and V4 (6 months ± 1 month) were compared. Wilcoxon´s rank sum test was performed to test the changes from V1 to V4. Results: Forty-four (88%) out of 50 PD patients  completed the study. The KPPS total score was reduced by 43.6% (from 40.04 ± 36.18 in V1 to 22.60 ± 21.42 in V4;  Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease characterized by the presence of motor symptoms and non-motor symptoms (NMS) . Among thttps://clinicaltrials.gov/ct2/show/NCT03841604 (accessed on 13 August 2021); NCT03841604).Safinamide is an oral α-aminoamide derivative marketed for the treatment of PD with both dopaminergic properties, namely highly selective and reversible inhibition of monoamine oxidase B, and non-dopamimetic properties, namely selective sodium channel blockade and calcium channel modulation, with consequent inhibition of excessive glutamate release . In prevWe observed very recently an improvement in the global NMS burden in 50 PD patients from the SAFINONMOTOR study . In thishttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999475/ (accessed on 13 August 2021) [SAFINONMOTOR is a multicenter, observational (phase IV), prospective, open-label, follow-up study conducted in five centers from Spain. Patients with PD according to the United Kingdom Parkinson’s Disease Society Brain Bank criteria  without st 2021) .https://www.mdpi.com/2076-3425/11/3/316/htm (accessed on 13 August 2021) [The study included 4 visits: V1 (baseline); V2 (1 months ± 7 days); V3 (3 months ± 15 days); V4 . Subjects completed the KPPS  in all vst 2021) . ImportaSafinamide was administered as once-daily 50 mg pill for 1 month and switched to 100 mg/day at V2 except at the discretion of neurologists (1 neurologist expert on PD in each center) according to the needs of the patients in their clinical practice. In the case of receiving rasagiline, the minimum washout period was 15 days. During follow-up, any other medications than safinamide should not have been modified  except if the neurologist considered these changes absolutely necessary. All the changes in medications and levodopa equivalent daily dose (LEDD)  were recData were processed using SPSS 20.0 for Windows. Continuous variables were expressed as the mean ± SD or median and quartiles, depending on whether they were normally distributed. Relationships between variables were evaluated using the Mann-Whitney U test, Student´s t-test, and the, Pearson´s or Spearman´s correlation coefficient as appropriate (distribution for variables was verified by Kolmogorov-Smirnov test). The change from V1 to V4 in the KPPS total score was the principal efficacy outcome variable in this analysis. Moreover, the change in the score of each domain of the KPPS, VAS-PAIN score, and “Pain and discomfort” PDQ-39 score domain were analyzed. Analyses of efficacy variables were performed with the ITT data set . A paired-sample t-test or Wilcoxon´s rank sum test, as appropriate, was performed to test the change from baseline.p-values < 0.20 were included in a multivariable model, and a backwards selection process was used to remove variables individually until all remaining variables were significant at the 0.10 level [p < 0.05 was considered significant.In order to investigate which factors were predictors of improvement in pain in this cohort, linear regression models were used . Any variable with univariate associations with 10 level . The varFinally, as was previously reported , adverseApproval from the Comité de Ética de la Investigación Clínica de Galicia from Spain  was obtained. All participants signed a consent form.The data that support the findings of this study are available from the corresponding author upon reasonable request.Fifty PD patients were included in the study between May 2019 and February 2020 . Data on sociodemographic aspects, comorbidities, antiparkinsonian drugs and other therapies have been previously published [p < 0.0001) (p = 0.009), KPPS-domain 3 (fluctuation-related pain) , KPPS-domain 4  , KPPS-domain 6  , and KPPS-domain 7 (radicular pain)  (p = 0.071) (p = 0.018). Changes from V1 to V4 in different scales of the SAFINONMOTOR study have been previously published [At 6 months, 44 patients completed the follow-up (88%) and a lower KPPS total score compared to baseline was observed in 28 out of 43 patients (65.1%), the same score in 6 patients (13.9%), and a higher score in 6 patients (13.9%). The KPPS total score was reduced from V1 to V4 by 43.6%  . Conside= 0.048) . With re= 0.071) . Compare= 0.071) . A signip values were computed using the Wilcoxon signed-rank test. Mild outliers (O) are data points that are more extreme than Q1 − 1.5 ∗ IQR or Q3 + 1.5 ∗ IQR.Data are presented as box plots, with the box representing the median and the two middle quartiles (25%–75%). KPPS-1—Musculoskeletal pain; KPPS-2—Chronic pain; KPPS-3—Fluctuation-related pain; KPPS-4—Nocturnal pain; KPPS-5—Oro-facial pain; KPPS-6—Discoloration, edema/swealing; KPPS-7—Radicular pain.p < 0.0001), VAS-PAIN , VAFS-Physical , PDQ-39SI , and PDQ-39SI-domain 8 (pain and discomfort) . By domains, a strong correlation was observed between the change from V1 to V4 in the KPPS-domain 2 (chronic pain) and the change in the NMSS total score . Other significant correlations between changes from V1 to V4 in the score of KPPS domains and the change from V1 to V4 in the score of the rest of scales are shown in p < 0.0001), so the higher score at baseline, the greater the decrease in the score from V1 to V4.A moderate correlation was observed between the change from V1 to V4 in the KPPS total score and the change from V1 to V4 in the scores of NMSS  and a higher KPPS total score at baseline  were associated with a greater decrease in the KPPS total score from V1 to V4   . In the p < 0.0001) (p = 0.175).When PD patients were divided in two groups, patients with a baseline KPPS total score < 50  and PD patients with a baseline KPPS total score ≥ 50 , a significant difference was observed in the change from V1 to V4 in the KPPS total score  . Howeverp values were computed using the Wilcoxon signed-rank test.Data are presented as box plots, with the box representing the median and the two middle quartiles (25%–75%). KPPS, King´s PD Pain Scale; VAS-Pain, Visual Analog Scale-Pain.Twenty-one adverse events in 16 patients (32%) were reported, 5 of them severe but not related to safinamide. This information has been reported before  Table S. At baseThe present study observes that pain improved in patients with PD 6 months after starting with safinamide. Specifically, patients improved in musculoskeletal, fluctuation-related, nocturnal, discoloration and/or edema/swelling and radicular pain. Moreover, patients improved their health-related quality of life (QoL) and a correlation between QoL improvement and pain improvement was observed. Safinamide, as it has previously reported, was well tolerated.p < 0.05), but the sample was small (N = 13), and the numeric value of the KPPS total score at baseline was not provided (this seems to be about 40 points according to a figure), and, importantly, they information about the domains of the scale was not given. Although our study is not a double-blind trial like that of Cattaneo et al. [Pain is a frequent and distressing symptom in PD occurring in 30%–85% of subjects (mean = 66%) . There ao et al. , it is aSome types of pain can improve with dopaminergic medication, especially musculoskeletal and dystonic pain, akathisia or, in general, any pain emerging during the OFF state ,6,10. InAlthough the involvement of dopamine in the central modulation of pain is well established , other nThe domain “Pain and discomfort” of the PDQ-39 improved at 6-month follow-up and a moderate correlation was observed between the improvement in pain  and QoL . In a post-hoc analysis, two of the three items of the PDQ-39 related to pain and the overall “Pain and discomfort” domain score improved with safinamide compared with placebo after 6 months  and evenhttps://clinicaltrials.gov/ct2/show/NCT03841604; (accessed on 13 August 2021) NCT03841604). Furthermore, the sample size is rather small and, for some variables, the information was not collected in all cases. The results are based on scales that collect the opinion of the patient and we did not include any objective method for assessing pain perception [The most important limitation of the present study is related to the study design itself and, since there is not a comparative placebo arm, the results should be interpreted very carefully. In line with this, a phase IV multicenter, randomized, double-blind, placebo controlled study about the effect of safinamide on pain in PD patients experiencing motor fluctuations and PD related chronic pain (rception . In factrception . Four virception  could haIn conclusion, safinamide is well tolerated and could improve pain in PD patients. Well-designed randomized double-blind trials are necessary to analyze in detail the effect of safinamide on pain. Especially interesting could be the analysis of pain with objective methods and with regards to action mechanism, dopaminergic and/or glutamatergic, in patients receiving safinamide.


Background: Although several treatments are currently available for chronic pelvic pain, 30–60% of patients do not respond to them. Therefore, these therapeutic options require a better understanding of the mechanisms underlying endometriosis-induced pain. This study focuses on pain management after failure of conventional therapy. Methods: We reviewed clinical data from 46 patients with endometriosis and chronic pelvic pain unresponsive to conventional therapies at Puerta de Hierro University Hospital Madrid, Spain from 2018 to 2021. Demographic data, clinical and exploratory findings, treatment received, and outcomes were collected. Results: Median age was 41.5 years, and median pain intensity was VAS: 7.8/10. Nociceptive pain and neuropathic pain were identified in 98% and 70% of patients, respectively. The most common symptom was abdominal pain (78.2%) followed by pain with sexual intercourse (65.2%), rectal pain (52.1%), and urologic pain (36.9%). A total of 43% of patients responded to treatment with neuromodulators. Combined therapies for myofascial pain syndrome, as well as treatment of visceral pain with inferior or superior hypogastric plexus blocks, proved to be very beneficial. S3 pulsed radiofrequency (PRF) plus inferior hypogastric plexus block or botulinum toxin enabled us to prolong response time by more than 3.5 months. Conclusion: Treatment of the unresponsive patient should be interdisciplinary. Depending on the history and exploratory findings, therapy should preferably be combined with neuromodulators, myofascial pain therapies, and S3 PRF plus inferior hypogastric plexus blockade. Endometriosis is defined as an endometrial-like tissue that occurs outside the uterine cavity. Endometriosis is an estrogen-dependent, chronic inflammatory disease, and is the major contributor to chronic pelvic pain (CPP). Due to the difficulty of making an accurate differential diagnosis of this disease through symptoms , it mighThere are conventional therapeutic options for management of endometriosis, including medical treatment  ,6 and suThe aim of this study was to report our experience in the interdisciplinary management of women who suffer from endometriosis and CPP unresponsive to conventional therapies and who were seen in our hospital over the course of the past 3 years.We reviewed clinical data from consecutive patients with endometriosis and CPP not responsive to conventional therapies at Puerta de Hierro University Hospital, Madrid, Spain from January 2018 to September 2021. Approval was granted by the Institutional Review Board. The main inclusion criterion was CPP and endometriosis patients who do not respond to conventional therapy persisting for at least 6 months. Conventional therapy for CPP was defined as medical treatment  ,4 with fData included a full history , comorbidities , pain in neighboring organs , duration of pain (estimated by the patient as the number of years between onset of symptoms and date of first consultation), characteristics, localization and irradiation of pain, and finally, the intensity of pain, measured using a visual analogue scale (VAS) ranging between 0 (no pain) to 10 (worst pain ever experienced) .(1)Neurologic examination S2–S4: (a) cotton swab test at the S2–S4 dermatome and vestibule; (b) assessment of the nerve’s motor response using the clitoris, bulbospongiosus, and perineal reflexes; (c) Tinel sign at the level of the sciatic spine to evaluate the third segment of the pudendal nerve ; (d) Tin(2)Exploration of the pelvic girdle: bilateral palpation to identify painful spots: retropubic, ischiopubic ramus, ischium, sacrospinous ligament, sacrum, and coccyx.(3)Exploration of pelvic floor muscles: (a) Levator ani muscle (LAM): assessment of painful palpation of the pubococcygeus muscle; (b) Obturator internus muscle (OIM): Contracture of the IOM with flexion and external rotation of the hip in the supine decubitus position and transgluteal exploration of IOM segments: pelvic (ischium), medium (midpoint between the trochanter and coccyx) and gluteal (hip); (c) Piriformis muscle (PM): 5 cm above the medium segment of OIM.Data were collected from exploratory findings, as our group reported in a previous study :(1)NeuroDuring the examination, the patient was also asked to state the level of pain on a VAS scale of 0–10. The median pain intensity was calculated from the sum of all PN segments after exploration.(a)Treatment with neuromodulators: amitriptyline as first-line agent and duloxetine, gabapentin, or pregabalin as second-line agent for 2 months, then dose adjustments, associations, or switch to another neuromodulator;(b)Physical therapy , tissue mobilization, biofeedback, transcutaneous electrical nerve stimulation, or posterior tibial nerve stimulation;Vaginal administration of 5 mg diazepam every 48 h, and maintenance of the treatment until initiation of physical therapy;Trigger point injection (TPI) with 10 mL of 0.25% levo-bupivacaine, in case of improvement, for at least 3 months (30–50% pain relief). Repeated series of injections are considered when appropriate;® by Allergan Inc., Irvine, CA). Each 100-unit vial is diluted in 10 mL of preservative-free saline, and 1 to 2 mL are injected EMG guided in bilateral LAM and OIM. Repeat injections are considered if the first series present without significant side effects, and if no sooner than 12 weeks;Levo-bupivacaine injection followed by 100 international units of onabotulinum toxin A (BTXA) , consisting of:(c)Protocol 2 for the treatment of visceral pain (nociceptive) with minor or major opioids combined with blockade of the inferior or superior hypogastric plexus (IHP or SHP);(d)Protocol 3 for patients with neuromodulators and neuropathic pain with peripheral nerve blocks.(e)® by Boston Scientific, Marlborough, MA) by means of a transsacral fluoroscopy-guided approach, entering the bilateral posterior S3 foramina, until a positive sensory (< 0.5 V) and motor stimulation (> 0.8 V) is attained, aided with a lateral X-ray to avoid entering the pelvic viscera. At this point, a PRF lesion is performed  and then the tip of the cannula is slightly introduced towards the anterior surface of the sacrum. Finally, contrast dye is used to identify the spreading around the anterior surface, avoiding vessel and viscera images. Subsequently, the blockade (Betamethasone 12 mg and L-Bupivacaine 0.25% 10 cc) is administered, distributed through the two cannulas.Protocol 4: Pulsed radiofrequency (PRF) of S3 with IHP block for the treatment of neuropathic and nociceptive pain in the same way. The technique consists of using a 10 cm radiofrequency cannula with 10 mm active tip  and the median VAS pain intensity was 7.8/10 . The most common symptoms were abdominal pain, located in the hypogastrium and/or iliac fossae. Pain during sexual intercourse was reported by 65.2% of patients, proctalgia by 52.1%, and urologic pain by 36.9%. A total of 73.9% of patients had associated comorbidities: 4.3% painful bladder syndrome, 6.5% migraine, 15.2% fibromyalgia, and 17.4% irritable bowel syndrome. Twenty-six out of 46 patients who did not respond to conventional therapy were examined in the chronic pelvic pain unit to obtain a complete map of the location of the pain. The results were as follows:The overall sensory deficit at S2–S4 was 17 out of 26 endometriosis patients. A total of 23 patients from the entire cohort had a pudendal nerve motor deficit, and 18 of 26 patients presented a positive cotton swab test at the vestibule. Exploration of the third segment of the pudendal nerve revealed pain in 22 patients, and 3 out of 26 patients had pain localized in the dorsal clitoris nerve. Of the 26 patients, 25, 24, and 18 presented pain localized to the LAM, OIM, and PM, respectively. There were 18 patients with pain in all pelvic muscles  and only one patient was without muscle pain. Clinical and exploratory findings are shown in After history and examination of the unresponsive patients with endometriosis, findings only compatible with nociceptive pain were identified in 26% of patients . Only 2% had neuropathic pain, and 62% had mixed symptoms (nociceptive and neuropathic). The treatment administered to non-responding patients was according to type of pain. Results are shown in Five out of 6 patients responded to botulinum toxin, obtaining a median pain symptoms relief of 40%  and median follow-up was 3.5 months . Seven of the 33 patients with nociceptive and neuropathic pain were treated with IHP block associated with PRF of S3. The median pain relief obtained was 50%  and median follow-up was 3.8 months . The use of neuromodulators including tricyclic antidepressants (TCAs) provided a benefit of 43% (12 responders out of 28) and 50% (11 out of 22), respectively.Conventional treatment for pain management in women with endometriosis can be summarized in three options: analgesics, which include non-steroidal analgesics (NSAIDs), hormonal agents, and surgical treatment. Treatment decisions are individualized and tailored to pain characteristics , reproductive desires, age, medication side effects or contraindications, final results of surgery, and cost of treatment).Apparently, good results in relieving endometriosis-related pain should be expected with conventional treatments. For example, success in pain reduction should be achieved through the administration of progestogens ,15,16,17Unfortunately, 25–33% of patients who undergo hormonal treatments do not achieve pain relief ,20,21,22If we delve deeper into the pathophysiology of CPP in endometriosis, we find a complex field that justifies the lack of response to different treatment options. The pathophysiology of CPP in endometriosis is an evolutive process initiated by an inflammatory response in the peritoneal fluid, which facilitates growth of endometrial-like tissue and generates a process of neuro-angiogenesis in endometriotic lesions. A direct activation of sensory nerve endings results in neurogenic inflammation, which leads to stimulation and activation of peripheral nerve endings, causing peripheral sensitization followed by central sensitization. In addition, a sensitization of multiple organ afferents can induce cross-organ sensitization.Other pain-related syndromes associated with peripheral and central sensitization, such as irritable bowel syndrome, painful bladder syndrome, fibromyalgia, and migraine, coexist in patients with endometriosis ,29,30,31Most medications used for non-responder endometriosis patients are not a US FDA-approved indication, although most of the evidence supports the safety and efficacy of those treatments in women with pelvic pain syndromes. Our results have revealed partial improvements in 70% of non-responder patients with any of the aforementioned therapies.In the face of such a bleak outlook, the medical management of endometriosis-related CPP should be integrated into an interdisciplinary approach. Before starting treatment in patients unresponsive to conventional therapy, all women should undergo a thorough examination, being classified as:For CPP unresponsive to targeted therapy, neuromodulators are widely accepted in the field of pain medicine, since, in this case, altered central pain processing adopts a significant role. Most of our patients (88%) were treated with neuromodulators, with a response rate of 43%. The TCAs are often considered the first-line treatment for centralized pain conditions and the treatment of neuropathic pain. There are no studies in which the use of amitriptyline has been researched in endometriosis. However, at least one multicenter, placebo-controlled trial has studied this compound in patients with female interstitial cystitis/painful bladder, reporting a moderate to marked improvement (55%) at 12 weeks of treatment, in the absence of significant side effects . In our After examination of the unresponsive patients, we identified that 85% and 12% of them complained of pain at the pudendal canal entrance and in the DCN, respectively. For women with significant pain symptoms, neuromodulators can be combined with peripheral nerve blocks (PNBs) and/or muscle relaxants. A PNB intervention that leads to a successful pain reduction supports the diagnosis of the disease, which happened in two-thirds of our patients. In order to offer long-term relief, PRF at PN or S3 should be recommended.Once neuromodulators have been used, it is important to emphasize that the patient should continue to explore nonpharmacologic treatments that improve her symptoms whilst she is progressing through the subsequent lines of therapies. Tramadol should be used cautiously when selective serotonin uptake inhibitors and TCAs are taken concurrently. Long-term opioid therapy in CPP is not recommended, since it has potential side effects, it is highly addictive, and has no proven benefit ,38,39,40Visceral pain reflects afferent input traveling with autonomic nerves, i.e., with sympathetic or parasympathetic nerves. The pelvic area is innervated by a mixture of sympathetic, parasympathetic, and somatic networks. Sympathetic innervation emerges from T12 to L2 spinal cord segments, carried through the SHP that contains afferent pain fibers from the endometrium and other pelvic organs. Parasympathetic innervation travels through the sacral roots that meet the preganglionic fibers descending from the SHP and join the hypogastric nerves that converge into the IHP. In addition, somatic efferent and afferent innervation to the endometrium comes from the S2–S4 spinal cord.More than half our patients were treated for visceral pain through the combination of minor opioids and/or sympathetic nerve blocks, which led to an overall response rate of 54%. Recent literature supports that SHP blockade can be an effective procedure for pain control and improvement of quality of life during refractory endometriosis . More reIn addition to these publications, there are some studies regarding the efficacy of IHP blockade as a new target to relieve pain from the lower pelvic organs and genitalia . SchultzIn our study, we observed similar results with SHP and IHP blocks (71% response) in comparison to previously published studies. In this regard, we have found a window of opportunity for patients unresponsive to conventional therapy with simultaneous visceral and neuropathic pain. For these patients, we used IHP blockade plus PRF of S3, because the access route is the same and because it decreases the pain rate by up to half over a period of approximately 4 months. Future research should assess the efficacy of this route.Prolonged muscle contraction, spasm, and inappropriately high muscle tone are hypothesized to diminish blood supply and increase oxygen demand of the pelvic floor muscles. Ischemic muscle may secrete pain-producing substances, which further sensitize muscle nociceptors, alter receptor field properties, and convert wide-band mechanoreceptors into nociceptors.Data supporting pelvic floor physiotherapy in CPP is limited. There are some studies on myofascial pelvic pain syndrome, painful bladder syndrome, and coccygodynia with improvement observed in patients ,52,53,54Several studies have reported that patients with pelvic floor myofascial pain might benefit from vaginal administration of 5 mg diazepam, while others see little or no benefit ,57,58,59TPI is the procedure to treat focal, hypersensitive nodules within muscles that are markedly painful and may contribute to the development of central pain amplification. TPIs have revealed efficacy in a variety of neuromuscular pain syndromes and elevator ani pain ,62,63,64However, BTXA in the pelvic floor is not a US FDA approved indication, but evidence supports the fact that it may reduce both general and myofascial pelvic pain and may be helpful for some women with CPP-related endometriosis ,68,69,70Most patients tolerate injections in the office setting. Side effects of BTXA during the first 5 days may include flu-like symptoms, constipation, urinary retention or incontinence, and fecal incontinence . All of Ninety-six percent of patients with endometriosis who did not respond to conventional therapy had myofascial pelvic pain syndrome. The vast majority of them received a combined therapy for pelvic pain . Vaginal diazepam, TPI, or BTXA may facilitate physical therapy if the focal area of pain is small. Sixty percent of non-responder patients could benefit from the combined therapy. In addition, while TPI or BTXA presented a response rate in 70%–80% of patients, the use of BTXA can provide up to 40% symptom relief over a period of 3.5 months. Additional prospective studies are needed to confirm this finding.Therefore, future research should be directed at improving early diagnosis and promoting any effective treatment for endometriosis. The delays in the diagnosis lead to the development of complex pain mechanisms and the lack of response to the treatment. Although an early search for effective treatments could prevent central pain sensitization, a multidisciplinary and multimodal approach focusing on patient history and examination is necessary.In conclusion, all of the procedures reported above caused partial and transitory benefit to these patients, but they showed a clear benefit to quality of life in women with no response to conventional therapy. First-line treatment would comprise the administration of neuromodulators and, in case of a low response, a switch to or combination with another agent. Combined therapies have shown efficacy in the treatment of myofascial pain syndrome. Finally, there is the possibility of prolonging the pain-free period with botulinum toxin administration or IHP blocks associated with S3 RFP.