Spinal surgery can be associated with significant postoperative pain. Erector spinae plane (ESP) block is a new regional anaesthesia technique, which promises effective postoperative analgesia compared with systemically administered opioids, but has never been evaluated in terms of patient-centred outcomes such as quality of recovery and overall morbidity after major thoraco-lumbar spinal surgery.We are conducting a prospective, randomised, double-blind trial in two hospitals in the Republic of Ireland. The sample size will be 50 patients (25 in the intervention group and 25 in the control group). Randomisation will be done using computer-generated concealed envelopes. Both patients and investigators collecting outcome data will be masked to group allocation. Participants will be male or female, aged 18 years and over, capable of providing informed consent and ASA grade I–IV. Patients scheduled to undergo posterior approach thoraco-lumbar decompression surgery involving 2 or more levels will be recruited to the study. Participants randomised to the intervention arm of the study will receive bilateral ultrasound-guided ESP block totalling 40 ml 0.25% levo-bupivcaine (20 ml each side), post induction of general anaesthesia and before surgical incision. The control group will not receive an ESP block. Both groups will receive the same standardised analgesic protocol both intra- and postoperatively. The primary outcome will be the quality of recovery at 24 h postoperatively as determined by the QoR-15 score. This score is determined by a questionnaire which measures patient responses to 15 subjective parameters, each response graded on a scale from 0 to 10. The maximum score achievable is 150 with a potential minimum score of 0. Higher scores indicate a higher quality of recovery experience.Secondary outcomes will include area under the curve (AUC) of VRS pain versus time at rest and on movement up to 24 h postoperatively, 24 h opioid consumption, time to first analgesia in recovery, length of stay (LOS), incidence and severity of postoperative complications as measured by the Comprehensive Complication Index (CCI) score.To the best of our knowledge, this will be the first randomised control trial to examine the efficacy and safety of the ESP block in terms of patient-centred outcomes in the setting of major spinal surgery. The QoR-15 is a validated means of assessing the quality of recovery after surgery and gives a more holistic assessment of the recovery experience from the patient’s point of view.NCT04370951. Registered on 30 April 2020. All items from the World Health Organisation Trial Registration Data Set have been included.This trial is pre-registered on ClinicalTrials.gov reference number The online version contains supplementary material available at 10.1186/s13063-021-05101-2. Major spine surgery is acknowledged to be associated with moderate to severe postoperative pain. A prospective cohort study of patients undergoing spinal surgery reported median verbal response scale (VRS) pain scores ranging from 5 to 7 on the first postoperative day . Severe Recently, a novel regional anaesthesia technique has been described for patients undergoing spinal surgery. First described by Forero in 2016 for the treatment of thoracic neuropathic pain, the erector spinae plane (ESP) block involves depositing local anaesthesia under ultrasound guidance on the transverse process of the thoracic vertebrae, deep to the erector spinae muscle complex –5. The pThe evidence base for ESP in spine surgery is sparse. The published literature that currently exists reports lower VRS pain scores postoperatively among those patients receiving ESP compared with systemic opioids –10. WhilRecent best practice in anaesthesia and perioperative medicine research has been to adopt a more holistic and patient-centred approach to the evaluation of the recovery experience. The QoR-15 score is internationally recognised as a validated means of assessing patients’ quality of recovery after surgery . The scoCurrently, opiate therapy is the primary treatment option for patients suffering acute postoperative pain after major spinal surgery. Adverse events associated with high opioid requirements postoperatively are well documented and include nausea, constipation, respiratory depression, lower respiratory tract infections and drug dependency . AvailabAdditionally, the ESP block appears to be relatively simple to perform and is associated with few adverse events . AlternaWe hypothesise that ESP block provides superior quality of recovery and reduced morbidity compared with systemic analgesia alone. This is based on the scientific rationale that it blocks both posterior and anterior rami of the spinal nerves, thereby providing extensive block and better analgesia.We propose a prospective, two-centre, randomised control trial of 50 patients scheduled for posterior approach thoraco-lumbar spinal surgery. The co-primary outcomes will be QoR-15 score at 24 h postoperatively and postoperative complications as measured by the Comprehensive Complication Index (CCI) score.Secondary outcomes include area under the curve (AUC) of VRS pain versus time at rest and on movement up to 24 h postoperatively, 24 h opioid consumption, time to first analgesia in recovery and length of stay (LOS). This paper describes the protocol for the intended trial.The trial protocol has been prepared and is reported in accordance with the SPIRIT PRO extension reporting guidelines . The schWe aim to complete a randomised control trial to test the hypothesis that the erector spinae plane block  provides superior quality of recovery as measured by the QoR-15 score.Secondary aims are to discover whether the ESP block has favourable outcomes on other metrics of patient-centred patient outcome: area under the curve (AUC) of VRS pain versus time at rest and on movement up to 24 h postoperatively, 24 h opioid consumption, time to first analgesia in recovery, length of stay (LOS) and incidence and severity of postoperative complications as measured by the Comprehensive Complication Index (CCI) score.This is a prospective, double-blind (participant and investigator), randomised controlled clinical trial. Two centres will participate. Recruitment commenced on 1 May 2020, and total recruitment is expected to take 9 months.The study setting comprises two tertiary level hospitals in the Republic of Ireland. Each hospital performs over 200 spinal surgeries per year.Patients will be randomised to one of the trial groups using computer-generated random number tables. Numbers ending in an even number integer will be designated to receive an ESP block; odd numbers will be allocated to the control group. The patient study number and group allocation will be typed on separate pages, folded and concealed in sequentially numbered sealed opaque envelopes. Block randomisation in groups of 6 will be applied to ensure an even number in each group as the study progresses. The groups will be named “ESP” erector spinae plane and “control”. A randomisation key will be held by an independent third party. Investigators will not have access to the randomisation key until all data is collected.After induction of general anaesthesia, the envelope will be opened by the treating anaesthesiologist to reveal the group allocation. The investigators, patients and researchers involved in data collection will be masked to group allocation. The attending anaesthesiologist will not be blinded to the group allocation. Group allocation will be revealed immediately if deemed clinically necessary, for example, if a concern regarding local anaesthetic toxicity arises.Potential participants will be screened by the surgical and anaesthetic teams who will then inform a member of the research team of the potential availability of the patient for the trial. A member of the research team will then approach the patient, confirm the initial screening for suitability and then obtain informed consent for study participation if the patient wishes to be involved in the study. Participants will be informed that their participation in the study is entirely voluntary and they are free to withdraw from the study at any time and this will have no bearing on the quality of care they receive. Patients who are unable to give informed consent due to cognitive impairment will be excluded from the trial. Patients who do not speak English will be enrolled to the trial if an interpreter is present and the patient gives informed consent through the interpreter.Active participation in the study will be until 30 days postoperatively. At 24 h, patients will be asked to complete the QoR-15 questionnaire.R). This data will be acquired by using our electronic patient record system to remotely track the progress of our patients in the postoperative period. Patient progression will be monitored for the entirety of their hospital stay or for 30 days post surgery (whichever is longer).Postoperative complications will be graded using the Comprehensive Complication Index calculator Previous history of opiate abusePre-existing chronic pain conditionPre-existing dementia (due to the need to co-operate in completing QoR-15 score day after surgery)Surgery involving cervical vertebraeSurgery due to queried or confirmed malignancySurgery involving 5 or more vertebral levelsPostoperative admission to ICU for continued ventilationStandard care will be identical in both groups. The only difference will be that one group will receive an erector spinae plane block and the other will not. Airway management strategy will be at the discretion of the treating anaesthesiologist. However, as patients will be in the prone position, all patients will be intubated with a reinforced endotracheal tube. Ventilation strategy, choice of haemodynamic monitoring and venous access will also be at the discretion of the attending anaesthesiologist. The haemodynamic goal will be to maintain systolic blood pressure within 20% of the baseline. Persistent intraoperative elevations above this point will trigger oxycodone administration intravenously. The frequency and dosage of this will be at the discretion of the treating anaesthesiologist.Post surgery, patients will be transferred to the post anaesthesia care unit (PACU) and then to ward level, once PACU discharge criteria are met. Patients will be prescribed oxycodone 1–2 mg IV as required for postoperative pain in PACU until the verbal rating scale (VRS) pain score is < 2 in accordance with our hospital policy. On discharge to the ward, all patients will be prescribed paracetamol 1 g IV 6 hourly, ibuprofen 400 mg orally 8 hourly and oxycodone immediate release 5–10 mg 2 hourly as required for rescue analgesia unless contraindicated. Ondansetron 4 mg PO/IV 8 hourly as required will be prescribed for treatment of nausea or vomiting in the PACU or on discharge to the ward. Remifentanil and ketamine will not be used in any patient enrolled in the study.Surgery will be performed by suitably qualified and experienced spinal surgeons. Surgical technique will vary as deemed necessary for each case. No other forms of analgesia  will be used during the trial.Participants randomised to the ESP group will receive an ultrasound guided bilateral ESP block post induction of general anaesthesia and prior to commencement of surgery. Blocks will be performed under full asepsis with patients in the prone position. Twenty millilitres of 0.25% levobupivacaine will be injected bilaterally at the level corresponding to the mid-point of the range of surgical dermatomes likely to be affected by the surgery. Typically, ESP will be administered at T6 level . The ESP block will be performed as follows:The approximate midpoint of the intended surgical incision will be identified first. The ultrasound transducer will then be placed approximately to 2–3 cm lateral to the midline in a longitudinal orientation to identify the hyperechoic line of the transverse process with its associated acoustic shadow. After identification of trapezius, rhomboid major and erector spinae muscle groups superficial to the transverse process, an echogenic needle will be advanced in a cranio-caudal direction. The needle tip will be advanced until it is located in the interfascial plane deep to the erector spinae muscle group and superficial to the transverse process. Once in position, 20 ml 0.25% levobupivicaine will be injected under ultrasound guidance. Correct needle tip position will be confirmed by the presence of linear spread between the transverse process and the erector spinae muscle group. The same process will then be repeated on the opposite side at the same vertebral level. Because patients will be under general anaesthesia during the block performance, no formal dermatomal sensory testing of block efficacy will be performed. Surgery will commence once the block is completed. There will be no further intervention to the routine conduct of surgery and anaesthesia after this point. Blocks will be performed by anaesthesiologists with subspeciality training in regional anaesthesia. To improve adherence to the intervention protocol, anaesthesiologists will be asked to document the block performance in the anaesthesiology patient record. Although the ESP has been established as a safe means of providing analgesia in spine surgery, we will make all our data available to local data monitoring committee.The following data will be recorded in the perioperative period:AgeBMIPre induction blood pressure and heart rateIntended surgeryTiming/duration of surgery anaesthesiaHaemodynamic parameters (highest and lowest BP and HR recorded)Total opioid givenSurgical or anaesthesia-related complications (including complications related to ESP block)Pain scores at rest and on movement at 6, 12 and 24 hAnalgesia use in the first 24 hTime to first analgesiaAntiemetic usageQoR-15 scoreLength of stayAll patient data collected will be handled in accordance with European Union General Data Protection Regulations (EU 2016/679).Quality of recovery will be measured using the QoR-15 questionnaire. Postoperative pain will be quantified using a verbal response scale (VRS) ranging from 0 to 10, where 0 equals “no pain at all” and 10 equals “the worst pain imaginable”. Reported pain scores will then be plotted against time to give the AUC of pain versus time. Pain scores will be recorded at 6, 12 and 24 h post surgery at rest and on movement.R). This data will be acquired using our electronic patient record system to remotely track the progress of our patients in the postoperative period. Patient progression will be monitored for the entirety of their hospital stay or for 30 days post surgery (whichever is longer).Postoperative complications will be graded using the Comprehensive Complication Index calculator  as appropriate.Data will be inspected and tested for distribution according to the Kolmogorov-Smirnov test. Normally distributed data will be compared between study arms using the unpaired n = 25 patients will be required in each group. To accommodate for participants who may withdraw from the study, we will aim to recruit n = 26 patients to each study arm.The primary outcome of this study will be the QoR-15 score at 24 h postoperatively. The established minimum clinically important difference in QoR-15 is 8.0 and the mean SD of QoR-15 scores after major spinal surgery is in the order of 14 [range of QoR score is 1–150]. Therefore, assuming type I error = 0.05 and type II error = 0.2 (80% power to detect this difference), then A patient information leaflet was written in “plain English” for trial participants. This was written in collaboration with and approved by our patient representative group. On the advice of the same group, we chose the QoR-15 questionnaire as opposed to the QoR-40 as the former was deemed to be easier for patients to read and comprehend. We also consulted with our patient advisory group on the drafting of our consent form. On their advice, we included a statement to say that their data protection rights would not be affected by participating in the study Fig. .Fig. 2SWe are conducting this multicentre, randomised control trial to investigate the efficacy of ESP in thoraco-lumbar spine surgery in terms of quality of recovery. The ESP block has become increasingly popular in recent times, and its use has been reported in a range of thoracic and abdominal surgery –20. Its Spine surgery is associated with significant postoperative pain and often a protracted recovery period. Current evidence suggests that the implementation of Enhanced Recovery After Surgery (ERAS) programmes in spine surgery may lead to improvements in functional recovery, length of stay, opioid use, complications and readmissions . BecauseMore than 70% of patients presenting for major spinal surgery will already be taking opioids for pain relief. Preoperative opioid use combined with poorly controlled pain scores postoperatively have been identified as risk factors associated with opioid misuse during the postoperative period . Given cThis protocol will result in the attending anaesthesiologist not being blinded to the group allocation as they will be required to perform the block. This is as an unavoidable situation, as for safety reasons will we feel that the treating anaesthesiologist should be aware that their patient has received 40 ml of 0.25% levobupivacaine. However, the primary outcome is the QoR-15 score at 24 h postoperatively which will be assessed by study members blinded to the group allocation.We have chosen to exclude patients requiring surgical intervention of five or more vertebral levels. The rational for this decision comes from cadaveric studies, which suggest the maximum spread of local anaesthetic from a single injection ESP block to be approximately 5 levels . TherefoPain scores and quality of recovery will be recorded up to 24 h postoperatively. We acknowledge that for many patients having major spinal surgery their recovery will continue beyond this point. We believe that any analgesic benefit derived from a single dose of local anaesthesia is unlikely to persist beyond 24 h, and so we will not assess pain scores after this point. However, length of stay and postoperative complications will continue to be monitored after this period.ESP blocks will be done under general anaesthesia, therefore formal dermatomal assessment of block function will not be performed. This raises the possibility that some blocks may not be fully effective. However, the practice of administering these blocks under ultrasound guidance after induction of general anaesthesia is consistent with routine clinical practice, and therefore our findings should still be applicable to widespread clinical practice.We do not intend to assess patients’ preoperative QoR-15 in this study. Consequently, we will not have a baseline from which to compare postoperative scores and this we accept is a limitation of the study. Nonetheless, QoR-15 was designed for postoperative use, and we will apply this tool to both randomised cohorts equally. Further, the ability of QoR-15 in the immediate preoperative period to give an accurate baseline has been questioned .Recovery from spinal surgery can be an arduous journey for our patients. By employing a patient-centred focus to our trial design, we hope to evaluate whether this relatively straightforward regional anaesthetic intervention can facilitate recovery and improve safety for patients by reducing postoperative morbidity and complications. This trial is designed to answer that question.As of May 11, 2020, 4 patients have been enrolled in this trial. Recruitment began on 1 May 2020 and is expected to be completed by 31 January 2021. This is protocol version 1 dated 3 April 2020.Additional file 1. Reporting checklist for protocol of a clinical trial.


The Japanese packaging instructions for methadone prohibit dose escalation within 7 days of administration initiation as this may result in overdose and subsequent adverse events. However, for terminal cancer patients, evaluation of the effects of methadone may be desirable within 7 days because they have limited prognoses. We aimed to determine the possibility of estimating the adequateness of methadone earlier than the 7th day by investigating the onset timing of analgesic effects and adverse events of methadone in Japanese terminal cancer patients. Japanese terminal cancer patients who started taking methadone in Ashiya Municipal Hospital were enrolled from January 1, 2013 to February 28, 2019. Verbal rating scale (VRS) scores on pain and adverse events before and after methadone administration  were retrospectively investigated from medical records. We enrolled 25 patients, of which 20 (80.0%) received methadone until day 7. The VRS score (mean ± standard deviation) on pain was significantly reduced to 0.90 ± 0.55 on day 3, compared with 1.65 ± 0.67 before the administration of methadone (p < 0.05). The mean VRS scores did not differ significantly on days 3, 5, and 7. Additionally, of the 23 patients who received methadone until day 3, 20 (87.0%) showed an analgesic effect on day 3 and 17 (85.0%) received methadone without experiencing serious adverse events until day 7. The adequateness of methadone in Japanese terminal cancer patients could be determined before day 7, considering the high analgesia incidence and few adverse events 3 days after the methadone administration under careful observation by a physician experienced in methadone administration. However, as this is a preliminary study, the relationship between pharmacokinetic parameters and analgesic effects was not evaluated. Further studies involving pharmacokinetics and multicenter prospective studies are required to support these findings.  Most cancer patients experience pain, and the treatments for these patients are based on the World Health Organization three-step analgesic ladder. For cancer patients with moderate to severe pain, strong opioids such as morphine, oxycodone, fentanyl are used, but these options may be inadequate for some patients. In Japan, methadone is usually used for intractable pain that is difficult to relieve by strong opioids.Japanese packaging instructions for methadone use prohibit the dose escalation of methadone before 7 days since the start of the administration as this may result in overdose, leading to serious adverse events, such as respiratory depression and long QT syndrome. This is because the half-life of methadone is 40 hours and methadone takes approximately 7 days to reach the steady-state.(1), it will take approximately 20 days or more to complete the dose adjustment in case the analgesic effect of methadone is judged on day 7. Thus, the patients’ quality of life (QOL) is severely compromised in the terminal stage with limited prognosis.However, in terminal care, there are many patients with intractable pain requiring methadone because strong opioids are not effective. Accordingly, it may be desirable to evaluate the effects of methadone earlier than 7 days because the prognosis of terminal cancer patients is limited. For example, even if the analgesic effect of methadone does not manifest within a few days of the administration, it is currently undesirable to increase the dose of methadone or to switch to other opioids within 7 days; thus, the only way to relieve the pain during this period is by using rescue drugs. Considering that the mean number of dose changes required to achieve daily dose stabilization in such patients was 3.2  (2). However, there is a lack of data on the adequateness of methadone for Japanese terminal cancer patients.Hence, in recent years, the possibility of determining the effect of methadone in less than 7 days has been under discussion. The American package insert of methadone regulates 3-5 days as the minimum duration for dose adjustment, and the National Comprehensive Cancer Network guidelines have mentioned the possibility of determining the analgesic effect of methadone in 5-7 days Therefore, in this study, we investigated the onset timing of analgesic effects and adverse events of methadone in Japanese terminal cancer patients and determined the possibility of estimating the adequateness of methadone earlier than the 7th day.(3), patients who had started taking methadone with the 3DS strategy were excluded from this study.Japanese terminal cancer patients who started taking methadone with the stop-and-go (SAG) strategy for the purpose of relieving pain in Ashiya Municipal Hospital from January 1, 2013 to February 28, 2019 were enrolled in this study. The start of administration methods of methadone are roughly divided into two types as follows: the SAG strategy and the 3-days switch (3DS) strategy. In the SAG strategy, methadone is introduced immediately after the discontinuation of previous opioids, whereas in the 3DS strategy, the previous opioids are gradually changed to methadone by cross-tapering within 3 days. Because the SAG strategy is recommended by a systematic review of methadone (4). For example, pain described as “sharp” or “stabbing” was counted as somatic pain, “pressing” or “heavy” pain was counted as visceral pain, and “allodynia” or “numbness” pain was counted as neuropathic pain. The usage counts of rescue drugs were assessed before and after methadone administration . The laboratory test values obtained one week before methadone administration were considered. When multiple measurements were conducted within that period, the latest result before the start of methadone administration was considered. The laboratory test values 7 days (±3 days) after the start of methadone administration were considered. If multiple measurements were conducted within that period, the latest result within 7 days since the start of methadone was considered.The following data were collected from medical records for each patient: age, sex, body-mass index (BMI), Eastern Cooperative Oncology Group Performance Status (ECOG PS), primary cancer site, metastases, type of pain , opioids before switching to methadone, morphine-equivalent daily dose, aspartate transaminase, alanine transaminase, γ-glutamyl transpeptidase, serum creatinine, estimated glomerular filtration rate, blood urea nitrogen, a medical history of heart disease, types and usage count of rescue drugs, and concomitant medications at the start of methadone. Types of pain  were generally classified according to the diagnosis described in the medical record, and where there was no diagnosis, pain was classified based on the McGill pain questionnaire (5).Pain scores on the numerical rating scale (NRS) or verbal rating scale (VRS) were investigated before and after methadone administration . NRS scores were converted to VRS scores as follows: NRS 0 = no pain (VRS 0), NRS 1-4 = mild pain (VRS 1), NRS > 4-7 = moderate pain (VRS 2), NRS > 7-10 = severe pain (VRS 3) VRS or NRS scores before methadone administration were defined as baseline scores. Patients who had VRS score decreased by one or more points from the baseline or NRS score decreased by 33% or more from the baseline after methadone administration were defined as the effective group.Of the adverse events that occurred until 7 days from the start of methadone administration, those caused by the discontinuation of methadone and the reasons for the discontinuation were investigated. In case there were two or more adverse events, they were counted in duplicates.The primary outcome was the change in VRS scores on pain before and after methadone administration. Secondary outcomes were continuous rate with the same dose until day 7 and comparison with the usage counts of rescue drugs before and after methadone administration .The change in VRS scores on pain and the usage counts of rescue drugs were analyzed using the Shirley-Williams multiple comparison test. Statistical analysis was conducted using the BellCurve program for Excel 2015  and P-values < 0.05 were considered statistically significant. This study was conducted in accordance with the ethical guidelines on medical research for human subjects and approved by the Ethical Review Board of Ashiya Municipal Hospital  and Osaka University, Graduate School of Pharmaceutical Sciences . Written consent was obtained from all patients to publish the information.Thirty-eight patients taking methadone were identified during the study period. Ten patients who started methadone in addition to opioids and 3 patients who switched to and administration strategy other than the SAG strategy were excluded. Finally, 25 patients who completely switched to methadone with the SAG strategy were included.2, and 17 patients (68.0%) showed ECOG PS 3 or higher. The most common primary cancer site was colon . Twenty-four patients (96.0%) had cancer metastasis and the most common site of cancer metastasis was lung , followed by bone and liver . On the types of pain, 21 patients (84.0%) had neuropathic pain, 17 (68.0%) had somatic pain, and 13 (52.0%) had visceral pain. Regarding concomitant medications at the start of methadone administration, 14 patients (56.0%) used analgesia and 13 (52.0%) used nonsteroidal anti-inflammatory drugs.Of 25 patients who started taking methadone with the SAG strategy, 20 (80.0%) received the same dose of methadone until day 7. The transition of the average VRS score on pain before and after methadone administration  for the 20 patients is shown in The reasons for discontinuation or methadone dose change until day 7 (5 patients) are shown in In this study, methadone showed analgesia on day 3 after the start of administration for 87.0% of terminal cancer patients, and 85.0% of them were able to continue methadone without experiencing serious adverse events until day 7. These results suggest that the analgesic effect of methadone may be determined earlier than the 7th day, under careful observation by a physician experienced in methadone administration. To the best of our knowledge, this is the first study to examine the possibility of determining the effect of starting methadone within 7 days in Japanese cancer patients receiving terminal care.In addition, in this study, both VRS score on pain and the average usage count of rescue drugs significantly decreased on day 3. Therefore, the decrease in VRS score on pain can be explained by the effect of methadone and not by the effect of the rescue drugs.(6). CYP2B6*6 is reported to reduce the expression and activity of CYP2B6 significantly (7), the incidence of CYP2B6*6 tends to be lower in Japanese than in Westerners (8). Taking these reports into consideration, it is expected that the clearance of methadone in Japanese individuals will increase and it will take a longer, and hence, the onset of the effects of methadone will be delayed. However, in this study, as in the previous report for Westerners (9), the onset of analgesia was observed 3 days after the start of methadone. In order to clarify our hypothesis, further studies examining the relationship between individual metabolic enzymes, blood concentration, and analgesic effects of methadone are required.Methadone is mainly metabolized by cytochrome P450 (CYP) 3A4 and 2B6 and the influence of CYP2B6 genotype is considered to be important in considering blood concentration of methadone and racial differences The risk of adverse events is considered to be high if the analgesic effect of methadone appears too early. However, in this study, of the patients who obtained the analgesic effect of methadone on day 3, only one patient (5.0%) discontinued administration due to serious adverse events (respiratory depression) until day 7. In addition, 8 patients (32.0%) who had heart disease obtained analgesic effects on day 3, but they did not experience serious adverse events until day 7. Most of the patients in this study received routine electrocardiography and appropriate monitoring. Thus, it was suggested that it might not necessarily be overdose in case appropriate safety managements were implemented even if the analgesic effects of methadone were obtained on day 3.(10) of administering methadone to opioid-naïve patients and let a physician experienced in methadone administration carefully administer the drug to him. However, the patient died 2 weeks after starting methadone. Since methadone was not recommended in this case, its administration in opioid-naïve patients should be considered very carefully. Von der Brelie et al. (11) suggested that it is desirable to use methadone even for opioid-naïve patients under careful observation when their prognosis is limited and an immediate analgesic effect is needed. In our study, another patient had been treated with oxycodone at a previous hospital but had temporarily switched to tramadol due to delirium. When the patient was transferred to Ashiya Municipal Hospital, he switched to methadone.Two patients who switched from tramadol and who were opioid-naïve were included in this study. One of them had severe neuropathic pain, so he received various analgesics including lidocaine. However, none of the analgesics worked and his prognosis was limited. Therefore, to prioritize the patient’s QOL, we referred to past reports There are several limitations to this study. First, this is a preliminary study; thus, the relationship between pharmacokinetics such as the blood concentration of methadone and its analgesic effects are not evaluated. Second, the level of evidence is poor because this is a retrospective preliminary study conducted with a small number of patients in a single institution. Further studies involving pharmacokinetics and a multicenter prospective study is needed to validate these findings.However, this study suggested that it is possible to determine the adequateness of methadone for Japanese terminal cancer patients earlier than 7 days, under careful observation by a physician experienced in methadone administration. In the future, the QOL of terminal cancer patients will be expected to improve by increasing pain treatment options through some validation studies of our findings.NoneK.N. and Y.O. conceived the presented idea. M.T. performed the medical chart review. K.N. performed the statistical analysis. Y.M., a physician experienced in methadone administration, examined terminal cancer patients who started taking methadone Both M.U. and E.U. contributed to the final version of the manuscript. All authors discussed the results and contributed to the final manuscript.No. 26  and No. 30-11


R = −0.931, p = 0.007), whereas Hβ correlation was at the edge of significance . Patients’ anxiety was correlated to pain intensity . Normalization of the low and high β global power spectrum (GPS) to the GPS of the full frequency range, while confirming the significant Lβ power decrease in chronic neuropathic pain patients, vanished the significance of the Hβ decrease, as well as the correlation between Lβ power and pain intensity. Our results suggest that the GABAergic Lβ EEG oscillation is affected by chronic neuropathic pain. Confirming the Lβ GPS decrease and the correlation with pain intensity in larger studies would open new opportunities for the clinical application of gamma-aminobutyric acid-modifying therapies.This preliminary investigation aimed to assess beta (β) oscillation, a marker of the brain GABAergic signaling, as a potential objective pain marker, hence contributing at the same time to the mechanistic approach of pain management. This case–control observational study measured β electroencephalographic (EEG) oscillation in 12 right-handed adult male with chronic neuropathic pain and 10 matched controls (∼55 years). Participants were submitted to clinical evaluation  and a 24-min high-density EEG recording (BIOSEMI). Data were analyzed using the EEGlab toolbox (MATLAB), SPSS, and R. The global power spectrum computed within the low  and the high  β frequency sub-bands was significantly lower in patients than in controls, and accordingly, Lβ was negatively correlated to the pain visual analog scale ( Pain is a major public health challenge, and a large number of available analgesic drugs do not prevent from high treatment failure rate . DespitePain can be evaluated by means of several clinical tools, among which the Visual Analog Scale (VAS), the Numerical Rating Scale , and theSuccessful analgesia is achieved when pain intensity  is <3 . This pavia several techniques, including transcranial magnetic stimulation , with the hypothesis that β waves would decrease and be negatively correlated with pain intensity, in accordance with most convincing data .This case–control cross-sectional, observational study involved patients suffering from CNP and sex -matched healthy controls of similar age (±5 years). Participants were recruited and investigated between September 2015 and January 2018.t-test: t(16.955) = 0.358; p = 0.738] fulfilled the same inclusion (except for the presence of pain) and exclusion criteria as patients.Patients  suffered from CNP due to a peripheral nerve lesion in the lower limbs lasting for ≥6 months. The diagnosis of peripheral neuropathy was made by a specialist  and supported by a “Douleur Neuropathique 4 questions” (DN4)  score ofThe study fulfilled the requirements of the Declaration of Helsinki and was approved by the Ethics Committee of Vaud under the reference 331/15. Each participant signed informed consent before any investigation.In total, 16 CNP patients and 14 healthy controls were screened. Among them, two controls were finally excluded because they happened to have exclusion criteria upon a second check. All recruited participants underwent individual, in-person interview following a standardized questionnaire including personal and medical data and information on their sleep behavior. In addition, sleep-related [Insomnia Severity Index ] and mooClinical examination was performed by medical doctors (JNC and JMA) or one trained medical student (MT) to confirm lower-limb localization of pain and absence of exclusion criteria.p = 0.002). Similar results were observed in controls : 2.07 (3.81) dB for the eyes-closed condition and −0.13 (3.42) dB for the eyes-open condition . Thus, lower α amplitudes in the eye-open condition confirm significant changes occurring in EEG signals, which could have introduced a bias in our analysis of other frequency bands if not taken into account. For this reason, only data recorded in the eye-closed condition were considered when performing all remaining analyses.All EEG recordings took place in the morning to exclude bias due to nychthemeral variations of pain . During The EEG data were continuously recorded at 1,024 Hz using a high-density (64 electrodes) EEG (BIOSEMI ActiveTwo) recording system referenced to the built-in CMS-DRL ground .Automated data preprocessing was performed using a customized MATLAB script based on the EEGLab Toolbox  and on tIt was important to analyze only data recorded in wakefulness because sleep stages were expected to interfere with fast EEG oscillations, including beta waves . Data anTo automatically select data recorded in wakefulness state, a data-driven analysis was developed following empirical evidence . This me∗log10)  and the delta  frequency range are presented. The δ frequency was selected as a negative control, owing to the absence of clear links between δ oscillations and chronic pain in the literature . The GPS∗log10) .Initial analyses evidenced that the β frequency domain was characterized by two prominent “peaks” (maxima) of power in most subjects, located approximately at 16 and 25 Hz, which corresponded to the centers, respectively, of the Lβ (13–20 Hz) and the Hβ (20–30 Hz) frequency sub-bands . Therefototal) was performed as follows: first, the logarithmic transformation used in the analysis of the non-normalized data to obtain near-normally distributed data was inverted, after that, the respective ratio between Lβ (GPSlβ) and Hβ GPS (GPShβ) and the GPStotal were computed, and finally, the logarithmic transformation of the ratio was computed back to obtain the normalized GPS . The following formula summarizes the normalization procedure for the Lβ GPS: Lβ GPSnormalized = 10∗log10 [10∗∗(GPSlB/10)/10∗∗].Normalization of computed Lβ and Hβ GPS to the GPS over the total analyzed frequency range . The procedure to compute the minimal GPS (GPSqmin) was exactly the same as for the GPSqmax, except that the minimum power was depicted instead of the maximum.To localize the power maxima on the scalp , the horizontal head section was divided into four quadrants in a way that avoided misleading or ambiguous interpretation  was corrected for multiple comparisons with the Bonferroni method (αc = 0.017). Correlations were assessed using the Pearson’s r correlation coefficient (two-sided).Statistical analyses were performed using the SPSS 24.0 software (IBM SPSS Statistics). All log-transformed EEG data (GPS) were successfully tested for normality . Unless otherwise specified, data are expressed as mean (SD). Differences among δ, Lβ, and Hβ frequency bands within groups were assessed using a multivariate analysis of variance. Group differences were evaluated using n = 12) and/or in all controls (n = 10) as appropriate.All participants underwent a formal interview and participated in the EEG assessment. However, only 12 patients and 10 controls were retained for the final analysis , as four patients had a DN4 score <4, whereas two controls suffered from low-intensity pain at the time of EEG assessment. Unless otherwise specified, analyses were performed in all CNP patients (via the VAS. The level of pain on the day of the EEG recording (VASd) was in general slightly lower than pain intensity perceived on average during the last 2 weeks . Answers to question no. 6 of the BPI questionnaire .  version ] corresprsion . The output of this analysis is shown in one illustrative patient and one control, respectively, in p = 0.004 for both EEG markers). There was a significant effect of frequency  and of group  but no interaction . On the contrary, there was no statistical difference in the δ GPS between patients [2.0 (1.7) dB] and healthy participants  (c0.017 with the Bonferroni method for multiple (n = 3) comparisons.As shown in = 0.069] . The sigp = 0.041], whereas the decrease noticed in the Hβ frequency range lost significance  , CNP patients still had significantly lower Lβ GPS compared with controls  .q; see section “Materials and Methods” for the detailed procedure) and considered the quadrant holding the maximal GPSq (GPSqmax) and the minimal GPSq (GPSqmin) as the localization of, respectively, the β maximum and minimum. In the Lβ range, most patients (regardless of their predominant pain side) and controls displayed GPSqmax in the posterior, left region . The pattern of GPSqmax localization was different in the Hβ range: 58.3% of patients showed the maximal averaged power in the anterior, left quadrant, whereas 70% of controls displayed their GPSqmax within the right hemisphere . The GPSqmin was variably distributed in controls , and in CNP patients , no relationship being observed with the predominant pain side. Here also, no remarkable difference was observed between patients and controls.As an attempt to localize the maximal and the minimal β power in the sensor-space, we computed β GPS for the four defined quadrants (GPSd ∼3)  nor in the Hβ range . Interestingly, when we further discriminated between patients with nonsignificant pain (VASd < 3) and those with significant pain (VASd ≥ 3), no correlation was found in the absence of significant pain (n = 6) , whereas in patients with VASd ≥ 3 (n = 6), a strong correlation was now observed both in the Lβ , while only at the edge of significance in the Hβ range . None of the two GABAergic markers was correlated to the VAS2w , even when splitting between patients with VAS2w < 3 and VAS2w ≥ 3 (data not shown). The GPS in the δ range did not correlate neither with the VASd  nor with the VAS2w , even when only considering patients with VAS ≥ 3 (data not shown).The GPS was clearly lower in patients than in controls, both in the Lβ and in the Hβ frequency ranges. Thus, we expected a negative correlation between the VAS and the GPS for both EEG markers. On the day of the EEG recording, patients had pain levels at the limit of significance (VASd ∼3) . When red , even when solely evaluated in CNP patients with VASd ≥ 3 . There was no correlation between Hβ GPS and VASd (data not shown).Upon normalization, no correlation was anymore observed between Lβ GPS and VASn = 12) were moderately anxious  but not controls [5.3(2.8)] , and the depression sub-score was normal in both groups . Interestingly, the HADanx positively correlated with the VASd in patients  most probably due to the subgroup with VASd ≥ 3 (n = 6), which was the only one displaying a significant, positive correlation , contrary to the one with VASd < 3 . No correlation was found between VAS2w (n = 12) and HADanx (data not shown). Altogether, these observations suggest that anxiety and pain intensity interacted daily but not on average. It was also interesting to assess the impact of pain on mood state. BPI question no. 9b (BPImood) is specifically related to this issue. The BPImood score was highly correlated to HADanx . Thus, pain-diseased patients were anxious and had their pain intensity increasing with anxiety level, and the influence of pain on their mood was measurable in the anxiety domain. However, this study was not specifically designed to measure this interaction. It should be noted that no correlation was observed between the HADanx score and all studied EEG markers.Because mood interacts with pain , particiIn the present pilot study, we recorded β EEG oscillations as an indicator of brain GABAergic activity  in patieIn our analyses, we considered the GPS as a quantitative measurement of β EEG oscillatory activity. The most important result of our study is that, in accordance with our assumptions, the β GPS was significantly lower in patients than in healthy controls both in the Lβ and in the Hβ frequency sub-bands but not in the δ range . Our results are in accordance with transcranial magnetic stimulation, magnetic resonance spectroscopy, and EEG-based measurements performed in chronic pain patients, which found, respectively, decreased cortical inhibition , corticaThe Lβ (but not the Hβ or δ) GPS was highly correlated with pain intensity when the latter was significant , reinforIn conclusion, the association between Lβ GPS, supposedly measuring brain GABAergic activity, and pain intensity suggests that Lβ oscillations is a potential CNP biomarker, even if the measured modality of pain is still to be more precisely determined and these preliminary results confirmed in larger investigation settings.qmin) to be located within the cerebral hemisphere contralateral to the pain side  had their Lβ GPSqmax located in the left and posterior hemisphere. A recent study conducted in healthy right-handed individuals found a positive and linear correlation between the β EEG oscillatory activity and the endogenous concentration of GABA in the somatosensory cortex only in the left hemisphere  was only at the edge of significance, whereas VASd was positively correlated with HADanx. Interestingly, emerging data suggest that Hβ GPS could possibly be related to anxiety and similar mood disorders, pointing out rather an increase of β oscillations in this context  EEG recording at rest. Furthermore, the marker we studied seems to be solely related to GABAergic signaling . This should therefore open a way to a mechanism-based classification of pain and subsequently toward a more personalized GABA-based analgesic therapy depending on the extent to which the GABAergic signaling is involved.In the future, it would be interesting to study the same markers in other pain models, assessing the role played by GABA in their underlying mechanisms.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by the Commission cantonale d’éthique et de la recherche sur l’être humain-Vaud (CER-VD). The patients/participants provided their written informed consent to participate in this study.MT: major contribution to the patients’ recruitment, contribution to the controls’ recruitment, major contribution to the data collection, and manuscript writing and revision. CM: contribution to the study conception and initiation, major participation to the controls’ recruitment, major contribution to the data collection, data interpretation, and data analysis, and contribution to the manuscript writing and revision. CW: major contribution to the data analysis and data interpretation and contribution to the manuscript writing and revision. GM: major participation to the patients’ recruitment and study initiation and contribution to the data discussion. TK: contribution to the study conception and initiation, participation in the patients’ recruitment, manuscript revision, and language editing. DC: major contribution to the manuscript revision and language editing. MM: participation in the data collection, contribution to the data analysis, manuscript writing, and manuscript revision. J-MA: contribution to the data interpretation and significant contribution to the manuscript revision. JC: study conception and initiation, data collection, data analysis, main data interpretation, manuscript writing, and manuscript revision. 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.


Several other proteins, which were not described earlier in the TMJ synovia, were detected but not related to surgical outcome. Bilateral masticatory muscle palpation pain had strong association to a poor outcome that was related to the diagnoses disc displacement and osteoarthritis. CIA and the patient-reported variable TMJ disability might be related to an unfavourable outcome according to the multivariate model. These findings of surgical predictors show potential in aiding clinical decision-making and they might enhance the understanding of aetiopathogenesis in TMJ disorders. Our knowledge of synovial tissues in patients that are scheduled for surgery as a result of temporomandibular joint (TMJ) disorders is limited. Characterising the protein profile, as well as mapping clinical preoperative variables, might increase our understanding of pathogenesis and forecast surgical outcome. A cohort of 100 patients with either disc displacement, osteoarthritis, or chronic inflammatory arthritis (CIA) was prospectively investigated for a set of preoperative clinical variables. During surgery, a synovial tissue biopsy was sampled and analysed via multi-analytic profiling. The surgical outcome was classified according to a predefined set of outcome criteria six months postoperatively. Higher concentrations of interleukin 8 ( Temporomandibular joint (TMJ) diseases might be painful and restrictive by nature, hampering dietary intake and with a negative impact on psychosocial well-being . SurgeryPotential predictive factors for TMJ surgery, such as age, TMJ pain, maximal interincisal opening (MIO), psychiatric co-morbidity, and masticatory muscle palpation pain, have been investigated ,11,12,13The primary aim of the present study was to investigate synovial tissue protein concentrations and relate them to surgical outcome. The hypothesis was that the concentrations of pro-inflammatory cytokines were higher in patients with inferior outcome, whilst the anti-inflammatory cytokines were higher in patients with superior surgical outcomes. The secondary aim was to control for recorded objective and subjective patient variables, and their relation to surgical outcome. Identifying clinical variables or synovial tissue proteins that might influence surgical outcome could be a valuable contribution to oral- and maxillofacial surgeons decision-making. To our knowledge, this is the first attempt to investigate TMJ synovial tissue proteins in relation to surgical outcome.A prospective cohort study was performed at the Unit of Cranio- and Maxillofacial Surgery, Karolinska University Hospital, Stockholm, Sweden. The Regional Ethics Review Board approved the study , DD without reduction (DDwoR), OA together with arthralgia, and CIA were eligible for inclusion. The patients were enrolled from December 2014 to January 2017 and written informed consent was mandatory before inclusion. The study was designed, and the article written, in accordance with the STROBE statement.TMJ diagnoses were set according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), except for CIA diagnosis, where the requirement was rheumatic diagnosis that was set by a rheumatologist . CriteriPatient-specific data were registered preoperatively, one and six months postoperatively, while using a standardised case record form. Patient inclusion and data gathering were performed by M.U., A.N.-A., C.K.-W, and B.L., who were calibrated for patient classification and clinical examination. The anamnestic variables collected included present illnesses, medication, prior jaw trauma, ongoing tinnitus/ear fullness affected side, duration of present TMJ symptoms, and subjective grading on a 0–10 graded VAS of TMJ pain, TMJ disability, psychosocial impact of TMJ problems, and global pain . Joint mSurgical outcome was based on four parameters: MIO, TMJ pain, TMJ disability, and TMJ psychosocial impact registered at the last planned visit six months after surgery, and classified as either successful, good, intermediate, or deteriorated. The criteria for successful treatment were objective measurement of MIO ≥ 35 mm, and all subjective VAS scoring of TMJ pain, TMJ disability, and TMJ psychosocial impact of ≤3 or ≥40% improvement. A good surgical outcome was defined as MIO ≥ 35 mm and whether one or two of the VAS values of pain, functional disabilities, and psycho-social impact showed ≥40% improvement or a VAS value of ≤3. If the above-mentioned criteria got obviously worse, then the outcome was deemed to be deteriorated. With minor or no improvements, the result was classified as intermediate. 2 tissue samples. Synovial tissue samples that were destined for protein extraction were placed in RNAlater  and then refrigerated for 24 h. RNAlater was then removed and the samples stored at −80 °C. According to the departments’ research-based guidelines, patients with DDwR were scheduled for discectomy, and patients with DDwoR, OA, or CIA had arthroscopic lysis and lavage generally. One surgeon performed all of the operations (M.U.). Two synovial tissue biopsies were taken from the posterior bilaminar zone in the superior joint compartment. The triangulation technique was used in order to collect biopsies under direct visualisation during arthroscopy  20]. Bi. Bi20]. g at 4 °C for 10 min., and the supernatant stored at −80 °C until analysis.Synovial tissue was ground in liquid nitrogen in order to disrupt the tissue piece. The proteins were extracted in ice-cold cell lysis buffer NP40, prepared according to the manufacturer’s instructions (ThermoFisher Scientific) . 50 µL cThe total protein concentration in each tissue sample was determined while using the Qubit Protein Assay Kit (ThermoFisher Scientific) and the Qubit Fluorometer (ThermoFisher Scientific). Magnetic bead panels HTMP2MAG-54K, HMMP2MAG-55K, and HCYTOMAG-60K , and LXSAHM-20 , were used in order to determine the levels of synovial tissue proteins with multi-analytic profiling while using a Luminex 200 system  and xMAP technology. Attained data were analysed by xPONENT 3.1 software (Luminex). HCYTOMAG-60K and LXSAHM-20 were customised and contained the following proteins: a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13), aggrecan, bone morphogenetic protein (BMP) 2, 4, and 9, collagen 1-α1, collagen 4-α1, epidermal growth factor (EGF), eotaxin, fibroblast activation protein (FAP), fibroblast growth factor 2 (FGF-2), fibronectin, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage (GM) CSF, hepatocyte growth factor receptor (HGFR), intercellular adhesion molecule 1 (ICAM-1), IL-1β, IL-1ra, IL-6, IL-7, IL-8, IL-10, IL-17, interferon gamma-induced protein 10 (IP-10), lumican, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, neural cell adhesion molecule (NCAM), osteoprotegerin (OPG), osteonectin, platelet-derived growth factor (PDGF) AA, PDGF-AB/BB, regulated on activation normal T-cell expressed and secreted (RANTES), syndecan-1, syndecan-4, tenascin C, transforming growth factor α (TGF-α), tumour necrosis factor α (TNF-α), TNF-β, triggering receptor expressed on myeloid cells 1 (TREM-1), and vascular endothelial growth factor (VEGF). In addition, HTMP2MAG-54K and HMMP2MAG-55K contained matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-7, MMP-9, MMP-10, tissue inhibitor of metalloproteinase 1 (TIMP-1), TIMP-2, TIMP-3, and TIMP-4. Fifty-one proteins were analysed in total. p-value of ≤0.05 was regarded as significant.Stata version 15  and IBM SPSS version 25.0  were used to analyse the data. The descriptive statistics were calculated as mean ± SD for all continuous data and as a number and percentage for bivariate data. Data on patient characteristics were analysed with Student’s T-test for continuous data and Fisher’s exact test for categorical data. For the statistical analyses of synovial tissue proteins, the surgical outcome groups intermediate and deteriorated were merged into one group, since there was only one patient in the deteriorated group. The concentration of specified proteins (pg/mL) was used in the statistical analyses. The surgical outcome was the dependent variable and ordered logistic regression were used for both univariate and multivariate computations. The multivariate regression model was tested with Akaike’s information criterion (AIC) in order to estimate the performance of the model. The best performance was reached by including the specific protein and the potential confounders CIA, TMJ disability, masticatory muscle palpation, and the interaction of CIA and positive finding of masticatory muscle palpation pain. Masticatory muscle palpation was dichotomised, and no finding of palpation pain was merged with unilateral positive sign, since it made the model perform better according to AIC. A p = 0.022) and they had more co-morbidities, classified as “other diseases” (p = 0.041). Both OA (p = 0.003) and DDwR patients (p < 0.001) had larger MIO as compared to the rest of the cohort. The group with DDwR had significantly lower TMJ pain VAS-value (p = 0.008) and fewer patients with both palpation pain of the masticatory muscles (p < 0.001) and the TMJ (p < 0.001). On the other hand, the CIA-group had significantly more patients with palpation pain on muscles (p = 0.006) and TMJ (p < 0.001). Patients with DDwoR had significantly lower TMJ psychosocial impact (p = 0.003), as well as lower global pain (p = 0.050), when compared to the other three diagnoses.One-hundred patients had followed the protocol at study closure . The 27 p = 0.044) and masticatory muscle palpation pain  were both positively associated to a worse outcome (p = 0.011), TMJ psychosocial impact , and global pain , but not for TMJ pain   . TinnituWhen examining the proteins in the multi-analytic profiling system, some of the proteins were identified as being below or above the standard limits, as defined by the manufacturers. Those samples that were below the lowest standard were set at the lowest standard value and those above the highest standard were set at the highest standard value. The processed tissue samples with protein measurements out of the assay’s precision and recovery were treated as the missing values.ADAMTS13, BMP-9, HGFR, IL-7, MMP-10, NCAM, osteonectin, syndecan-1 and 4, TIMP-4, and TREM-1 were found with detectable concentrations in most patients. These proteins have not been previously described in the human TMJ.−3; p = 0.038) and syndecan-1  significantly changed the outcome in a negative direction. None of the other proteins had any significant correlation to outcome.All of the analysed proteins were related to outcome in a univariate ordered logistic regression model. Higher concentrations of both eotaxin , TMJ psychosocial impact , global pain , and masticatory muscle palpation pain . p-values of ≤ 0.075. Patients with the interaction CIA and bilateral masticatory muscle palpation pain showed a significant association to a positive surgical outcome in the analysis of ADAMTS13, IL-1β, and TNF-β (The significant results from univariate analyses with respect to patient-specific variables were tested in a multivariate model. The tested variables were TMJ disability (coef., 0.23; nd TNF-β . All of The success rates in TMJ surgery have been reported as variable and they often not better than 80%. Identifying patient-specific predictors might be a valuable tool for surgeons, patients, and health-care providers to improve outcome. The investigation of TMJ synovial fluid proteins potentially reflecting surgical outcome has to our knowledge been done twice before, where higher concentrations of IL-10 were significantly associated with a positive outcome of arthrocentesis, and TMJ pain was associated with higher concentrations of IL-6 and IL-8 indicating a negative outcome ,22. The In the univariate statistical analyses, higher concentrations of eotaxin and syndecan-1 showed a correlation to a suboptimal surgical outcome. Eotaxin is a chemokine that has been shown to increase osteoclast activity in bone inflammation, while syndecan-1 might be associated with attempted cartilage repair ,36. FibrThe age of the patient and preoperative MIO have previously been described as predictive factors for TMJ surgical outcome ,13,38,39The association between masticatory muscle palpation pain and negative outcome has earlier been presented by our group in two different patient cohorts ,13. ConsA shortcoming of the study was the loss of 27 eligible patients, who did not participate for different reasons. Potential bias might be considered because the only variables possible to analyse for the non-participant group were sex, age, and TMJ diagnosis. A relatively short follow-up period was used, which might also implicate a bias in some of the diagnostic groups. Because only four out of 51 proteins correlated with outcome, there was a risk that these associations are by chance. This suggests that further investigations should be made to verify these findings.To conclude, preoperative bilateral palpation pain of the masticatory muscles was found to be a predictor for negative surgical outcome, and it might alert the surgeon to consider non-invasive interventions that have not yet been tried before scheduling surgery. However, in patients diagnosed with CIA, bilateral masticatory muscle pain did not indicate a negative surgical outcome when compared to the other included TMJ diagnoses. TMJ disability was the only outcome measure that showed potential as predicting factor. IL-8, lumican, MMP-7, and TIMP-2 were individually shown to have a positive correlation to worse outcome. Altogether, the results demonstrate that the clinical variable bilateral masticatory muscle palpation pain seems to be a more robust predictor for surgical outcome when compared to any of the investigated proteins. Description of protein alterations due to diagnosis, severity, and progress of TMJ disease, but also in relation to different treatment modalities, has to continue. Further mapping will possibly reveal more of the potential multi-factorial pathogenesis.


It is well appreciated that traditional analgesic delivery routes used to treat pain associated with temporomandibular disorder (TMD) often have harmful unintended side effects as a consequence of systemic distribution. Further, localized delivery of analgesic medication via intra‐articular injections involves a different set of issues limiting their clinical viability. As an option, transdermal analgesic delivery provides for prolonged pain relief and flexibility in dose administration, while limiting systemic exposure and minimizing adverse events. Incorporation of a novel electroporation technique may further increase transdermal drug penetration into synovial tissue/fluid and enhance pain reduction. The present feasibility study compares the effectiveness of an electroporation‐enhanced transdermal application of diclofenac sodium to a conventional intra‐articular injection of triamcinolone acetonide suspension (corticosteroids) to treat patients with TMD associated pain.Pre‐ and post‐treatment maximal incisal mouth opening (MIO), pain visual analog scale (VAS) and surface electromyography (EMG) of 22 patients treated with electroporation‐enhanced diclofenac and 37 patients treated with corticosteroids injections were collected and analyzed.p‐value = .01) compared to the standard treatment, but both methods were similarly effective for improvement of MIO  and improvement of all EMG indices .In general, patients treated with electroporation exhibited better results in terms of pain improvement (corrected The enhancing effect of electroporation in transdermal delivery of diclofenac sodium was demonstrated by decreased pain, increase MIO and EMG improvement to normal values. Its analgesic and inflammatory results are comparable with standard treatment offered by corticosteroids. Additionally, NLC/TDD offers controlled and continuous administration of the drugs, which is particularly useful in drugs with short biological half‐lives  administration in relieving TMD related pain and improving jaw joint function.2This study followed the ethical principles of Declaration of Helsinki guideline and all patients were given a thorough explanation regarding the procedures. After answering all their questions, patients signed a written consent form. The protocol was approved by the ethical committees from each of the two units (IRB012019 MQ03AL01 and UCSFIRB 241418).SD 13.2 years) who were treated with two electroporation‐enhanced  who received a one‐time intra‐articular injection of triamcinolone acetonide injectable suspension at the Oral and Maxillofacial Surgery Department at the San Francisco Veterans Health Care System in San Francisco, California, from January 1, 2019 to the end of June 2019 .Inclusion criteria:A painful joint(s) during mastication  in which 1 (no pain) and 10 (the greatest possible pain).Limitation during opening  or during left and right excursion or protrusion <7 mm.Additional inclusion criteria:If patients had received any TMJ treatment in previous the 6 months.If the patients have an existing allergy, sensitivity, cross‐function or contraindications with the experimental drug.Exclusion criteria:2.1The pre and post treatment assessment of patients was made by a clinician blinded to the actual treatment modality. Patient's clinical history was collected according to the Research Diagnostic Criteria for TMD  for inter‐group differences of described study design was calculated using GPower software (version 3.1.9.4) and reached 56%. Moreover, the calculated effect size resulted in 0.49 for Mann–Whitney U test and 0.24 for Wilcoxon signed‐rank test.All patient's data were assessed quantitatively in IBM SPSS Statistics 25 software. Nonparametric Wilcoxon signed‐rank test was used to compare the initial and final MIO and VAS scores of each patient, and pre‐ and post‐treatment EMG data. Student 3p‐value < .05) in sex and age distribution from a statistical point of view. Patients treated with electroporation enhanced diclofenac were significantly younger (mean age 36.5 years) compared to patients who received a one‐time intra‐articular injection of triamcinolone acetonide injectable suspension (mean age of 53.7 years). Two groups of patients without significant differences in the initial MIO, VAS and EMG scores were compared . Table Twenty‐two and thirty‐seven patients were finally recruited because there was a lack of patients fulfilling inclusion criteria and several patients did not consent. The two groups were composed of Caucasian patients in order to be considered homogenous in terms of ethnicity (the only ethnicity available from the two study locations). The groups significantly differed . Similar result of pain decrease was observed in the comparator group of patients treated with the conventional care (corticosteroids injections) , however, the improvement in MIO was not significant  in electroporation group and 2.16 VAS score points (SD 1.58) in the comparator group. The mean improvement in MIO was 5.55 mm (SD 6.45) in electroporation group and 2.19 mm (SD 6.79) in the comparator group  and millimeters (for MIO) between two patient groups. The mean improvement in VAS score reached 4.64 VAS points (All patients treated with electroporation enhanced diclofenac delivery reported a decrease in pain and 95% (21/22) of those patients showed also improvement in MIO. One patient showed lower MIO after the treatment. In the comparator group, 86% of patients (32/37) reported a decrease in pain, 10% (4/37) of patients reported the same pain and 1 patient (3.7%) reported increased pain. Similarly, 68% of patients (25/37) showed improvement in the MIO after the treatment, 24% showed (9/37) decreased mouth opening and 8% of patients (3/37) did not show any improvement.p‐values > .05). In the comparator group treated with corticosteroids, the improvement was observed in all variables. The statistically significant improvement was detected in a bilateral symmetry coefficient for temporalis muscles  ‐ indices ranged in normal values after the treatment. The significant improvement was also found in Torque coefficient, coefficient  however, both pre‐ and post‐ mean values of TORS ranged in normal values over 80%. In terms of improvement, the actual pre‐ and post‐treatment EMG score differences were compared between two patient groups for each observed index. Overall, no significant differences were found in the overall improvements of all indexes ; cell fusion; gene therapy and DNA vaccination; and for general TDD  muscle sides. Value 80% is considered as normal function of the masseter and temporal muscles with standardized muscular symmetry  in larger multi‐centric studies. This fundamental step is essential in order to better establish the procedure limitations as an adjuvant tool in the non‐invasive therapy of our patients.In the future, all possible variables should be controlled and the influence of age, sex, ethnicity, menstrual cycle or severity of disease should be studied. Side effects of single and repeated application of electroporation to TMJ must be described. Our preliminary data showed the potential of electroporation in the treatment of TMJ diseases and further investigations on this procedure are being planned. Similarly, the study described effects of electroporation‐enhanced diclofenac 1 week after two applications. In the described feasibility study no side effects were observed. Future 6 months recall appointments were planned for patient to evaluate its long‐lasting effects. Future studies of repeated application of electroporation must be also performed to assess safety of such approach and its possible advantages/disadvantages compared to a control group using placebo in order to better define the effect of drug electroporation per se and prognostic time set in TMD arthralgia patients. This is a feasibility study designed to reduce the economical and biological cost and at the same time enlist the highest number of patients looking for a clinical solution in a defined time frame. The lack of a control group, and significant differences in age and sex of patients are the weakness of this protocol and further investigations in this direction are being planned because the feasibility approach was encouraging. This age difference might be caused mainly due to the experimental nature of diclofenac electroporation application, as older patients preferred not to undergo it. On the other hand, this is the first description, to our knowledge, regarding the application of this technique in dentistry and a cautious approach on the study design was planned to reduce the risk of patients' treatment failure.5Acute arthralgia is a well‐identified disease in the taxonomy of TMD problems with very good prognosis with early diagnosis and treatment. TDD is one of the treatment options with two advantages. In the foreground, it is fast and secondly, it is economic, and thus it allows us to help the patients more efficiently. With the limitation of this study, TDD demonstrated to be a useful tool compared to standard intraarticular injection for its non‐invasiveness and minimal discomfort. Further clinical trials are indicated to better define the clinical technique and applications along a broader cohort of TMD patients.All authors have no conflict of interest.


Background: Arthroscopic rotator cuff repair surgery may lead to significant postoperative pain. Interscalene block (ISB) is an effective analgesic technique in these surgeries but there is a risk of the phrenic blockade. Subacromial local anesthetic infiltration is a phrenic sparing alternative technique for postoperative analgesia. The primary aim of our study was to compare the ISB with a continuous subacromial infusion (SAC) with regard to postoperative analgesia.Methods: This prospective randomized, interventional parallel arm trial was conducted in 60 ASA grade I and II, adult patients (30 patients in each group) posted for arthroscopic rotator cuff repair surgery. Patients were randomly assigned to receive either ultrasound-guided ISB (Group ISB: 15 ml of 0.75% ropivacaine) or continuous SAC . Intraoperative hemodynamic parameters, visual analog scores (VAS), and rescue analgesic requirements for 24 hours, patient satisfaction, and complications were recorded.Results: Rescue analgesic requirement was significantly higher in SAC at zero hours (P=0.000), while it was significantly higher in ISB at 12 hours (P=0.02). The VAS scores were comparable at all time points and patient satisfaction at 24 hours was similar. None of the patients had rated satisfaction related to pain relief as poor in any group. Complications like ptosis and motor weakness were seen only with ISB.Conclusion: Both the techniques provided effective analgesia and comparable patient satisfaction with lesser incidence of complications in the SAC group. ISB provided more effective immediate postoperative pain relief while SAC was more effective in delayed analgesia for arthroscopic rotator cuff repair surgeries. SAC can be considered a reasonably safe alternative to ISB in patients with contraindications to the latter. Arthroscopic rotator cuff surgery is associated with substantial pain . OptimalAmong regional approaches, interscalene block (ISB) is the most frequently used analgesic technique after major shoulder surgery . Though,Most recently, pre-emptive LA injected into subacromial space has been shown to provide superior pain relief compared to placebo -9. AnalgAlthough the efficacy of continuous SAC infusion has been substantiated previously by many authors, there are conflicting reports of the degree of pain relief and its role as an analgesic technique is not established ,12,14. A2) were excluded from the study.This prospective, interventional, randomized parallel-group study was conducted in the Department of Anesthesia and Critical Care at a Sports Injury Centre of a tertiary care institute of north India, after obtaining approval from the institutional ethical committee and written informed consent from all the patients. We prospectively recruited 60 adult patients of 18-60 years of age of either sex, belonging to the American Society of Anesthesiologists (ASA) grade I-II physical status, who were scheduled to undergo unilateral arthroscopic rotator cuff repair and acromioplasty under general anesthesia. Patients with any contraindications to blocks , allergy to LA, pre-existing neurological deficit, pulmonary, cardiac, hepatic and/or renal diseases, inability to understand the pain score (VAS) and those who were morbidly obese : In this group patients were given 15 ml of 0.75% ropivacaine as a pre-emptive bolus in subacromial space before induction of anesthesia. In the postoperative period, ropivacaine 0.5% continuous infusion was started at 3 ml/hour for 24 hours using a disposable elastomeric pump.ISB (n=30): In this group, patients were given ISB block before induction of anesthesia using 15 ml of 0.75% ropivacaine under ultrasound guidance.The randomization technique used was the computerized block randomization technique.All patients underwent a detailed pre-anesthetic checkup and were kept fasting overnight. Patients were explained about the advantages and the side effects of both techniques. The use of the VAS (0-10) was also be explained. All patients have given tablets Alprazolam 0.25 mg, Ranitidine 150 mg, and Metoclopramide 10 mg at night and two hours before surgery with a sip of water as per institutional protocol.2), and neuromuscular blockade [train of four (TOF) stimulation] were attached. Oxygen was administered using a Hudson mask and an end-tidal carbon dioxide (EtCO2) monitor was attached; baseline heart rate (HR), mean arterial blood pressure (MAP), SpO2, and respiratory rate (RR) were recorded. Intravenous access was secured using 18-20G cannula in the opposite limb and intravenous infusion of Ringer’s lactate was be started. The procedure was explained to the patients. Injection midazolam 0.02 mg/kg and injection fentanyl 1 μg/kg were administered for sedation to all the patients before performing the blocks. A single experienced anesthesiologist proficient in ultrasound-guided blocks performed all the blocks and was not involved in the study any further. Both the blocks were performed using the assistance of a high frequency (7-12 Hz) 38 mm linear ultrasound transducer , after ensuring skin and probe asepsis.Patients were wheeled inside the operation room and standard monitors including non-invasive blood pressure (NIBP), electrocardiogram (ECG), pulse oximetry , patients were given 15 ml of 0.75% ropivacaine in subacromial space as a pre-emptive bolus dose using 20G intravenous cannula. Then, general anesthesia was administered. At the end of the surgery, a multi-orifice epidural catheter was inserted in the subacromial space by the surgeon under arthroscopic guidance. After tunneling the catheter in the subcutaneous tissue, it was connected to the elastomeric pump containing 0.5% ropivacaine which was infused at 3 ml/hour for 24 hours.Interscalene BlockPatients were placed supine with the head facing away from the side to be blocked. Block was given using a high-frequency linear ultrasound transducer. Under all aseptic precautions, skin wheal was raised using 2% lignocaine after identification of brachial plexus between two scalene muscles. Thereafter, a 20G, 50 mm nerve block needle was advanced using a lateral to medial in-plane approach close to C5-C7 roots. After negative aspiration of blood, hydro dissection was done to exclude severe pain or resistance on injection. Then, 15 ml of 0.75% ropivacaine was injected in aliquots.Sensory blockade was taken as a loss of sensation to alcohol sponge in C5-C7 dermatomes. Motor blockade was assessed by loss of shoulder abduction. Immediate complications such as hematoma formation, intravascular/spinal/epidural injection, Horner’s syndrome, hoarseness, or respiratory distress was assessed during this period and postoperatively.2:N2O (40:60) and isoflurane (0.6-1%). Injection diclofenac 75 mg intravenously was given pre-emptively as a part of multimodal analgesia. Despite the good anesthetic depth and adequate muscle relaxation, if mean arterial pressure or heart rate increases to >20% of the baseline value, patients were given a fentanyl top-up dose of 0.5-1 µg/kg assuming pain to be the cause and the need of such supplementation was noted. Intraoperative hemodynamics was also noted. Ondansetron 0.1 mg/kg intravenous was administered as prophylaxis for postoperative emesis. At the end of the surgery, muscle relaxation was reversed with injection glycopyrrolate 0.01 mg/kg and injection neostigmine 0.05 mg/kg. Patients were shifted to recovery and monitored for two hours before shifting to the ward. All patients were routinely given injection paracetamol 1 g intravenously every eight hours in the postoperative period.General anesthesia was administered to all the patients using injection fentanyl 1 μg/kg and injection propofol 2-2.5 mg/kg. After checking for adequate ventilation, neuromuscular blockade was achieved with injection vecuronium 0.1 mg/kg. The trachea was then intubated with an appropriately sized endotracheal tube. All patients were mechanically ventilated. A single experienced surgeon performed all the surgeries. Anesthesia was maintained by OPostoperative pain was evaluated at zero hours (postanesthetic care unit), 2, 6, 12, and 24 hours after surgery at rest using VAS ranging from 0 (no pain) to 10 (worst pain imaginable). Rescue analgesia was provided using injection tramadol 1 mg/kg intravenously whenever VAS was ≥4. The total amount of rescue analgesia used in 24 hours was noted. Adverse effects related to block  and catheter placement were noted. A prolonged motor blockade that was defined as the sensation of shoulder heaviness at 12 hours was noted as a complication. Patient satisfaction in terms of pain relief will be rated at 24 hours as poor, fair, good, and excellent. All the data were collected by an anesthesiologist not involved in the administration of anesthesia.Sample size calculation was based on the mean consumption of rescue analgesia as per the study by Koltka et al. . They obStatistical analysisCategorical variables are presented in number and percentage (%) and continuous variables are presented as mean ± SD and median. The normality of data was tested by the Kolmogorov-Smirnov test. Non-parametric tests were used when the normality was rejected. Quantitative variables were compared using the unpaired t-test/Mann-Whitney Test between the two groups . The qualitative variable was compared using the Chi-Square test /Fisher’s exact test.A p-value of <0.05 was considered statistically significant. The data were entered in MS EXCEL spreadsheet and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0 .This prospective randomized interventional study was conducted in a tertiary care center in north India. Seventy patients between 18 and 60 years of age, posted for arthroscopic rotator cuff repair and acromioplasty surgery were assessed for eligibility, and after screening for exclusion criteria, remaining 60 patients were included in the present study . There was no statistically significant difference in the VAS at all time points . It was found that rescue analgesic requirement at zero hours was significantly higher in the SAC group (P=0.000), whereas it was significantly higher in ISB (P=0.02) at 12 hours  . We did LimitationsThere are certain limitations to our study. First, the blocks were performed by an experienced operator, so the results may not be the same in hands of inexperienced operators. Second, patient and outcome assessor blinding was not feasible because of the different sites of injection and the use of catheters with continuous infusions in the SAC group. However, the investigators assessed the outcomes without being involved in the block procedure to minimize any possibility of bias. Lastly, VAS scores were assessed only at rest and dynamic scores could not be assessed because of the application of shoulder brace by the surgeons, prohibiting any movement on the shoulder joint.SAC is equally efficacious as ISB for arthroscopic shoulder surgeries in terms of intraoperative fentanyl consumption, postoperative VAS scores recorded over the first 24 hours, and patient satisfaction regarding the quality of analgesia. Side effects and complications like ptosis and motor weakness were seen exclusively in the ISB group. ISB provided more effective immediate postoperative pain relief while SAC was more effective in delayed analgesia for arthroscopic rotator cuff repair surgeries. ISB is known to lead to phrenic nerve blockade with commonly used dosages which can be detrimental to patients with lung pathology. SAC blocks the terminal endings of nerves supplying the shoulder joint and is, therefore, a phrenic sparing block. Hence, continuous SAC of LA can be considered a reasonable alternative to ISB in patients with contraindications to later. Large multicentric studies comparing both the blocks are desirable in the future to prove this conclusively.


The objective of the study was to compare the effects of neuromobilization (NM) techniques and routine physiotherapy on pain and functional disability in patients having shoulder impingement syndrome (SIS). Present study was aimed to discover evidence based conservative and cost effective remedy on pain and functional disability.Single blinded randomized control clinical trial.A total of 80 patients with SIS were randomly assigned into care and experimental groups (40 in each group). After the baseline assessment routine physiotherapy was executed on both groups, while NM was applied additionally to experimental group. Pain and functional disability score were evaluated by Visual Analogue Scale and University of California at Los Angeles rating score at baseline, 5th and 11th week. Differences in outcome between groups were evaluated with clinical improvement.P < 0.001 and Partial ƞ2 = 0.33, similarly functional disability score 28.58(27.32–29.83) vs 20.10(18.84–21.36); between group difference,5.62; 95%CI, (4.32–6.92); P< 0.001 and Partial ƞ2 = 0.49 respectively. In experimental group NM was a more effective technique to reduce the pain severity and disability in SIS patients as compare to care group.The experimental group compared with care group at 11th week had lower mean pain score 2.15(1.66–2.64) vs 4.90(4.41–5.40); between group difference, 1.82; 95% (CI), − 2.38 to − 1.25; Neuromobilization techniques in addition to routine physiotherapy were significantly effective for the treatment of SIS.IRCT20190121042445N1, Registered 19 February 2019. The shoulder impingement syndrome (SIS) consists of the rotator cuff tendonitis and bursitis of the shoulder . It showSIS comprises of three stages, the 1st stage is defined by edema and hemorrhage of the subacromial bursa and rotator cuff muscle; it has been detected in patients where age group is less than 25 years. The next stage indicates irreversible changes, which are fibrosis combine with tendinopathy of the rotator cuff muscle. It is highly prevalent among 25 to 40 years old population. At 3rd stage impingement is evident by more severe changes, like partial or complete tears of the rotator cuff, mostly observed among patients who are above 40 years age [The execution of specific components of body movements to generate particular mechanical incident in the neural system is called NM. Mechanical management may therefore be used to augment physiology in the nervous system .It has already been observed that there are three theories projected for the local etiological origin of tendon pain: 1-mechanical, 2-vascular and 3- neural , 7.Mechanical and vascular theories are regularly used for the treatment of tendon pain. The mechanical theory is based on the idea of mechanical overload of the tendon resulting in damage to the collagen. Tendons that receive high strain loads such as the Achilles are often loaded during movement and have been suggested to sustain physiological strain up to 6–8%.The vascular theory is based on the concept that tendon may experience vascular compromise and neurovascularization. Due to lack of vascularity, the tendon is not capable of healing because of repetitive high strain load. A study conducted by Rees JD et al. observed mechanical, vascular and neural theories which have proposed for tendinopathy and point out the potential appropriate use of NM. The use of NM has the potential to lessen the perception of pain. The movement of the nervous system during NM may restore axoplasm flow, restoring nutrients to the nerves. The restoration of nerve function may then lessen sensitivity (i.e ion channels) to the area and restore normal blood flow to the tendon .Physiologically we may explain that a nerve which closely passes to a joint is mostly kept in a tunnel or it is attached with collagen fibres or fascia to the nearby musculoskeletal components. Nerves move side by side within the upper limb hence the neuromobilization given during management cause break of the cross linkages. The possible effect of stretch on axons is the improved ion flux in stretch sensitive ion channels. The mechanical stimulation used at low frequency, low intensity ultrasound is indicated to arouse neurons in mouse brain by activating voltage gated sodium and calcium channels. The slow elongation can cause structural changes in myelin sheath, axon regeneration, deposition of endoneurial collagen. The nodes of ranvier can open further as it causes the Schmidt- Lanterman clefts which affects the levels of local cytoplasm .The neural component is over looked due to poor outcomes among patients with tendinopathy. Matocha MA et al. highlighted neural involvement in patients with tendon pain and discussed the role of NM for tendon pain . The utiThe objective of the study was to compare the effects of NM techniques and routine physiotherapy on pain and functional disability in patients having SIS. Present study was aimed to discover evidence based conservative and cost effective remedy on pain and functional disability.The model of study was single blinded randomized controlled clinical trial. This controlled trial used a parallel design where patients were allotted by 1:1 ratio in two groups’ experimental group as well as care group. These patients had gone through a complete systemic physical examination that included the whole neurologic and musculoskeletal assessments. Patients with history of shoulder surgery, shoulder injury, trauma, shoulder joint dislocation, cervical radioculopathy and having other systemic diseases were excluded from the study. The patients with positive upper limb tension test , Neer teA sample of 80 participants was selected and allocated in to two groups experimental and care group by using computer generator method in simple random sampling technique.An independent assessor, who specialized in musculoskeletal injuries with more than 5 year experience of dealing patients with shoulder injury, had performed allocation of patients.Diagnosed patients with SIS was participated in this research. The study purpose was described to all patients and informed consent was taken from them. After approval from Institutional Review Board “The University of Lahore” and present study was completed at physiotherapy department of Social Security Hospital Gujranwala.After initial assessment, the investigator used to take demographic details of the participants along with visual analogue scale (VAS) and functional disability rating score.All the patient related information was kept confidential and they were free to quit the study at anytime.VAS was used to evaluate the severity of pain and it was considered as primary outcome of the current study. A constant scale had been employed to inquire the patients about the shoulder pain during the activity and to classify it by indicating on a 10-mm line; it was connected “no pain” and the “worst pain you have ever felt”. This is common method of evaluating severity of shoulder pain. The findings of the study indicate the VAS is a high reliable as well as valid method to assess the severity of pain . The UCLRoutine physiotherapy was performed on both groups while NM was done on experimental group. Patients were treated thrice a week on alternative days.2 [The routine Physiotherapy consisted of pulsed Short Wave Diathermy (SWD) with frequency 27.12 MHZ , Ultraso2  and Tran2 .Table 1NM was applied by using Butler’s recommendations . InitialAs an outcome measure for pain severity (0 = no pain and 10 = severe pain) VAS was used with reliability 0.94 at baseline, 5th and 11th week . Pain waUCLA score was assessed at baseline, 5th and 11th week. The UCLA score was used to assess functional disability and it has total 35 points, with higher values indicating better shoulder condition. The UCLA score has 5 domains; pain 10 points, function 10 points, active forward flexion 5 points, strength of forward flexion 5 points and satisfaction of the patient 5 points . The scoSample size calculation was derived from Yamany AA et al. study . AccordiZa/21 −  is type 1 error = 1.96, Zβ = 0.84, d = μ2 − μ1 = 10.7.Where SD = Standard deviation = 14.08, Based on this a total sample size of around 80 was calculated to be an adequate mean to reach the conclusion. Considering a loss of 20% follow-up, at least 80% patients followed the treatments . An expeData were analyzed by using (SPSS Version 22.0) software. Qualitative data were presented in frequencies and percentages while mean and S. D were calculated for Quantitative data. Line chart was drawn at various times in weeks during the treatment vs pain score and UCLA score.p value ≤0.05 was considered as significant.Repeated measure ANOVA was applied to compare average pain score as primary outcome while average UCLA score as a secondary outcome at different time points . The confidence level of 95% was used as well as The current study was started on September 2016 and last follow up was occurred on March 2018 and then trial ended. It was considered regarding the number of the participants in each group laid within the range estimated (40 each group). Data was collected at Social Security Hospital Gujranwala.One hundred and twenty participants had been observed for eligibility process at the time of September 2016 till February 2018, among 30 participants had not been found eligible. The ineligible participants were excluded from the current study and was given the routine physiotherapy treatment. The reasons for ineligibility of the patients are presented in Fig. The experimental sheet/ flow sheet is presented through Fig. The baseline characteristics are presented in Table The results of primary outcome were reported in Table The results of secondary outcome were reported in Table P value < 0.001 and partial ƞ2 = 0.33. For the main effect of time and interaction (time*group) were ƞ2 = 0.79 and ƞ2 0.43 respectively that was shown in Table P value < 0.001 and Partial ƞ2 = 0.49. For the main effect of time and interaction (time*group) were ƞ2 = 0.81 and ƞ2 0.49 respectively that was shown in Table Comparison of VAS between experimental and care group was assessed at 11th week. Statistically significant difference was found with Total six participants were dropped out on 11th week in experimental group, two patients were dropped out because they were not satisfied with the treatment, one patient dropped out due to worsening of the symptoms and three patients due to lack of time. Similarly in control group four patients dropped out due to dissatisfaction of the treatment given to them and two participants due to lack of time.The results of the current study demonstrated the improvement of pain among the two groups with SIS at 5th and 11th week. So, it was greater betterment in the experimental group as compared to the care group. The results of a study by Pritam Deka revealed that NM has fruitful effects in mitigating the pain by restoring neurodynamics properties in upper limb . Robert The results of current study were also similar with Pritam Deka, who explored that neuromobilization was effective treatment for pain. When neurombilization combined with TENS were used, more effective results were found on cervical radiculopathy . The curIn a systemic review efficacy of neuromobilization was examined, this study concluded the positive therapeutic effects of the neuromobilization .The results of the current study have shown improvement in UCLA scores of experimental group as compare to care group at 5th and 11th week. Findings of this study indicated NM has positive effects to improve UCLA score.The given findings of our study confirm this NM is effective in improving UCLA score on 5th week and 11th week. The similar results were also noted in the study of Richard F. Ellis et al. who found that shoulder pain and disability scores were significantly improved in the experimental group .Neurophysiological result of spinal mobilization was earlier shown that mobilization of nervous tissue enhances peripheral blood flow, using a physiological shift toward parasympathetic domination , 29.Different neuromuscular responses  associated with neuromobilization indirectly indicates the spinal cord mediated effect of the NM. Neuromobilization had an quick hypoalgesic effect on C-fibre mediated pain perception, as not on A-delta fibre mediated pain perception .Another reason of more improvement of function in the experimental group may be shown the restoration of mobility due to the biomechanical effects which are inter-linked with NM .There are several limitations of current study that warrant the further discussion. However, benefits of a smaller sample size were the ability to supervise the exercises program and more closely interaction with patients on a daily basis during the exercise sessions for better results. In particular, the adherence to the prescribed exercise intensity and program was excellent for both exercise treatment groups. Second, the present study (11 weeks) was also relatively reasonable in duration compared to previous training investigations .Improvements in pain and functional disability score was found in the present study which indicated that 11 weeks exercise training period was a sufficient time frame to demonstrate significant training effects.After recognizing the close relationship between physical capacities and life style, it is likely to be declared that implementation of NM recommended standard part of the treatment for SIS patients will decrease shoulder pain and improve function. This study shows that NM is not only feasible as a part of the treatment, but it also has a large effect size and efficient for all the times.Patients of SIS who suffer from many challenges, so it is important to recognize that shoulder pain and functional disability score constitute an important part of overall health and daily tasks. Since shoulder impingement syndrome are known to be important key factor for daily life activities in term of pain and function. Importantly, this study, as well as neuromobilization regimes is feasible and safe to carry out within this patient group.Trial Registration: IRCT20190121042445N1.On the basis of results it is concluded that addition of NM with routine physiotherapy has greater improvement to reduce pain severity and disability in SIS patients than without NM.