Transcranial direct current stimulation (tDCS) is used for various chronic pain conditions, but experience with tDCS for acute postoperative pain is limited. This study investigated the effect of tDCS vs. sham stimulation on postoperative morphine consumption and pain intensity after thoracotomy.This is a single-center, prospective, randomized, double-blind, sham-controlled trial in lung cancer patients undergoing thoracotomy under general anesthesia. All patients received patient-controlled (PCA) intravenous morphine and intercostal nerve blocks at the end of surgery. The intervention group  received anodal tDCS over the left primary motor cortex (C3-Fp2) for 20 min at 1.2 mA, on five consecutive days; the control group (n = 31) received sham stimulation. Morphine consumption, number of analgesia demands, and pain intensity at rest, with movement and with cough were recorded at the following intervals: immediately before (T1), immediately after intervention (T2), then every hour for 4 h (Т3–Т6), then every 6 h (Т7–Т31) for 5 days. We recorded outcomes on postoperative days 1 and 5 and conducted a phone interview inquiring about chronic pain 1 year later (NCT03005548).A total of 62 patients enrolled, but tDCS was prematurely stopped in six patients. Fifty-five patients  had three or more tDCS applications and were included in the analysis. Cumulative morphine dose in the first 120 h after surgery was significantly lower in the tDCS [77.00 (54.00–123.00) mg] compared to sham group . On postoperative day 5, maximum visual analog scale (VAS) pain score with cough was significantly lower in the tDCS group , and pain interference with cough was 80% lower . One year after surgery, there was no significant difference between groups with regard to chronic pain and analgesic use.In lung cancer patients undergoing thoracotomy, three to five tDCS sessions significantly reduced cumulative postoperative morphine use, maximum VAS pain scores with cough, and pain interference with cough on postoperative day 5, but there was no obvious long-term benefit from tDCS. Thoracotomy is a painful incision that involves multiple muscle layers, rib resection and pain is exacerbated by ongoing continuous movement due to breathing . In addiThoracic epidural analgesia is considered as gold standard for pain after thoracotomy, whereas systemic analgesia is used in patients not eligible for epidural analgesia . BecauseTranscranial direct current stimulation (tDCS) is a noninvasive cortical stimulation technique with neuromodulatory effects, altering cortical excitability through subthreshold modulation of neuronal resting membrane potentials by constant weak electrical current .The proposed mechanism of pain alleviation by tDCS is based on modulation of cortical excitability in locations that can be considered as entry points for the wider areas of neuronal networks, the so-called “pain matrix” . HoweverPublished data suggest that tDCS, when used as part of multimodal postoperative analgesia can result in reduced postoperative opioid use and reduced pain in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) , total kAdvantages of tDCS use for postoperative analgesia include simplicity of use, patient comfort, absence of a magnetic field, and low cost, and therefore tDCS is a promising option as non-pharmacological addition to a multimodal postoperative analgesia regimen . FurtherThe primary objective of this single-center, prospective, randomized, double-blind clinical trial is to evaluate the effect of anodal tDCS combined with patient-controlled analgesia (PCA) morphine, on intravenous (IV) morphine consumption for analgesia after thoracotomy. The intervention group received treatment with anodal tDCS, whereas the control group received sham stimulation. We hypothesized that tDCS will result in reduced postoperative morphine use (primary outcome) and lower postoperative pain intensity at rest, with movement and with cough (secondary outcome) in patients receiving IV morphine PCA for analgesia after thoracotomy.https://clinicaltrias.gov (registration number NCT03005548). All eligible patients received detailed information about the study protocol and goals and gave written consent before enrolling in the study.This prospective, randomized, double-blinded sham/controlled study was carried out in the Department of Cardiothoracic Surgery and the Department of Anesthesia and Intensive Care at the Military Medical Academy in Belgrade (Serbia) in the period from June 15, 2016 to March 27, 2018. The study was approved by the Institution Ethics Committee and was registered in Clinical Trials: Inclusion criteria were patient willingness to participate, ability to understand the protocol and provide written informed consent, age 18–80, scheduled thoracotomy for confirmed primary malignant lung disease, and planned tracheal extubation in the operating room immediately after surgery. Exclusion criteria were pregnancy, treatment for neurological or psychiatric diseases, any chronic pain condition, history of alcohol or drug abuse, chemotherapy, history of previous thoracic or cardiac surgery, allergy to medications used in the study, presence of pacemaker, automatic implantable cardioverter/defibrillator or any other implanted device in the head, spinal cord, or peripheral nerves, and confirmed brain lesion, including tumor or metastasis . The floPatients in both groups received intraoperative IV morphine followed by postoperative IV morphine PCA  using the CADDLegacy PCA Pump . Patients assigned to the active treatment group , received tDCS , whereas patients assigned to the sham control group  received sham tDCS stimulations over the left primary motor cortex for 5 days.Sample size calculation was conducted using the freely available from the University of Dusseldorf, Germany, G*Power statistical program v. 3.1.9.2  and was Participating patients were instructed to continue the study for 5 days. Criteria for early discontinuation of the study included the absence of any pain, patient request (for any reason), adverse analgesic medication or tDCS effects and any complications requiring prolonged postoperative intubation, mechanical ventilation, or additional surgical interventions.In order to preserve blinding, only one independent physician (TVI) was in charge of the randomization procedure and adjusted tDCS in either anodal or placebo mode but had no contact with the patient and was not involved in any stage of collecting or processing data. All other investigators were blinded to group assignment. The tDCS stimulation session was performed by an investigator who had no knowledge of other aspects of patient data. After the first tDCS session, all patients were asked if they thought they were receiving active or sham stimulation. Analysis of their response did not show any significant findings, therefore we concluded that the blinding procedure was probably successful.Group allocation was masked as group 1 or 2 for statistical analysis. Group allocation to the active tDCS (intervention) group or the sham (control) group was revealed after final data analysis.A computer-generated permuted block randomization method (1:1) was used to allocate patients to the active or sham tDCS groups based on order of inclusion in the study, in order to ensure concealment.2; charge density 0.127 mAh/cm2) per session. In sham stimulations, current was applied over the same electrode montage for 60 s with a ramp time of 10 s and then gradually turned off at the start of the 20-min period. At the end of the period, the current was ramped up slowly and then turned off more quickly (tDCS was transmitted through two circular Ag/AgCl electrodes (1 cm radius) with conductive gel fixed by the neoprene head cap and was delivered by a battery-driven, wireless Starstim tDCS neurostimulator . The anode was placed over the left primary motor cortex, Brodmann area 4 , and the return electrode was placed over the contralateral supraorbital region (Fp2). The anodal tDCS group received stimulation for 20 min at 1.2 mA (current density 0.38 mA/cm quickly .−1) and propofol (5 µg ml−1), while cis-atracurium (0.2 mg kg−1) was given for muscle relaxation. After induction, placement of double lumen endotracheal tube and confirmation of appropriate tube position with bronchoscopy, anesthesia was maintained with TCI of remifentanil (1–5 ng ml−1) and propofol (5 µg ml−1), while cis-atracurium (0.03 mg kg−1) was given as needed to maintain neuromuscular blockade. Entropy levels  were maintained in the 40–60 range throughout the procedure and FiO2 was set at 80% in order to keep SaO2 > 92%.Patients were screened for possible inclusion in the study the day before surgery. Then, an investigator approached each eligible patient and provided information about the study, perioperative course, the expected level of acute postoperative pain, and incidence of chronic pain after thoracotomy. After signing a written consent, patients were instructed on the use of the visual analog (VAS) for assessment of pain and on the use of the PCA pump and received additional information about the tDCS procedure. In addition, on the morning of surgery patients were once again checked to ensure that they understand the pain assessment score and had their VAS for anxiety and depression assessed. After arrival in the operating room, standard monitoring was placed, IV access was obtained, and midazolam 2 mg was given as premedication. General anesthesia was induced using target-controlled infusion (TCI) of remifentanil  . After tPostoperatively, as soon as VAS at rest was below 30 mm, tDCS was started and each patient was switched to morphine IV-PCA  with a dedicated PCA pump . For patient convenience PCA morphine bolus was increased from 1 to 2 mg based on the individual increased number of attempted requests recorded with pump. Patients received IV morphine PCA for 5 days, but PCA was continued beyond postoperative day 5 if needed, but could also be discontinued earlier if no longer needed or at patient request. At the ward, all patients were monitored by pulse oximetry. If analgesia was inadequate (VAS score in rest ≥30 mm), the IV line was checked, additional morphine 1–2 mg was given as bolus, and analgesia was supplemented with IV diclofenac 75 mg twice a day and a single 1000 mg dose of IV paracetamol. After discontinuation of the IV PCA, patients received IV paracetamol 1000 mg every 6 h. After hospital discharge, patients received a prescription for oral nonsteroidal analgesics or paracetamol but not for any opioids. For the purposes of this study, data were collected during the first five postoperative days.The primary outcome of this study was the amount of morphine used for analgesia after thoracotomy in a group of patients receiving tDCS in comparison with the amount of morphine used for analgesia in patients receiving sham stimulation for up to 5 days.Secondary outcomes were pain scores measured using VAS (from 0 no pain to 100 mm the worst possible pain) at rest, during movement, and during cough in patients receiving tDCS and IV morphine PCA, compared to patients receiving sham stimulation and IV morphine PCA.After surgery, the first tDCS session was applied when the VAS pain score at rest fell below 30 mm. Morphine consumption, the number of analgesia demands, and pain intensity at rest, with movement and with cough were recorded at predetermined time intervals as follows: immediately before the intervention (T1), immediately after the intervention (T2), then regularly every 1 h for 4 h (Т3–Т6), and then every 6 h (Т7–Т31) for 5 days Figure 2A researcher blinded to group assignments evaluated all patients in the morning on postoperative day 1 and postoperative day 5 using the patient-related outcomes (PRO) survey . The PROBaseline anxiety level was assessed with VAS for anxiety , whereasManagement of the chest tube was at the discretion of the surgeon. Based on the publication by During hospitalization, after discontinuation of the intervention we recorded opioid analgesia requests besides regular paracetamol therapy and the amount of morphine used. If patients agreed to be contacted, a phone interview was conducted 1 year after surgery. The interview contained questions about presence of chronic pain after surgery; if pain was present, additional questions included time when pain appeared, medications used for pain treatment, and the influence of pain on daily activity. Because of concern about possible adverse effects of tDCS, we prepared a structured questionnaire in accordance with questionnaire surveys for tDCS adverse effects , and admIn total, 55 patients who received three or more tDCS stimulation sessions were included in data analysis Figure 1nd tDCS, after the 3rd tDCS, after the 4th tDCS, and after the 5th tDCS session. Morphine dose was calculated as cumulative dose before every preceding stimulation, i.e., the dose of morphine between two consecutive stimulations, including the period 24 h after the last tDCS stimulation. VAS pain scores were recorded in three different conditions: at rest, with movement, and with cough at regular time intervals between consecutive tDCS sessions. The highest VAS score among these measurements for the individual patient served as representative for that time frame. Then, we calculated and presented a median (IQR) of maximum VAS pain scores of all patients in the group for a particular time frame. The same principle was applied separately for pain in different conditions.The period between two consecutive stimulations was used as a time frame for data analysis, starting with the time frame between the first and the second session, the second and the third, and so on, and therefore there were five time frames: time after the first session, after the 2Overall 62 patients enrolled in the study. One patient was excluded because he required emergency re-operation. tDCS was prematurely stopped in six patients due to surgical complications (n = 2), absence of pain (n = 2), or per patient request without a specific reason (n = 2). Patients were included in the analysis only if they received three or more tDCS applications, and data were analyzed “per protocol”  in the tDCS group , and the difference was statistically significant Figure 3On postoperative day 5, maximum VAS pain score with cough was lower by 34.83% in the tDCS group [29.00 (20.00–39.00)] vs. sham stimulation [44.50 (30.00–61.75)], p = 0.018; this difference was confirmed by PROs, where interference of pain with cough was 80.00% lower  B. Also,We did not record any complications from tDCS, except for “itching” and “tingling” in the control group. Postoperative complications included respiratory complications, arrhythmias, surgical complications, and infections but there was no significant difference between groups (p = 0.522).There was no significant difference between groups regarding anxiety, mood, and presence of depression Table 4.From the time tDCs was discontinued until discharge, the number of patients treated with opioids was not significantly different between groups: 4 (14.8%) patients in tDCS group and 7 (25%) in sham group (p = 0.544). Additionally, there was no significant difference in the amount of morphine used in tDCS vs. sham group patients (20.00 (4.25–54.50) mg vs. 8.00 (3.00–30.90) mg, (p = 0.788). The number of patients treated with nonsteroidal anti-inflammatory drugs was 6 (22.2%) in tDCS group vs. 3 (10.7%) in sham group (p = 0.295).No patient contacted us after discharge due to pain problems. The phone interview conducted 1 year after surgery revealed that 9 of 21 (43%) patients in the tDCS group and 11 of 22 (50%) patients in the sham group had chronic pain (p = 0.87). Timing of chronic pain appearance was not significantly different between groups (p = 0.409): pain was persistent from the discharge in 4 (14.8%) tDCS patients and in 6 (27.3%) sham patients. Pharmacologic chronic pain treatment was needed by 6 (28.6%) patients in tDCS group vs. 8 (36.4%) patients in the sham group (p = 0.444), but only one patient in the tDCS group required opioid therapy. Pain influence on daily activities 1 year after surgery was reported by two patients in the sham group (p = 0.299).Our results suggest that three to five anodal tDCS sessions on consecutive post-operative days over the left primary motor cortex (Brodmann areas 4) as an adjunct to IV morphine PCA significantly reduce cumulative morphine use, pain with cough and interference of pain on cough in patients with acute pain after thoracotomy.The use of opioid consumption given by IV PCA as the primary outcome in our study is based on the principle that all patients should have access to good quality postoperative analgesia. Several published studies  have useThe variable opioid-sparing effect in different tDCS studies can be explained by high heterogeneity of study protocols (twice daily vs. once daily), use of different cortical targets , different non-opioid analgesics, including metamizole, paracetamol or ketorolac, different types of surgical procedures, and localization in the human body. Some studies used a combination of spinally delivered local anesthetic and opioid for intraoperative analgesia and postoperative systematic opioid , while oIn our study we tried to overcome some of these issues by excluding patients with chronic pain and preoperative opioid use. In an attempt to use fewer medications, propofol, and remifentanil were used for anesthesia, combined with a single intercostal block and a single dose of paracetamol intraoperatively, followed by postoperative analgesia using morphine IV-PCA. During the intraoperative period there was no difference in the amount of remifentanil infused for intraoperative analgesia and in the amount of morphine used to provide analgesia at rest (VAS < 30 mm), before the first intervention session in the immediate postoperative period. In the postoperative period, paracetamol was given only when a patient requested additional analgesia, and none of the patients requested it. However, despite well-defined exclusion criteria, our patients were still using different medications for treatment of chronic comorbidities.Propofol was chosen as primary anesthetic because data suggest it confers neuroprotective effect against intercostal nerve injury after thoracotomy  and may Cumulative opioid use in our study showed divergent trajectories between the two groups, with the divergence getting wider after the second tDCS session, a finding similar to the results reported by While the Ribeiro et al. study only included female patients, our study included both men and women. When analyzing data in male patients only and in female patients only, we did not find any significant difference between tDCS vs. sham groups with regard to cumulative morphine use and maximum pain scores. However, when comparing male vs. female patients, data analysis showed significantly higher cumulative morphine use in male patients at all time points in the postoperative period. Published studies have not shown sex to be a consistent predictor of analgesic efficacy of morphine: some studies found reduced morphine efficacy  or increIn our study, VAS pain scores at rest, with movement and with cough were not different between the two groups, but cumulative opioid use was significantly lower in the tDCS group. This finding is in agreement with the findings reported by Our decision to include in data analysis only patients who had three or more tDCS sessions was based on the concept of cumulative tDCS effect. Driven by the positive benefits of repeated rTMS sessions for the treatment of depression, many trials have applied the same concept using tDCS. Clinical trials have applied repeated tDCS sessions with the assumption that repeated stimulation will result in cumulative and sustained changes in cerebral function . Recent We believe that the 34.83% reduction of maximum VAS pain during cough observed after the fifth tDCS session is clinically significant, based on mean value which stratifies tDCS group patients with mild pain compared to moderate pain in sham group .Some published studies have not shown a benefit from tDCS with regard to pain scores . The besPostoperative pain is complex and not a single entity. Use of tDCS in patients with chronic pain state  can result in mood improvement , whereasIn our study, tDCS showed short-term benefit as evidenced by significant reduction of morphine use. However, patient follow-up during hospital stay and the follow-up phone interview 1 year later did not show a difference between groups with regard to analgesic medication use and incidence of chronic pain, which were not the primary aims of the study. This short-term beneficial effect of tDCS could still be clinically relevant as part of multimodal post-thoracotomy pain treatment in cases where regional techniques have failed or are contraindicated. Because the severity of acute post-thoracotomy pain has been associated with chronic pain after surgery , differeStrengths of our study include the use of a nonpharmacological and safe technique as part of multimodal analgesia regimen for a very painful surgery (thoracotomy), prospective study design, small but adequate sample size, sound blinding and randomization procedures, and a clinically meaningful primary outcome. The finding of reduced “worst possible pain” during cough is clinically important for patients in the postoperative period and is especially useful after video assisted thoracoscopic surgery (VATS) and in cases where epidural analgesia is contraindicated.Limitations of our study include the small  number of patients, and the absence of preoperative qualitative sensory testing which could provide additional insight into the character of patient distress. The fifth intervention session was performed in 11 patients in the tDCS group and 16 patients in the sham group, therefore we calculated Cohen’s criteria of d 0.42, which shows that sample size has low impact on results.Although previous publications have used two tDCS sessions per day , we chosThe short-term (5 days) follow-up period is a significant limitation of this study, but was based on average hospital stay after thoracotomy in our Institution. This was a “proof of concept” study, as there are no published data about the effects of tDCS as part of multimodal management of acute post-thoracotomy pain. However, after patients leave the hospital, our experience showed that it is difficult to achieve high patient response rates to phone interviews and patients are generally not willing to participate in repeated follow-up audits. Therefore, in order to respect the wishes of our patients to only be contacted once after surgery, we determined that a 1-year follow-up period was the most suitable.Recently, tDCS has been increasingly studied as an effective pain treatment technique . This tyNonpharmacological techniques can be viewed as measures aiming to reduce postoperative opioid use. Resources among hospitals vary widely and not all analgesia modalities are available in every hospital; therefore, exploration of the appropriate use of certain analgesic techniques can widen the panel of analgesia techniques available and result in improved hospital analgesic protocols. We suggest that future studies could define proper timing for a preoperative tDCS session because there are data suggesting that preoperative tDCS can also be beneficial .In conclusion, our study suggests that postoperative daily tDCS confers significant benefits with regard to postoperative analgesia after thoracotomy, and this benefit is probably applicable not only for open thoracic surgery, but also for postoperative pain management after VATS, when planned thoracoscopic procedures require conversion to open surgery and after emergency thoracotomy. Because the conclusion about lack of long-term tDCS efficacy on pain in our study is based only on one telephone survey conducted 1 year after surgery, we suggest that future studies could better explore possible tDCS effects on chronic postoperative pain presence by also collecting data about pain 3 and 6 months after surgery.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by the Institution Ethics Committee of Military Medical Academy. The patients/participants provided their written informed consent to participate in this study.DS initiated study design, collected data, interpreted data, did literature search, and wrote the manuscript. KM collected data, interpreted data, and wrote the manuscript. NR performed statistical data analysis, did literature search, and collected data. VC did literature search, collected data, and performed the surgery. NM did literature search, collected data, and performed the surgery. VN did literature search, collected data, and performed the anesthesia. SZ did literature search, collected data, and performed the anesthesia. MK interpreted data, did literature search, and revised the manuscript. TI initiated study design, interpreted data, and revised the manuscript. All authors read and approved the final manuscript.This work was supported by a grant from the Ministry of Defense of the Republic of Serbia (Project MFVMA/05/19-21) for TVI.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.


Significantly reduced analgesic usage was reported in 28/30 patients. Two grade I complications were reported according to the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) classification system. According to the results of the present study, solely performed computed tomography-guided radiofrequency neurolysis of splanchnic nerves can be considered a safe and efficacious single-session technique for pain palliation in patients with pancreatic ductal adenocarcinoma suffering from abdominal pain refractory to conservative medication. Although effective in pain reduction the technique seems to have no effect upon survival improvement.The aim of this paper is to prospectively evaluate the efficacy and safety of percutaneous computed tomography (CT)-guided radiofrequency (RF) neurolysis of splanchnic nerves as a single treatment for pain reduction in patients with pancreatic cancer. Patients with pancreatic ductal adenocarcinoma suffering from abdominal pain refractory to conservative medication who underwent CT-guided neurolysis of splanchnic nerves by means of continuous radiofrequency were prospectively evaluated for pain and analgesics reduction as well as for survival. In all patients, percutaneous neurolysis was performed with a bilateral retrocrural paravertebral approach at T12 level using a 20 Gauge RF blunt curved cannula with a 1cm active tip electrode. Self-reported pain scores were assessed before and at the last follow-up using a pain inventory with numeric visual scale (NVS) units. The mean patient age was 65.4 ± 10.8 years . The mean pain score prior to RF neurolysis of splanchnic nerves was 9.0 NVS units; this score was reduced to 2.9, 3.1, 3.6, 3.8, and 3.9 NVS units at 1 week, 1, 3, 6, and 12 months respectively ( Patients with pancreatic ductal adenocarcinoma will complain of abdominal pain at some stage during the disease’s course; abdominal pain in these patients is multifactorial and its pathophysiology includes either a mixture of neuropathic, visceral, and somatic mechanisms or can be due to side effects of medication and other treatments . This paTherapeutic armamentarium for abdominal pain in patients with pancreatic ductal adenocarcinoma includes pancreatic enzyme replacement therapy, chemotherapy, and analgesic therapy, according to the “WHO analgesic ladder” and neurolytic techniques ,4. NeuroThe purpose of this study is to evaluate the efficacy and safety of percutaneous computed tomography (CT)-guided neurolysis using continuous radiofrequency as a single-session palliative technique solely performed in patients with pancreatic ductal adenocarcinoma with abdominal pain refractory to standard treatments proposed in the WHO three-step analgesic ladder.The present study is a prospective observational study evaluating patients with pancreatic ductal adenocarcinoma suffering from abdominal pain refractory to conservative medication treated by CT-guided neurolysis of splanchnic nerves by means of continuous radiofrequency. The primary objective was pain reduction at the end of the follow-up period. Secondary objectives included reduction of analgesics uptake and overall survival evaluation. Inclusion criteria included patients ≥18 years old with pancreatic cancer, coagulation parameters within normal limits, and a life expectancy of >3 months. Exclusion criteria included non-compliance of patients, uncontrollable international normalized ratio (INR), systematic or local infection, expected survival less than 3 months, an Eastern Cooperative Oncology Group (ECOG) score less than 3, and presence of a medical or psychiatric illness that would preclude informed consent or follow-up. Each patient underwent laboratory coagulation tests at least 24 h prior to the percutaneous neurolysis session. The patients were fully informed about the procedure, the possible complications, and the medical alternatives available; informed written consent for both the technique and the study was obtained in all cases. Patient characteristics, radiofrequency technique, efficacy, and complications were evaluated.Radiofrequency neurolysis of splanchnic nerves was always performed in an inpatient setting. Computed tomography guidance with sequential scanning  was used for planning, targeting, and intra-procedural modification during the session. A combination of local anesthesia with lidocaine hydrochloride 2% and intra-venous analgesia with paracetamol was used to treat intra-procedural pain [Computed tomography assessed potential immediate complications during and at the end of the neurolysis session. The patients remained in the hospital overnight and were then discharged. We evaluated technical success, treatment response , and complication rates. Technical success was defined as successful radiofrequency electrode placement at the level of interest on both sides. Clinical success was defined as pain reduction (>4 pain score units) as recorded in the numeric visual scale (NVS) pain scores. The definition of complications was assigned according to the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) classification system .p < 0.05 and analyses were conducted using SPSS statistical software .Quantitative variables were expressed as mean values (SD), while qualitative variables were expressed as absolute and relative frequencies. Repeated measurements analysis of variance (ANOVA) was adopted to evaluate the changes observed in pain levels over the follow-up period. Bonferroni correction was used in order to control for type I error. To longitudinally assess changes in pain, mixed linear regression models were fit that account for multiple measurements per individual obtained at different time points. All analyses were conducted using a random coefficient model with the intercept being random and a covariance structure of variance components. Gender and age along with their interaction with time were also tested in the models. All reported p values are two-tailed. Statistical significance was set at The sample consisted of 30 participants with a mean age of 65.4 years (SD = 10.8 years) and a median age of 67 years . Most ofp < 0.001). The changes between the following consecutive measurements were not significant (p > 0.05). Overall mean change from prior measurement to 12 months was significant and equal to −5.8 (SD = 2.8) (p < 0.001). Pain was significantly diminished throughout the follow-up period . Furthermore, it was found that pain decreased significantly from prior to the first week measurement  and then it remained at a similar level until 12 months after  (The pain measurements are presented in = 0.127) .p = 0.479), indicating a similar pain decrease in both genders. Similarly, the interaction of time with age was not significant (p = 0.098), indicating a similar pain decrease in both age groups. Pain level decreased in all subgroups. Significantly reduced analgesic usage was reported in 28/30 patients.Participants’ pain measurements descriptive statistics are presented in Two cases of pneumothorax requiring nothing but observation and not prolonging the programmed hospitalization (Grade I) were reported according to the CIRSE classification system.As far as follow-up is concerned, all patients were evaluated for pain reduction at 3 months post neurolysis while 13 and 19 patients had died due to disease progression at 6 and 12 months follow-up, respectively.The present study adds to the growing number of case series showing that percutaneous neurolysis of splanchnic nerves is an efficacious and safe technique for pain reduction in symptomatic patients with pancreatic ductal adenocarcinoma who complain of abdominal pain refractory to analgesics and other medications ,14,15,16A retrospective propensity score matching analysis by Oh et al. reported that celiac plexus neurolysis, although efficient for pain reduction, did not affect survival for patients with unresectable pancreatic cancer . SimilarComplications of celiac plexus neurolysis include among others hypotension, diarrhea, and neurological injury ,18,19. NDirect percutaneous ablation of pancreatic carcinoma under imaging guidance has been shown to result apart from local tumor control to pain reduction and quality of life; up until now, there are no reports published concerning the comparison of tumor ablation versus neurolysis aiming for pain palliation ,22.Limitations of the present study include the small number of participants; the lack of comparison to a group of patients undergoing alternative  approaches for pain reduction.In conclusion, according to the results of the present study, computed tomography-guided radiofrequency neurolysis of splanchnic nerves solely performed can be considered a safe and efficacious single-session technique for pain palliation in patients with pancreatic ductal adenocarcinoma suffering from abdominal pain refractory to conservative medication. Although effective in pain reduction the technique seems to have no effect upon survival improvement.


Chronic pain has been associated with alterations in brain structure and function that appear dependent on pain phenotype. Functional connectivity (FC) data on chronic back pain (CBP) is limited and based on heterogeneous pain populations. We hypothesize that failed back surgery syndrome (FBSS) patients being considered for spinal cord stimulation (SCS) therapy have altered resting state (RS) FC cross-network patterns that 1) specifically involve emotion and reward/aversion functions and 2) are related to pain scores.RS functional MRI (fMRI) scans were obtained for 10 FBSS patients who are being considered for but who have not yet undergone implantation of a permanent SCS device and 12 healthy age-matched controls. Seven RS networks were analyzed including the striatum (STM). The Wilcoxon signed-rank test evaluated differences in cross-network FC strength (FCS). Differences in periaqueductal grey (PAG) FC were assessed with seed-based analysis.2 = 0.76, p<0.0022) between STMFCS index and pain scores. The PAG showed decreased FC with network elements and amygdala but increased FC with the sensorimotor cortex and cingulate gyrus.Cross-network FCS was decreased (p<0.05) between the STM and all other networks in these FBSS patients. There was a negative linear relationship (RFCS index may represent a more objective measure of chronic pain specific to FBSS which may help guide patient selection for SCS and subsequent management.Decreased FC between STM and other RS networks in FBSS has not been previously reported. This STM Increasing evidence suggests a critical role of central nervous system (CNS) plasticity in the development and maintenance of chronic low back pain (cLBP). Understanding altered neural networks implicated in the pathophysiology of cLBP, in turn can lead to development of new management strategies. Resting-state (RS) functional connectivity magnetic resonance imaging (fcMRI) is a powerful tool for elucidating the areas of the brain involved in cLBP perception and modulation,–3 as it The belief that brain activity associated with chronic pain is localized to a discrete neural substrate (“pain matrix”) is no longer justifiable. Instead,Since previous fcMRI studies have been based on heterogeneous populations of non-specific cLBP patients with different inciting pain events and unknown pain phenotypes (neuropathic vs. nociceptive or constant vs. intermittent pain), our second goal was also to study a more homogeneous group of cLBP patients with a common inciting event of previous back surgery. Moreover, we studied a specific subpopulation of these failed back surgery syndrome (FBBS) patients with refractory, constant, neuropathic cLBP. These patients are considered as clinically ‘end-stage” to the extent that they have extensively navigated through the healthcare system and have exhausted and failed all other treatment modalities to the point that they are being considered as potential candidates for spinal cord stimulation (SCS). Patients who are referred to our comprehensive multi-disciplinary chronic pain center undergo extensive evaluations and are provided with behavioral therapies and treatments prior to consideration for spinal cord stimulation. SCS is a safe, effective treatment that administers doses of electrical current to the spinal cord for the management of refractory chronic pain with over 30,000 patients receiving SCS for treatment of chronic pain each year. SCS can We hypothesize that these FBSS patients with end-stage constant, neuropathic cLBP that are being considered for SCS therapy have altered FC between different RSNs, specifically those involved in emotion and reward/aversion functions. We also hypothesize these changes in FC are related to pain levels. The group of patients studied here represents the most clinically homogeneous population of chronic pain patients ever studied with functional imaging.The Medical College of Wisconsin/Froedtert Hospital Institutional Review Board approved this study. Written informed consent was obtained for all participants of the study.Non-pregnant, English-speaking adult FBSS patients with constant, severe, neuropathic cLBP who passed a trial of SCS were included in the study. Patients who were non-English speaking, pregnant, or otherwise unable to undergo MRI due to safety reasons or claustrophobia were excluded from the study.Adult patients with a diagnosis of failed back surgery syndrome (FBSS) who had undergone a spinal cord stimulation (SCS) trial with positive effects  and therefore thought to be good candidates for long-term SCS were screened for our study. The patients who met the inclusion criteria and wished to participate in our study signed an informed consent and were asked to fill out a questionnaire prior to completing their imaging study where they were asked to rate their level of pain using the visual analog scale (VAS) from 0–10, where 0 meant no pain and 10 meant the worst pain imaginable.Anatomical and RS fcMRI scans were completed on all FBSS patients prior to their planned surgery for implantation of a permanent SCS system. Anatomical and RS fcMRI for healthy age-matched control subjects were obtained from the healthy control subject MRI data bank from a previous study.The imaging studies were acquired using a Discovery MR750 3T Signa GE scanner with a standard quadrature transmit receive head coil. During the resting state acquisitions, the study participants were asked to close their eyes and relax. Modest acquisition parameters were selected to enable comparison with previously acquired data, and to allow for the potential of protocol-matched imaging of these participants following the placement of SCS without RF irradiation of the implanted device (data not included in this study). Sagittal RS fcMRI datasets of the whole brain were obtained in 6 minutes with a single-shot gradient echo-planar imaging (EPI) pulse sequence. The fcMRI imaging parameters were: TE/TR/flip angle/slices: 25ms, 2s, 90° and 36. The slice thickness was 4mm. Matrix size is 64×64 with 24cm field of view. Anatomical reference used the High-resolution 3D-SPGR axial images which has 144 slices, slice thickness 1mm, and 256×256 resolution. The respiration and heart beat signals were recorded using a respiratory bellows and pulse oximeter for the data analysis in the RETROICOR nuisance regression as implemented in AFNI (3dRETROICOR), to reduce signal variance associated with physiologic noise., 18http://afni.nimh.nih.gov/afni/) and MATLAB (Mathworks). First, the first five volumes of the raw functional imaging data were removed for T1 equilibration. Second, corrected the time shift caused by the Interleaved slice acquisition-dependent using the AFNI command, to3d). The third, the AFNI command (3dDespike) were used to remove the Spikes in time series data. The fourth step is the motion correction. The fifth step is to remove the trend signal AFNI commands: 3dDetrend).The data processing were performed by the software of Analysis of Functional NeuroImages (AFNI)  and (http://afni.nimh.nih.gov/pub/dist/data/TT_csf+tlrc) and together with whole brain global mean signals were regressed out from the 116 regional average time series.The whole brain was segmented into 116 anatomical regions using the Atlas template Seven RSNs were analyzed: motor network (MTN), default mode network (DMN), salience network (SAN), striatum network (STM), temporal network (TEP), hippocampus network (HIP) and dorsal attention network (DAN). Detailed brain regions for each network are listed in The regional FCS was calculated by the Pearson correlation coefficient (CC) between the BOLD time series from two brain regions for each subject. The time series of each region were obtained by averaging the time series of all voxels within the region for each subject . Based oThe Wilcoxon-rank test was performed for each pair of FC between the CN and FBSS groups. The Bonferroni method (p<0.05) was applied to evaluate significance of the difference in FCS between CN and FBSS groups.The cross-network FCS between two network A and B were produced by the mean of all possible regional FCs between Ai and Bi. Ai and Bi are brain regions that belong to network A and network B, respectively.The non-parametric Wilcoxon signed-rank test was performed to test group differences of each cross-network FCS. Multiple comparison correction was performed using the Bonferroni method with p<0.05 to avoid false positives.STMFCS index is a network-based singular index of rsFC, obtained by averaging of all cross-network FCS between STM and the other six networks. The use of a network-based singular index of rsFC as a biomarker for evaluating the functional connectivity strength of a specific disease process has been proven reliable and has been validated in various brain disease processes in our previous studies. [The studies. , 28 The studies.  AdditionFCS idenx is related to pain in FBSS patients, we applied a linear regression model (STMFCSindex = β0 + β1 * PL + ε) between STMFCS index and pain scores for each subject. The PL is the Pain Level easement. The β0 is the intercept of the fitting curve. The β1 is the effect of the pain level. The ε denotes random errors. We defined the STMFCS index to have a significant linear relationship with PL if the model had p<0.05.To test if the STMEach subject’s PAG whole brain FC was obtained as follows: First, the PAG ROI were separately extracted with the MNI coordinates of x = 1, y = −29, z = −12 provided by a previous study. The ROI 3, α = 0.01, voxelwise p<0.05).A two-sample student t-test was used to compare PAG FC between the CN and FBSS groups (AFNI: 3dttest++). The result pattern from the two-sample t-test was corrected using the AlphaSim program  prior to permanent implants. . This exAs opposed to the cross-network FC, within network FC strength is the average value of all possible connections between regions within each network. Only the STM network showed significantly decreased within network FC (uncorrected) in FBSS group compared to CN group (p<0.05). . The FCSThe FCS across all seven networks (i.e. cross-network connectivity) for the CN and FBSS groups are depicted in STMFCS index was related to pain in our patients, we applied a linear regression model between STMFCS index and the pain score for each subject. A significantly negative linear relationship  was found between STMFCS index and the corresponding pain scores in FBSS subjects, indicating that smaller STMFCS indices associates with higher pain scores  patients, however the STM network was not assessed. We did nSome of the previously reported DMN FC changes occurred only after a pain duration of 10–15 years, suggesting that a putative, “end-stage” chronic FC pattern may be associated with the suffering of refractory pain for a prolonged period of time , in our group of cLBP patients as compared to controls, consistent with an altered descending inhibitory pain system especially as it pertains to back representation in the SS cortex. Although this has not been reported before for cLBP, previous studies have demonstrated altered cortical representation of painful CRPS limbs and other chronic pain states that can be normalized with effective treatment such as mind-body interventions, physical therapy, or therapeutic SCS.–36a priori defined regions of interest. Given the limited sample size, this analysis is preferable for this data. As more data are acquired in larger studies, data driven analysis, like independent component analysis, will offer an opportunity to further evaluate this hypothesis and, potentially, inform alternative or supporting hypotheses.In this work, hypothesis driven analysis is presented based upon Correlations between altered FCS and severity of pain have been reported . RecentlApkarian and colleagues have elegantly demonstrated how brain activity reorganizes with transition from acute, to subacute, early and late cLBP states, including a shift in activity from brain regions involved in acute pain to more emotion or reward circuitry.–3, 5 As θ) is envisioned to be generated through connections between the MPFC, hippocampus and striatum, modulated by limbic and cortical inputs.[FCS index may represent a quantitative measure of the proposed θ value.[FCS index will have a lower threshold for persistent pain (θ) develops with increased reported pain scores. Although the patients studied here did not receive SCS, we speculate that long-term successful SCS therapy may restore the abnormal altered connectivity patterns to more normal levels such that therapeutic benefits of SCS may be associated with normalization of the STMFCS index  have recently proposed that a chronic pain threshold  might be more amenable to correction with alternative patterns of SCS. Therefore, the STMFCS index may be used to help select patients for SCS with different stimulation parameters (tonic vs. bursting). Therapeutic benefits maybe associated with normalization of the STMFCS index , but also of the long-term outcomes of SCS. Cross-network FC studies could be extended to patients with other pain phenotypes . A profile/spectrum of imaging-based pain biomarkers may exist for a given patient with a given pain phenotype that could help guide choice of personalized treatment options . The progress of an intervention could be monitored with subjective clinical assessments in combination with changing imaging-based pain biomarker status. Future studies with higher temporal resolution on the order of seconds or less with the use of electrophysiological techniques or MEG may serve to complement fcMRI studies [We were unable to examine the effects of age, sex or smoking because of our small sample size which is due, in part, to our narrow inclusion criteria. With this in mind and to avoid false positives, our cross-network functional connectivity analysis was subjected to rigorous multiple comparison correction utilizing the Bonferroni method. The duration of pain varied greatly in our FBSS patients which may compromise the homogeneity of our study population. However, we did not see a correlation between duration of pain and changes in connectivity patterns. Furthermore, some of the variation in pain duration may be due to the time it can take for any given patient to eventually navigate towards a SCS healthcare provider. Since we studied a very specific group of patients, our results may not be generally applicable to other pain patients. We did not control for pain medications during imaging studies. However, even with patients on heterogeneous profiles of medications , the inv studies , 34 and  studies , 40 FinaWe present the first report of altered cross-network functional connectivity involving emotion/reward brain circuitry that is negatively correlated with individual patient pain scores. This measurement may represent a quantitative, objective measure of chronic pain specific to FBSS patients with moderate to severe constant, neuropathic back pain. Based on previous reports, our new findings suggest that a spectrum of image-based biomarkers may exist that are associated with a range of chronic pain phenotypes based on inciting events, pain pathology, history, quality, consistency, location, and duration and patient emotional state. A profile of such biomarkers could potentially be developed and catalogued to help guide management and prevention of different chronic pain conditions.S1 FigA: Surface rendering figure showing the GMD changes in the FBSS group. Warm and cold color depict increasing and decreasing GMD changes, respectively. B Boxplot showing GMD changes in L/R PreCG for CN and FBSS groups. C. Boxplot showing GMD changes in L/R HIP/PHG for CN and FBSS groups. Legend: Precentral gyrus (PreCG), hippocampus (HIP), parahippocampal gyrus (PHG).(TIFF)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


The majority of postoperative patients report moderate to severe pain, possibly related to opioid underdosing or overdosing during surgery. Objective guidance of opioid dosing using the Nociception Level (NOL) index, a multiparameter artificial intelligence-driven index designed to monitor nociception during surgery, may lead to a more appropriate analgesic regimen, with effects beyond surgery. We tested whether NOL-guided opioid dosing during general anaesthesia results in less postoperative pain.In this two-centre RCT, 50 patients undergoing abdominal surgery under fentanyl/sevoflurane anaesthesia were randomised to NOL-guided fentanyl dosing or standard care in which fentanyl dosing was based on haemodynamics. The primary endpoint of the study was postoperative pain assessed in the PACU.P=0.006). Postoperative morphine consumption (standard deviation) was 0.06 (0.07) mg kg−1 (NOL-guided group) and 0.09 (0.09) mg kg−1 . During surgery, fentanyl dosing was not different between groups , although the variation between patients was greater in the NOL-guided group (% coefficient of variation 66% in the NOL-guided group vs 37% in the standard care group).Median postoperative pain scores were 3.2 (inter-quartile range 1.3–4.3) and 4.8 (3.0–5.3) in NOL-guided and standard care groups, respectively (Despite absence of differences in fentanyl and morphine consumption during and after surgery, a 1.6-point improvement in postoperative pain scores was observed in the NOL-guided group. We attribute this to NOL-driven rather than BP- and HR-driven fentanyl dosing during anaesthesia.www.trialregister.nl under identifier NL7845. The index ranges from 0 (absence of nociception) to 100 (extreme nociception). The algorithm was validated in multiple studies.,9During surgery, the administration of opioid analgesics is directed at controlling nociception and accordingly preventing an adrenergic stress response evoked by surgical tissue injury.,A large proportion of postoperative patients report moderate to severe pain.www.trialregister.nl) under identifier 7845. The study took place from June 2019 to December 2019 at two medical centres in the Netherlands; the Leiden University Medical Centre, a tertiary referral centre, and the Alrijne Hospital, Leiderdorp, a secondary referral centre. The study was performed at both sites by anaesthesia caregivers who were trained in the use of the NOL. Standard care was comparable between the two sites. The study protocol is available from the authors at a.dahan@lumc.nl.Patient recruitment started after the protocol was approved by the Leiden Human Ethics Committee in March 2019. All patients gave written informed consent before enrolment. The study was registered at trial register of the Dutch Cochrane Centre  in the operating room before induction of anaesthesia and could not be altered. Subjects and surgeons were not informed on the group assignment. In both allocation groups, the NOL monitor  was connected to the patient by a finger probe, placed on the left or right middle finger. In cases of NOL-guided analgesia the monitor screen was visible to the anaesthesia team and used to steer fentanyl administration. In cases of standard care, the nociception monitor screen was concealed and the NOL index was not available for guidance of fentanyl dosing, but index values were measured and collected on the hard disk of the monitor.Patients were enrolled by the investigators 1–2 weeks before surgery, so that the patient had ample time to consider participation. The study had a randomised, parallel, superiority design, with primary endpoint pain score in the first 90 min in the PACU. Randomisation to either NOL-guided analgesia or standard care was performed automatically within the electronic data capture system CASTOR  for neuromuscular monitoring, and bispectral index (BIS) monitoring  for measurement of depth of anaesthesia. As mentioned, all subjects were connected to the nociception monitor by a finger probe, placed contralateral to the BP cuff. Additionally, a separate i.v. line was placed in the cubital vein for blood sampling used for stress hormone measurement. To measure hormone concentrations, 8 ml of blood was drawn at six time points: 10–30 min before induction, 1–2 min after intubation, 1–2 min after incision, at skin closure, 15 min into the PACU, and at discharge from the PACU. Both hormones were measured in plasma by an electrochemiluminescence immunoassay using the Cobas 8000 module e 602  with detection limit 1–1200 ng L−1) followed by propofol (1–2 mg kg−1). After consciousness was lost as detected by BIS values <60, absence of eyelash reflex, and no response to verbal stimulation, a neuromuscular blocking agent, rocuronium 0.6 mg kg−1, was administered. After full relaxation, the trachea was intubated. During induction additional doses of fentanyl and propofol could be given. Next, sevoflurane inhalation started . The ventilator settings were such that the end-tidal Pco2 was kept between 4 and 5 vol.%. Fluid administration was standardised to 5–6 ml min−1; additional fluids could be administered in cases of moderate to severe blood loss. Towards the end of surgery, the inspired sevoflurane concentration was tapered down. All patients with a residual neuromuscular block (train-of-four ratios <0.9) were reversed with sugammadex 2 mg kg−1 and extubated when neuromuscular function had normalised (train-of-four ratio ≥0.9), were breathing spontaneously, and were awake; in cases where neuromuscular function had normalised spontaneously at the end of surgery, no reversal agent was given. Each subject received preemptive treatment for postoperative pain: acetaminophen 1 g i.v. 30 min before surgery and an i.v. opioid, morphine (0.1–0.15 mg kg−1) or piritramide (0.06–0.10 mg kg−1), 45–60 min before the end of surgery.Anaesthesia was induced with fentanyl , ranging from 0 (no pain) to 10 (most intense pain imaginable): morphine 1–2 mg or piritramide 2–3 mg could be given at 5–10 min intervals until NRS<4. Pain scores were queried and opioids administered by fully study-blinded PACU nurses.In the test group, fentanyl dosing was dependent on the NOL index, but BP and HR were additionally monitored and considered. In cases where the NOL index was >25 for at least 60 s, fentanyl 50–100 μg was administered in a patient >70 kg, and 25–50 μg in a patient of 70 kg or less.−1), or both, fentanyl 50–100 μg was administered in a patient >70 kg, and 25–50 μg in a patient of 70 kg or less.In this group, fentanyl dosing was dependent solely on haemodynamics  as NOL index values were not available. If systolic BP was >140 mm Hg, tachycardia , sevoflurane concentrations, surgery and PACU times, time between reversal of neuromuscular block and extubation, morphine/piritramide consumption in the first 90 min of PACU stay , and occurrence of awareness. Tertiary endpoints were: BIS values during surgery, median pain score in the PACU, morphine/piritramide dosing during surgery, percentage of subjects with pain scores ≥6 or ≥8, stress hormone concentrations (ACTH and cortisol), and Aldrete scores in the PACU. The Aldrete score is a composite index with 0–2 points for limb movement, respiration, circulation, consciousness, and oxygen saturation, and reflects the level of recovery from anaesthesia.,Since this study is the first to assess the effect of NOL-guided analgesia on postoperative pain scores, we based our sample size calculation on the assumption that a mean pain score difference of 2 NRS points on the NRS (with standard deviation=2) in the first 90 min of PACU stay, is clinically highly relevant.https://www.R-project.org). Additionally, the median pain scores obtained over time were compared by the Mann–Whitney U-test. For secondary and tertiary endpoints, because statistical testing was exploratory rather than confirmatory, power calculations were not performed. Analyses of these data were by an independent two-tailed t-test, the Mann–Whitney test, or the χP-value <0.05 was considered significant; for all endpoints, post hoc Bonferroni corrections for multiple comparisons were made to control for type one errors. Data are presented as mean (standard deviation) unless otherwise stated.The primary endpoint, the pain scores over time, was compared between treatments by generalised estimation equation with covariates sex and centre. Data analysis was performed in R , high BP upon screening (n=4), or logistic reasons . Fifty subjects were enrolled in the study, randomised, and allocated to treatment with 25 subjects in each treatment arm. Data from all 50 subjects were analysed with no subjects lost during follow-up. Subject characteristics are given in A total of 75 patients were approached for participation in the study . RecruitP=0.002, with no effect of covariates sex or centre). The median pain scores of individual subjects in the PACU were 3.2 (inter-quartile range 1.3–4.3) and 4.8 (3.0–5.3) in NOL and control groups, respectively . No difference was observed in patients with intense pain (NRS≥8): control group 6/25 vs NOL-guided group 3/25 (P=0.270).PACU pain scores over time are given in −1 (remifentanil given from t=120–180 min surgery time). Two other subjects, randomised to NOL guidance, received an equivalent of fentanyl 14 μg kg−1 (t=90–210 min), and a fentanyl equivalent of 8 μg kg−1 (t=130–260 min), respectively. The cumulative administered fentanyl dose did not differ between treatment groups at 120 min into surgery with 6.4 (4.2) (NOL-guided group) vs 6.0 (2.2) μg kg−1  and 180 min (mean difference 4.15 μg kg−1 with 95% CI −2.8–11.1 μg kg−1) no differences in fentanyl dosing were observed. In terms of dose per kg, the variability was higher in the NOL-guided group: 66% vs 37%. The area-under-the curve (AUC) of the receiver operating characteristic curve was calculated to evaluate the relevance of the effect of the intervention (opioid dosing based on NOL vs standard care) on opioid dosing at 2 h into surgery and at the end of surgery. The AUC was not significantly different from 0.5 (random effect) at both time points: 2 h into surgery, AUC=0.51 with 95% CI 0.29–0.73, P=0.930, and at the end of surgery, AUC=0.56 with 95% CI 0.39–0.72, P=0.484. The number of doses and the average amount of fentanyl given per dose did not differ between groups. At the time of fentanyl dosing, MAP, systolic BP, and NOL did not differ between groups. However, HR was higher in the standard care group; 69 (13) against 79 (13) beats min−1 .Three subjects received remifentanil because of the inability of fentanyl to subdue hypertension (standard care group) or high NOL values (NOL-guided group). When remifentanil was given, no further fentanyl was administered. One subject, randomised to standard care, received an equivalent of fentanyl 8.5 μg kg−1vs standard care 0.09 [0.09] mg kg−1, mean difference −0.03 mg kg−1, with 95% CI −0.08–0.02 mg kg−1, P=0.204).Cumulative morphine or piritramide consumption  in the PACU did not differ between groups, albeit the absolute values show 30% less morphine use in the NOL-guided group  and 0.312 (0.122) nmol L−1, respectively. Hormone concentrations relative to baseline levels are given in P<0.01).ACTH and cortisol concentrations at baseline (measurement 1) were 27 (15) and 23 (16) ng L−1 in the NOL-guided group and 0.94 (0.3) ng ml−1 in the standard care group . Two hours after the end of surgery the plasma fentanyl concentrations decreased by 39 (7)% and 38 (9)% in the NOL-guided group and the standard care group, respectively .Estimated plasma fentanyl concentrations at the end of surgery were 1.05 (0.5) ng mlWe observed that multiparameter NOL index-guided opioid dosing rather than dosing based on haemodynamic indices (BP and HR) results in a 1.6-point reduction in postoperative pain scores. In addition, an important finding was that stress hormone concentrations during and after surgery were on average 50% lower in subjects who received opioid treatment based on their nociceptive state during surgery.,,The majority of postoperative patients experience relatively high pain scores during recovery, which, apart from causing reduced patient wellbeing, is a source of preventable morbidity.per se was not the determinant of reduced postoperative pain scores, as we observed similar cumulative fentanyl doses administered in the two treatment groups. In order to obtain an indication of the plasma fentanyl concentrations at the end of surgery, we performed a simulation study taking the individual fentanyl doses and timing of dosing during surgery into account. Estimated plasma concentrations were similar between treatment groups (NOL-guided group 1.05 ng ml−1vs standard care group 0.94). However, we did observe a difference in the fentanyl dose variability between the two treatment groups . The finding that nociception was more effectively treated is additionally grounded in the finding that stress hormones concentrations were lower in the NOL-guided group, both at the end of surgery and during PACU stay.While the result of our study was affirmative, we also show that the opioid dose given during surgery ,Currently, several nociception monitors are available for detection of nociceptive events during surgery.−1 in the standard care arm. One may argue that using haemodynamic cut-offs relative to presurgical baseline values would have been a more appropriate approach. We based our thresholds on previous outcome and validation studies with the NOL index.,vs fixed thresholds in the comparator groups. Just seven of 15 studies use a relative BP threshold) whereas 14/15 use a fixed threshold in the intervention arm. This indicates the absence of agreement in the use of thresholds of comparator groups in nociception monitoring studies. In addition, it is questionable whether presurgical BPs are a valid reflection of the patients' ‘true’ BP and are useful during anesthesia.,We used absolute cut-offs to initiate fentanyl dosing , fentanyl was unable to sufficiently subdue hypertension or high nociception values. In these patients, continuous remifentanil was administered during the course of the surgical procedure. Given the rapid offset of remifentanil effect after the end of infusion, this may have impacted (increased) postoperative pain scores in these three patients. However, since the number of patients that received remifentanil was small and two of these subjects received NOL-guided care, we do not think that this influenced the outcome of our study. Second, both piritramide and morphine were allowed for treatment of postoperative pain. This was related to the fact that morphine is the opioid of choice in one centre  and piritramide in the other. As the distribution was similar between groups and the opioids were given in response to the pain score of the patient, we contend that this did not affect our study outcome, particularly since there was no effect of centre (and consequently of pain treatment) on postoperative pain scores. Third, the sample size was relatively small, but our intention was to detect a relatively large difference in postoperative pain scores that are clinically relevant. We observed a difference of 1.6 points (a 33% difference) on the 11-point NRS scale between groups with 84% of subjects who had received NOL-guided anaesthesia with pain scores of 4 or less In this two-centre RCT, we observed that subjects undergoing elective abdominal surgery experience less pain when opioid dosing is guided by the multiparameter Nociception Level index compared with standard care. As opioid dosing did not differ between groups, we relate the difference in outcome to individualised dosing targeted at increased nociception. Future studies in larger more diverse populations, under uncontrolled conditions, should address the long-term outcome benefit of intraoperative analgesia guidance by the NOL index.Substantial contribution to conception and design: AD, MN, CM, LA, MBAcquisition of data: FM, MH, TR, STSupervised the experimental part of the study: MB, CM, PC, AD, MNData analysis: EO, AD, MvV, MNInterpretation of the data: all authorsDrafting of the manuscript/commenting on the manuscript (including revision): all authorsApproved the final version of the manuscript: all authorsAll authors agree to be accountable for all aspects of the work and ensure that all questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.MSD Nederland BV, Grünenthal GmbH (Germany), Bedrocan BV (Netherlands), AMO Pharma (UK), all unrelated to the current project. All other authors report no conflict of interest.AD received a speaker fee from Medasense. The Anesthesia & Pain Research Unit received/receives funding from Medasense Ltd (Israel), and from institutional and departmental sources.


Thyroidectomy is a frequently performed surgical procedure and head and neck extension during this operation facilitates surgery. Patients may experience postoperative neck pain and cervical range of motion (ROM) limitation due to the surgical position following thyroidectomy. It was aimed herein to investigate the short-term effects of kinesiotaping (KT) applied to the cervical spine on neck pain, ROM, and disability in patients following thyroidectomy. This was a randomized, double-blind, sham-controlled study.A total of 74 patients were randomly assigned to be treated with either KT  or sham taping  using a computer-generated random number list. Neck pain, cervical ROM, and neck disability were evaluated with a visual analog scale (VAS), inclinometer, and the Neck Disability Index (NDI) questionnaire, respectively. While there were no significant differences with respect to improvement of the VAS and change of the ROM and NDI values between the groups, patients in Group 1 needed less paracetamol than patients in Group 2 (P = 0.011). There were no significant differences with respect to age, sex, educational background, or body mass index between the groups.This study showed that cervical KT application following thyroidectomy does not have a positive effect on neck pain, ROM, or disability, but nonetheless, it reduces analgesic consumption.  Head and neck surgeries, such as thyroidectomy and parathyroidectomy, are some of the most common surgical operations. During these procedures, the patient is placed in the supine position with neck extension in order to provide better access to the gland and facilitate the surgical operation [1]. However, patients may experience postoperative posterior neck pain, occipital headaches, shoulder and neck movement difficulties, shoulder stiffness, and cervical range of motion (ROM) limitation due to the surgical position . These symptoms may be observed for a long time after surgery and may even negatively impact the patients’ quality of life . Moreover, some serious complications, such as bilateral hypoglossal palsy [5], cervical artery dissection [6], and tetraplegia [7] caused by neck hyperextension secondary to intubation or dental or thyroid surgery procedures, have been reported in the literature. The degree of neck extension and risk factors such as advanced age and the presence of spondylosis and/or spinal stenosis are considered by clinicians before medical procedures requiring prolonged neck hyperextension .Although more than 80% of patients complain of posterior neck pain, headaches, and ROM limitations following thyroidectomy, the majority of studies have focused on pain originating from the incision site, and these symptoms have often been ignored . Analgesics have been commonly administered and they are useful for the control of incisional pain , but there has been no direct evidence to show their effectiveness for discomfort symptoms such as posterior neck pain, neck movement difficulties, and cervical ROM limitation following head and neck surgeries [3]. Recently, a variety of treatment modalities have been used to overcome these disturbing symptoms, such as intraoperative transcutaneous electrical nerve stimulation (TENS) [1], preoperative bilateral greater occipital nerve (GON) block , bilateral superficial cervical plexus block combined with bilateral GON block [12], and postoperative neck stretching exercise . Kinesiotaping (KT) was created in the mid-1970s by Dr Kenzo Kase (https://kinesiotaping.com/about/). It was initially used in the treatment of musculoskeletal disorders or the prevention of sport injuries, but it began to be used over time for other purposes, including hypertension, premenstrual syndrome, and constipation [13–15]. The application of KT improves blood and lymphatic circulation, reduces pain with analgesic system activation, increases ROM, and also supports muscular activities [16–19]. Herein, it was aimed to investigate the short-term effects of KT applied to the cervical spine on posterior neck pain, cervical ROM, and disability in patients following thyroidectomy. A total of 80 patients were enrolled in this prospective, double-blind, randomized controlled study. The study was performed at the Ankara University Faculty of Medicine in Ankara, Turkey, between January 2017 and January 2018, with patients who underwent a total thyroidectomy. Patients who were younger than 18 years of age, had an open wound or cellulitis that would compromise KT application, or had a history of cervical surgery, diagnosis of cervical radiculopathy or myelopathy, skin hypersensitivity to tape material, or medical therapy including analgesics, opioids, and corticosteroids were excluded from the study. The demographics, American Society of Anesthesiologists (ASA) physical status, body mass index (BMI), relevant comorbidities, and surgery duration were analyzed. As a routine procedure of the Department of Anesthesiology in our hospital, all of the patients were taken to the Post Anesthesia Care Unit (PACU) after surgery. Patients in the PACU were evaluated in terms of consciousness, mobility, breathing, circulation, color, and O2 saturation with the modified Aldrete score [20]. Scores of 9 and above indicate that the patient can be discharged from the PACU to their rooms. Neck pain was assessed using a visual analog scale  before surgery (BS) and 30 min, 4 h, 12 h, 24 h, and 7 days after discharge from the PACU. The ROM of the cervical spine in flexion, extension, lateral flexion, and right-left rotation were measured using a bubble inclinometer before and 24 h after the procedure. The inclinometer was placed in the sagittal and frontal plane on the head while the subject was seated for measurement of the flexion and extension ROM and the lateral flexion ROM, respectively. The right and left cervical rotation ROM was measured while the subject was in the supine position and the inclinometer was placed in the transverse plane on the forehead [21]. Moreover, disability was evaluated using the Turkish version of a validated 20-item Neck Disability Index  before and 7 days after surgery (AS) [22].Before the surgical procedure, the patient was positioned supine with a shoulder roll. The head was placed on a donut cushion and the neck was extended to provide maximal exposure [23]. Standardized surgical procedures were performed by the same surgeon (VG), who was not aware of patient group assignments. Application of the KT  was performed as soon as the patients were taken into their room AS. It was applied to participants in Group 1  in accordance with the standardized protocol described by Kase et al. [24]. While the patient was seated, the 5-cm Y-shaped strip was placed symmetrically over the posterior cervical extensor muscles with a degree of tightness of 25% and placed from the dorsal region (T1–T2) to the upper-cervical region (C1–C2). Each tail of the bandage was attached to the skin so as to provide the cervical spine with contralateral flexion and rotation. The second strip was 5 cm wide and shaped like a capital I. It was applied perpendicular to the Y-strip, over the midcervical region (C3–C6), with the cervical spine in flexion to apply tension to the posterior structures. In Group 2 (sham group), only a 5-cm-wide I-shaped tape was placed over the midcervical region with the patient’s cervical spine in flexion to apply tension to the posterior structures without applying tension in the transverse plane. Tapes were administered by the same certified KT practitioner (BST), who masked the treatment group, and were replaced for the patients at the end of the first week. Whether there were side effects related to the KT was recorded. The assessment of pain with the VAS, ROM measurement, and NDI application were performed by the same researcher (AG), who was not aware of patient group assignments. All of the patients were discharged on the first postoperative day. The need for analgesics  was also recorded within the first 7 days after the operation.All of the data were collected by a researcher (SUÇ) who was not aware of patient group assignments. Data were expressed as the mean (standard deviation) and range for continuous variables and frequency (percentage) for the categorical variables. The Shapiro–Wilk test was used to assess the normality assumption for the continuous variables. The differences in proportions between the groups were compared using chi-square or Fisher exact tests as appropriate. The Mann–Whitney U test was used to evaluate differences between the groups in terms of nonnormally distributed continuous variables. The Wilcoxon signed rank test was used to evaluate differences between, after, and before the measurements. P < 0.05 was considered statistically significant. All of the statistical data were analyzed using SPSS 16.0 .Six patients were excluded from the study and a total of 74 patients were randomly assigned to receive either KT  or sham taping  using a computer-generated random number list . From each group, 3 patients dropped out of the study and each group was completed with 34 patients. The participants, the surgeon, the researcher who administered the KT, and the researcher who evaluated the outcomes were all blinded as to the group allocations.of the Group 1 and Group 2 participants were 51.6 ± 14.9 and 49.2 ± 16.3 years, respectively. Table 1 shows a comparison of the baseline demographics and clinical characteristics between the two groups. There was no significant difference with respect to age, sex, educational background, BMI, ASA score, or surgery duration.The mean agesIn terms of the VAS, there was a significant difference between the groups in favor of Group 1 (P = 0.006). Moreover, there were significant time effects between the time points, except between BS and 7 days AS, 30 min, and 4 h (P < 0.001). However, interaction between group and time was not statistically significant (P = 0.838) . There was no significant difference with respect to the change of ROM values of the cervical spine in flexion, extension, right-left flexion, and right-left rotation between the groups during the study. Changes between the preoperative and postoperative 7th day of the NDI score were 0.6% in Group 1 and 3.1% in Group 2, but the differences were not statistically significant (P = 0.486) (Table 2). However, the mean requirement for the use of analgesics within the first 7 days after the operation was significantly (P = 0.011) less in Group 1 (1720 ± 1755 mg) than in Group 2 (2574 ± 1620 mg).We have demonstrated that cervical KT application following thyroidectomy did not have a positive effect on neck pain, ROM, or disability; it only reduced analgesic consumption. In the postoperative period, effective pain management is essential and the primary target is to improve postoperative comfort and satisfaction of the patient, facilitate recovery and functional ability, and promote rapid discharge from the hospital. To the best of our knowledge, this was the first study to evaluate the efficacy of KT on posterior neck pain after a surgery requiring cervical hyperextension. Occasionally, postthyroidectomy pain comes to mind as incisional pain. However, two types of pain have been expressed by patients following thyroidectomy. The first is incisional pain, while the other is positional posterior neck pain, caused by hyperextension applied to the patient’s neck during surgery. For the first type of pain, the patient localizes the pain at the incision site, while for the second type of pain, the patient defines pain in the back of the neck. Therefore, the type of pain can be easily distinguished after surgery. Both pain types usually occur immediately after surgery and last for a couple of days.Surgical procedures that require neck hyperextension are performed frequently and although posterior neck pain and stiffness are seen at a very high rate, it is interesting to note that this issue has not been adequately discussed in the literature. In one of the limited studies that specifically addressed posterior neck pain after thyroidectomy, Han et al. reported that 80% of patients complained of this and showed that preoperative bilateral GON blocked with bupivacaine effectively reduced posterior neck pain and occipital headaches after thyroid surgery [3]. In another study, Takamura et al. found that stretching exercises effectively reduced postoperative neck symptoms, such as discomfort, and also reduced the use of analgesics following thyroidectomy [4]. A recent study by Park et al. reported that intraoperative TENS applied to the trapezius muscle reduced posterior neck pain after thyroidectomy [1]. To date, no published report has described the use of KT for decreasing analgesic consumption in patients undergoing thyroidectomy. In recent years, there has been an increasing amount of literature demonstrating that KT had a positive effect on pain and the prevention and treatment of joint injury, and provided excellent pain-free ROM in the musculoskeletal system. Thus, the use of KT has increased dramatically over the last decade . However, the underlying mechanisms for the possible beneficial effects of KT on musculoskeletal pain remain unclear. It is thought that the application of KT improves blood and lymphatic circulation, reduces pain intensity with analgesic system activation, increases ROM, and also reduces muscle tension . Kelle et al. found that KT provided significant improvements in pain and disability in patients with acute nonspecific low back pain [26]. In a randomized, double-blind, placebo-controlled study, Ay et al. analyzed the data from 61 patients and concluded that the application of cervical KT in cervical myofascial pain syndrome led to improvements in pain, the pressure pain threshold on the trigger point, ROM, and disability measures [27]. Hernandez et al. compared the effectiveness of cervical spine thrust manipulation and KT applied to the neck and revealed that KT was as efficacious as cervical thrust manipulation for decreasing neck pain and disability in patients with mechanical idiopathic neck pain [18].The current findings observed in this study contradict previous studies examining the effect of KT on various musculoskeletal system conditions. In the current study, no significant difference was identified with regard to improvement of the ROM values of the cervical spine in flexion, extension, right-left flexion, and right-left rotation between the KT group and the sham taping group. In terms of neck disability, while the KT group revealed a similar NDI score when comparing baseline to day 7 AS (9.23% to 9.87%), the mean NDI score had deteriorated in the sham group (16.01% to 19.14%), but this difference was not statistically significant. Ay et al. reported positive effects of KT on the ROM values and NDI scores in patients with cervical myofascial syndrome, but these patients were treated with KT for 15 days [27]. Moreover, Takamura et al. followed the effects of stretching exercises on postoperative neck discomfort until the end of the first year after thyroid surgery [4]. We applied KT for only 7 days and evaluated ROM values and NDI scores in very short intervals. While the results of this study indicated no positive influence of KT on pain intensity, it did result in a reduced requirement for the use of analgesics within the first 7 days after the operation. Although these data appear to contradict each other, we think that analgesic consumption is not only related to pain, but also to unpleasant symptoms like feelings of stretching, choking, or pressing in the neck. Indeed, Takamura et al. [4] revealed this relationship in their study. However, these unpleasant symptoms were not evaluated in this study. A limitation of this study was that it did not have a no-treatment control group, which could draw comparison between the KT and sham taping groups. Therefore, the possibility of a placebo effect of the tapings cannot be excluded. Another limitation was that the study focused on only the short-term results of KT application. The key strength of the current study was that the data were prospectively collected and the study was designed as double-blinded and sham-controlled.In conclusion, this study showed that cervical KT application following thyroidectomy did not have a positive effect on neck pain, ROM, or disability; it only reduced analgesic consumption. However, further prospective studies with larger numbers of subjects are needed to provide definitive evidence for this relationship.


Pain is the most common and disabling non-motor symptom in patients with cervical dystonia. Here, we report four patients with painful cervical dystonia in whom burst spinal cord stimulation (SCS) in the cervical region produced sustained and significant improvements in both dystonic pain and motor symptoms. Further studies need to be performed to investigate the clinical efficacy of burst SCS for patients with cervical dystonia. Cervical dystonia (CD), the most common form of focal dystonia, is characterized by involuntary contractions of neck muscles that frequently cause repetitive twisting movement or abnormal posture ,2. PatiePatients with burst SCS fulfilling the following criteria were included in the study: (1) diagnosis of CD refractory to ordinary medical treatments, (2) male or female aged 18–80 years, (3) intractable pain not caused by an etiology other than CD, and (4) written informed consent to participate in the study. The clinical characteristics of four patients with painful CD who underwent burst SCS are summarized in For subjective measurements of pain severity, the visual analog scale (VAS) and the Japanese version of the Short-Form McGill Pain Questionnaire, which provides a list of Japanese words that describe some of the different qualities of pain , were us® leads  were inserted percutaneously into the epidural space of the spine under X-ray radioscopy. The upper edges of both electrodes were finally positioned slightly lateral to the midline at the C2 level after obtaining the stimulation-induced paresthesia over the region of dystonic pain  through the same procedure used in the trial stimulation under local anesthesia. The parameters for stimulation were set to those used to achieve optimal stimulation in the trial periods. Burst SCS was continuously performed during the follow-up periods. The position of the leads was confirmed by X-ray on the day after the operation and at least once a year during the follow-up period.The surgery was performed under local anesthesia. For the trial, two Octrodenic pain . During t-test following Shapiro–Wilk normality test was employed to assess the statistical significance between preoperative baseline and the last follow-up. All values were expressed as means ± S.D. p-Values of less than 0.05 were considered to be statistically significant.With respect to the four clinical assessments (TWSTRS and BFDRS), the Student’s p > 0.05 for both).All four patients with painful CD underwent burst SCS in the cervical region. There were no issues related to lead movement during the follow-up period. No perioperative complication was reported in any patients. The mean follow-up period was 21 months (range: 6–42 months). The clinical outcomes of the four patients with painful CD who underwent burst SCS are summarized in Burst SCS led to a marked improvement in dystonic pain in all patients who did not report pain relapse after the pain relief by SCS. As shown in p < 0.001). The mean improvement in TWSTRS was 49.9% ± 10.3% . As shown in p < 0.05). The mean improvement in BFMDRS was 82.1% ± 7.6% .Burst SCS led to a significant improvement in dystonic motor symptoms in all patients; the dystonic postures and movements were progressively alleviated by the burst SCS. As shown in Patients with CD often suffer from intractable dystonic pain ,2,3. TheThis open-label study is the first to show that burst SCS can produce sustained and significant improvement in the motor symptoms of patients with CD during a long mean follow-up period of 21 months . Since the first study by Gildenberg, who reported good results with tonic SCS utilizing high frequencies 800–1100 Hz) at the C1–C2 level for the treatment of CD , several0 Hz at tSCS is generally accepted to have the ability to alleviate the motor symptoms of CD by interrupting the tonic neck reflex pattern that is regulated by propriospinal fibers . ConversDystonic neck pain is a disabling condition that markedly impairs the quality of life in patients with CD. However, optimal therapies for painful CD are currently lacking. Among the variety of therapeutic interventions, intramuscular BTX injection is considered the first-line therapy for CD; however, few reports have addressed its efficacy and safety in patients with CD. Indeed, BTX therapy did not yield satisfactory results in any of the three patients who received the treatment in the present study. In contrast, we showed that burst SCS could produce sustained and significant improvements in dystonic pain as well as motor symptoms in patients with painful CD. Further studies are necessary to investigate the clinical efficacy of burst SCS in patients with CD.