The primary objective of the study was to compare the percentage of back pain surface decrease after 3 months, using a computerized interface to obtain quantitative pain mappings, combined with multi-dimensional SCS outcomes. Back pain surface decreased significantly greater for the ”SCS + PNfS” group (80.2% ± 21.3%) compared to the “SCS only” group (13.2% ± 94.8%) (p = 0.012), highlighting the clinical interest of SCS + PNfS, in cases where SCS fails to address back pain.While Spinal Cord Stimulation (SCS) provides satisfaction to almost 2/3 of Persistent Spinal Pain Syndrome-Type 2 (PSPS-T2) patients implanted for refractory chronic back and/or leg pain, when not adequately addressed the back pain component, leaves patients in a therapeutic cul-de-sac. Peripheral Nerve field Stimulation (PNfS) has shown interesting results addressing back pain in the same population. Far from placing these two techniques in opposition, we suggest that these approaches could be combined to better treat PSPS-T2 patients. We designed a RCT (CUMPNS), with a 12-month follow-up, to assess the potential added value of PNfS, as a salvage therapy, in PSPS-T2 patients experiencing a “Failed SCS Syndrome” in the back pain component. Fourteen patients were included in this study and randomized into 2 groups (“SCS + PNfS” group/ Spinal Cord Stimulation (SCS) has been used for more than 50 years and is nowadays considered as an effective therapy to treat refractory chronic back and/or leg pain ,3,4,5,6 Three different scenarios can lead to what could be described as “Failed SCS Syndrome”, with persistent back pain component: (i) First scenario, despite SCS implantation, the patient has never experienced any substantial relief of his back pain; (ii) Second scenario, the patient was initially considered as a good SCS responder since his neuropathic leg component was addressed by neurostimulation and he was not suffering from any kind of backpain at the time of implantation, but he later developed a new pain onset at the back, which became progressively refractory to pain medical management and with no mechanical cause accessible to any etiological treatment, including further spine surgery. (iii) Third scenario, the patient has been previously implanted for back and leg pain, and was initially considered as a positive responder to SCS, but presented a loss of efficacy over time regarding the back pain component, a phenomenon which is often called ‘SCS tolerance’, and reported in up to 20–40% of patients .In this specific context, we can assume that Peripheral Nerve field Stimulation (PNfS) could be considered as salvage therapy for these patients. Indeed, Deer et al.  reportedn = 28) or a combination of PNfS+SCS (n = 74). The authors reported that without any statistical difference PNfS was as effective as the combination of PNfS+SCS to improve refractory pain relief. In another RCT, van Gorp et al. [Far from opposing these two techniques to one another, it has been suggested that for a given patient, these approaches could be combined to treat PSPS-T2 and even that a potential synergistic effect of SCS and PNfS could ensue. In this perspective, a prospective multicenter RCT  assessedp et al.  comparedWe hypothesized that considering PNfS as a salvage therapy, rather than any another alternative approach or other SCS stimulation paradigm, could offer new opportunities to optimally treat patients already implanted with SCS and suffering from long-term back pain. To validate this hypothesis, we designed a prospective, comparative, randomized controlled study aimed at evaluating the potential added value of PNfS as a means of relieving back pain in PSPS-T2 patients suffering from persistent low back pain despite previous SCS implantation and initial success.CUMPNS is a prospective, randomized controlled open-label monocentric study with a 12-month follow-up period, which was designed to assess the added value of implanting PNfS in PSPS-T2 patients previously implanted with SCS, who did not achieve adequate back pain relief after attempting to achieve optimal pain coverage and relief using all possible SCS programming modalities and optimized medical management.Patients were enrolled from the University Hospital of Poitiers between February 2013 and April 2017. Informed consent was obtained from all patients before any data collection. The study was conducted in accordance with the Declaration of Helsinki and complied with CONSORT guidelines for RCT, Good Clinical Practice guidelines and was approved by an ethics committee (CPP-Ouest-III and ANSM: 2012-A00532-41). The study is registered at clinicaltrials.gov (NCT02110888).Patients aged between 18 and 80 years were eligible when they were diagnosed as PSPS-T2   and for After approving the informed consent, the patient was given the study notebook in order to report baseline characteristics and questionnaires.Patients for whom back pain could be treated surgically  and patients presenting surgical, psychiatric, or anesthetic contraindication to be implanted with a PNfS device were not included. In line with our daily practice, patients who did not receive any Transcutaneous Electrical Nerve Stimulation (TENS) treatment within 6 months and who did not respond to this therapy were likewise excluded. Patients who presented progressive psychosis or history of severe psychosis that required hospitalization, active cancer pathologies, and women of childbearing age without effective contraception  were not included either.https://www.dirc-hugo-online.org/csonline, accessed on 31 August 2021) designed for the purpose of this trial, accessible to the investigators through a personal identifier and password. Neither the study medical staff, nor the patients were blinded to the randomization. In addition to SCS device implantation, patients in the intervention group (“SCS + PNfS”) were implanted with PNfS at baseline, whereas patients in the control group (“SCS only”) were implanted with SCS alone for 4 months and then implanted with a PNfS device at the 4-month visit , depending on the extent of back pain surface. Lead(s) was/were implanted surgically under general anesthesia in prone position. Lead(s) was/were positioned subcutaneously in accordance with back pain surface, documented by tactile informatics pain mapping interface the day before surgery, and was/were connected to an 8-contact extension, which was plugged on the preexisting internal pulse generator (IPG) used for SCS. Since available IPGs contained only two ports at the time of the study, in case the 16 channels  were previously used by SCS .TM software/Please see previous publications mentioned above for further details); functional capacity measured with the Oswestry Disability Index (ODI) score [Secondary outcomes, collected at baseline and each visit, included back pain relief assessed with VAS; back pain paresthesia coverage corresponding to the percentage of pain surface covered (or not) by stimulation-generated paresthesia (using N-3D-LI) score ; health-I) score ; psycholI) score ; medicatI) score .Based on our clinical experience and available data on PNfS use for back pain, we hypothesized that we could expect a difference of 40% between the groups, with a common standard deviation of 25%. With a power of 95% and a significance level of 5%, 19 patients would allow us to detect statistical significance between the groups. Because of the relatively limited follow-up duration before collection of the primary endpoint (3 months), no dropout was considered. Per following these calculations, the original plan was to include 20 patients (10 patients per group).Quantitative variables were described by their means and standard deviations (SD) or by their medians and interquartile range (IQR) depending on the skewness of their distribution. Qualitative variables were described by the number of subjects for each class and their percentage. Normality of all the data was verified using a Shapiro-Wilk test.The primary endpoint (percentage decrease of back pain surface from baseline to 3 months between groups) was compared using the non-parametric Mann-Whitney test. The secondary quantitative endpoints were compared between the two groups at 1-month and 3-month follow-up using the parametric Student test for low back pain surface, back pain VAS, variation in back pain coverage, ODI score, and HAD score, and the non-parametric Mann-Whitney test for the EQ-5D-3L index.Qualitative variables were compared between the groups using the Fisher’s exact test.Quantitative data evaluating the benefit of PNfS at 6 and 12 months after implantation were compared between baseline (inclusion visit for ”SCS + PNfS” group and 3-month visit for “SCS only” group) using a one-factor repeated measures ANOVA or the non-parametric Friedman ANOVA in case of non-normality. When the ANOVA yielded statistically significant results, pairwise comparisons between baseline and 6-month follow-up and 12-month follow-up were conducted using a paired Student test or Wilcoxon test in case of non-normality of the difference between visits. Qualitative variables were compared between visits using a McNemar test.In the safety analysis, rates of adverse events and severe adverse events were reported. p-value < 0.05 was considered as statistically significant. All tests were two-tailed. The analysis was conducted based on an ITT principle.A Statistical analyses were conducted using the R software .n = 6 in the “SCS + PNfS” group vs. n = 8 in the “SCS only” group). One patient withdrew his consent because he was not compliant with the randomization result. The final analyzed sample consisted in 6 patients in the SCS + PNfS group and 7 patients in the “SCS only” group. No patient was lost during the follow-up period. Baseline characteristics of the patients are presented in As developed in the statistical plan, 20 patients were planned to be included in the study initially, but due to prolonged recruitment challenges, we decided to terminate the study after having included 14 patients with complete follow-up. Early study termination was approved by the RCT Steering Committee. p = 0.012) (The percentage of back pain surface decreased significantly more in the ”SCS + PNfS” group compared to the “SCS only” group at 3 months (= 0.012) .The relative and absolute change in secondary and primary outcomes at 1-month and 3-month follow-up for each group are presented in p = 0.003), back pain paresthesia coverage (p = 0.017), back pain VAS (p = 0.001), ODI score (p = 0.034), but not for EQ-5D-3L (p = 0.40), HADS anxiety (p = 0.190) and depression (p = 0.40) scores, or MQS-III score (p = 0.07).At 1-month, decrease was significantly greater in the “PNfS+SCS” than the “SCS only” for the back pain surface (p <0.001). No difference was observed in the percentage of decrease of leg pain VAS at 3-month between groups (p = 0.4). At 3-months, back pain paresthesia coverage increase was significantly greater in the “SCS + PNfS” compared to the “SCS only” (p = 0.016). At-3 months, our results did not show any significant difference between “SCS + PNfS” and “SCS only” for the ODI (p = 0.07), EQ-5D-3L (p = 0.18), HADS depression (p = 0.8) and anxiety (p = 0.7), or MQS-III score (p = 0.07).Pain VAS at 3-month follow-up was significantly greater in the “SCS + PNfS” compared to the “SCS only” group (The mean back pain surface and back pain VAS at baseline and at 1 and 3-month follow-up for the two groups are presented in p = 0.03), back pain VAS (p = 0.03) and ODI (p = 0.04), but not in EQ-5D-3L (p = 0.06), HADS depression score (p = 0.39) and HADS anxiety score (p = 0.37). At 1-month, no significant changes were found for the “SCS only” group. At 3-month follow-up, we found a significant change for the “SCS + PNfS” group in back pain surface (p = 0.01) and back pain VAS (p = 0.03) but not in EQ-5D-3L (p = 0.17), HADS depression score (p = 0.28) and HADS anxiety score (p = 0.78). At 3-months, no significant changes were found for the “SCS only” group.We found significant change between baseline and 1-month follow-up for the “SCS + PNfS” group in back pain surface (p = 0.015). Paired comparisons showed that back pain surface significantly decreased at 6-month follow-up after PNfS implantation (p = 0.013). The significant decrease in back pain surface observed at 6 months did not persist at 12 months (p = 0.27). For this analysis, the data of the two groups were pooled. The mean differences and paired comparisons for all outcomes are presented in p < 0.0001). In the paired comparisons, we found a significant difference of back pain VAS between baseline and 6 months (p = 0.0003) and 12 months (p = 0.001) following PNfS implantation. Time effect of PNfS on leg pain VAS score was not significant (p = 0.7).Repeated measures ANOVA analysis showed a main effect of time of PNfS on back pain VAS (p = 0.001). The ODI score showed a significant decrease at 6 months (p = 0.02) and 12 months (p = 0.03) after PNfS. Repeated measures ANOVA analysis showed a main effect of time of PNfS on ODI score (p = 0.03). The EQ-5D-3L score showed a significant increase between baseline and the 6-month (p = 0.017) but not between baseline and 12-month (p = 0.1) follow-up. Repeated measures ANOVA analysis showed a main effect of time effect of PNfS on HADS anxiety score (p = 0.006). Anxiety score showed a significant decrease 6 months (p = 0.03) and 12 months (p = 0.008) after PNfS implantation from baseline. Time effect of PNfS on HADS depression score was not significant (p = 0.5). Repeated measures ANOVA analysis showed a main effect of time of PNfS on EQ-5D-3L score score  were reported during the study of which 4 were severe. The most frequent AE was postoperative pain at the site of lead/IPG implantation (15.2%), followed by falling (12.1%) and early depletion of IPG battery (9.1%), fatigue induced by stimulation (6.1%), digestive disorders (6.1%), nausea with headache (3.0%), leakage and delayed healing in the left lumbar scar (3.0%), bursitis of the gluteus medius (3.0%), hematoma in the lumbar region (3.0%), displacement of the neurostimulation device (3.0%) and others AE such as allergy to TENS patch, unstable diabetes, anxiety, etc. (36.4%). No infection occurred and no patient required any explantation of the PNfS or SCS device during this study.Our study shows that PNfS added to SCS can significantly reduce back pain surface by more than 80% in comparison with SCS alone after 3 months in PSPS-T2 patients, already implanted with SCS and experiencing SCS failure to address their back pain component. Long-term follow-up (6 and 12 months) results also showed a significant decrease of pain intensity, a significant increase of back pain paresthesia coverage provided by the combination of PNfS and SCS, and a significant decrease of ODI and Anxiety scores.While SCS has shown some limitations in pain relief specifically for the back pain component in the past ,30, PNfSFrom PNfS, through Peripheral Nervous System, Dorsal Root Ganglion, SCS, Deep Brain Stimulation and Motor Cortex Stimulation, it appears that the selection of the appropriate target, all along the pain nociceptive transmission pathway, becomes more and more difficult as time goes by. Given this nebulosity, it would be artificial but useful to distinguish: (a) a central SCS approach, mainly targeting neuropathic pain components, affecting the periphery  from (b) a peripheral PNS/PNfS approach, mainly targeting mixed nociceptive and neuropathic pain components, affecting axial dermatomal distribution of the trunk (such as the back component in PSPS-T2 patients), which is characterized by a pain typology, which is rarely pure, often mixing neuropathic and mechanical features, insofar as this anatomical organization depends on axial architecture, centered on spine anatomy , and for which innervation depends on the posterior branches of the corresponding nerve roots, in opposition to (a) ,33,34,35It is well-established that radicular pain refers mainly to neuropathic pain, whereas the nature of back pain can be associated with neuropathic and/or mechanical pain. Our results suggest that the neuropathic pain component corresponding to the leg level could be adequately treated by SCS and it appeared legitimate, as SCS was failing to relieve pain in these PSPS patients, to try using PNfS for neuropathic/mechanical residual pain components localized at their back. The potential overlap between SCS and PNfS efficacy on the same patient has yet to be the subject of analysis and publication. In this context, we observed that patients experienced a substantial gain in function after PNfS implantation, associated with back pain coverage increase, back pain decrease and improvement in quality of life. In parallel, it is interesting to note that whereas all patients had a positive global DN4 neuropathic assessment at the time of SCS implantation and during their follow-up, only 8/13 patients had a specific back pain DN4 positive score, before additional PNfS implantation. Similar back pain relief was observed between patients with positive and negative back pain DN4, that clearly shows that SCS + PNfS appears to work not only on back pain neuropathic features, but also on mechanical aspects. The differential response on this potential partially mechanical back pain component is a strong argument for potential synergistic action of SCS + PNfS combination, especially when significant residual mechanical back pain occurs, and also a strong argument confirming that SCS alone is not working well on mechanical aspects , as largely suggested in the literature ,30.We would carefully hypothesize that PNfS, as peripheral nerve stimulation, implanted in front of paravertebral muscles, innervated fascia and aponeurosis, could have an electrical influence on proximal structures, and could play an indirect role as a spinal musculoskeletal system electronic booster, helping to regain function by improving muscular adaptation and to increase proprioceptive feedback coming from this complex musculature. This concept has been the subject of new developments in peripheral nerve stimulation, as published by Eldabe’s team ,38, and We could also hypothesize that PNfS could retrogradely influence other spinal structures, likewise innervated by the posterior distribution of the spinal nerves, which constitute the “electrical vehicle” transporting PNfS information towards the central nervous system, up to DRG and the Spinal Cord (SC) junction ,35. ThesInterestingly, echoing on the previous discussion, as a non-invasive tool, the TENS application can be placed on specific residual pain locations, eventually mechanical ones, in patients already implanted with SCS. This is desirable for two main reasons. First, it matters to try to recapture a therapeutical effect when SCS shows its limitations, and as a symptomatic treatment for this population, TENS is altogether non-invasive. However, patients are exposed to long-term skin allergy or discomfort ,41, decrAs illustrated on Despite its originality and robust methodology, this study presents some limitations.Up until now, only a few devices have allowed physicians to plug subcutaneous leads without substantial impact on SCS programming capacity. Indeed, the vast majority of IPGs comprise 2 ports to welcome 2 channels of stimulation, enabling management of one 8-contact cylindrical SCS lead and one 8-contact PNfS lead or two leads with 4 contacts. But in the event that a patient has already been implanted with a more sophisticated lead, whether a 16-contact cylindrical SCS lead or a surgical paddle lead, any attempt at implanting PNfS weaken the opportunities offered by the SCS device by reducing the number of available contacts to deliver the electrical current, and consequently restricting the number of programming capabilities. As detailed above, we were compelled to disconnect one channel in order to be able to plug in the PNfS devices used by most of our patients. While our results did not show any decrease of SCS efficacy on leg pain component after 12 months, we cannot rule out a potential loss of efficacy over time, which would necessitate finding a new spatial target(s) of stimulation localized under deliberately inactive contact of the initially implanted SCS lead. Long-term follow-up would thereby be necessary to determine the possible loss of efficacy over time. To prevent patient this occurrence, a new generation of IPGs has been specifically developed over recent years, adding two channels to support the use of two 8-contact PNfS leads if required. These IPGs represent a great opportunity to add PNfS without losing what SCS has accomplished for the patient and will avoid research bias in future studies, bias arising from inter-individual outcome variability due to technical limitations and variability.First, due to paresthesia generated under tonic stimulation, it was impossible to blind the SCS + PNfS combination. This was the price to pay to respect a RCT design with techniques combined on the same patient, in the context of a “salvage therapy” concept. Secondly, the patients assigned to the “SCS only” group might be susceptible to developing a waiting effect. However, this limitation could rather be considered as a potential strength of this study since patients were their own control and since it has been demonstrated that waiting effect in chronic pain patients can also impact negatively on patient outcome. In this scenario, our conclusions and the added value of PNfS would be reinforced.Our last study limitation arises from the sizable length of time since the initial design of this study in 2011, the challenging recruitment of patients between 2013 and 2017, and the confusion which appeared in the implantation community, exactly at the same time of this study. Indeed, after having spent four decades of SCS trying to find the best spatial neural target to stimulate ,53,54,55As a synthesis of our clinical experience and the research conducted over the last 10 years, we present two different algorithms built at a 10-year interval. The first algorithm  correspoIn 2021, given the new context brought about by recent changes in the paradigm of neurostimulation  on the back component, refractory to spatial and temporal retargeting that: (3) we would propose to add TENS to SCS as a predictive screening trial, of our potential CUMPNS approach, using the same modalities as those described above for . All algAdding PNfS to existing SCS in previously successfully implanted PSPS-T2 patients, when back pain component remains difficult or impossible to address despite multiple SCS reprogramming, appears promising as a salvage therapy. In this study, we were able to document patient improvement using objective quantitative measurements, and to correlate 3D back pain surface decrease to patient pain relief using multidimensional composite pain assessment tools. The place of PNfS, in the therapeutical armentorium should be discussed as a potential added-value to existing SCS but might benefit from further clarification, especially given the new temporal modalities, which can now be tried by simple reprogramming and/or connecting to an adapter, depending on implanted devices and patient preference. These various strategies appear as promising as their goal is noble: pushing back the technological limitations to be able to convert SCS failure into new success. However, these new insights need robust studies to document clear added-value and establish legitimacy for the novel modalities.


There are large variations in symptoms and prognostic factors among patients sharing the same musculoskeletal (MSK) diagnosis, making traditional diagnostic labelling not very helpful in informing treatment or prognosis. Recently, we identified five MSK phenotypes across common MSK pain locations through latent class analysis (LCA). The aim of this study was to explore the one-year recovery trajectories for pain and functional limitations in the phenotypes and describe these in relation to the course of traditional diagnostic MSK groups.We conducted a longitudinal observational study of 147 patients with neck, back, shoulder or complex pain in primary health care physiotherapy. Data on pain intensity and function were collected at baseline (week 0) and 1, 2, 3, 4, 6, 8, 12, 26 and 52 weeks of follow up using web-based questionnaires and mobile text messages. Recovery trajectories were described separately for the traditional diagnostic MSK groups based on pain location and the same patients categorized in phenotype groups based on prognostic factors shared among the MSK diagnostic groups.There was a general improvement in function throughout the year of follow-up for the MSK groups, while there was a more modest decrease for pain intensity. The MSK diagnoses were dispersed across all five phenotypes, where the phenotypes showed clearly different trajectories for recovery and course of symptoms over 12 months follow-up. This variation was not captured by the single trajectory for site specific MSK diagnoses.Prognostic subgrouping revealed more diverse patterns in pain and function recovery over 1 year than observed in the same patients classified by traditional diagnostic groups and may better reflect the diversity in recovery of common MSK disorders.The online version contains supplementary material available at 10.1186/s12891-021-04332-3. It is generally accepted that the majority of patients with common musculoskeletal (MSK) pain disorders have non-specific symptoms without clear pathogenesis , 2. TradThe multiplicity of biological, psychological, and social factors often seen in patients with MSK complaints challenges the idea of selecting treatment based on diagnosis or site of pain alone . TraditiWe recently identified five MSK phenotypes across common non-specific MSK complaints based on generic prognostic factors in MSK pain conditions . The pheThis longitudinal study used data from a large observational study in Norwegian primary health care physiotherapy (FYSIOPRIM) designed to describe patients, treatment and outcome in the sector as a whole . For thewww.sms-track.com).Data was collected at 10 time-points: baseline  and at 1, 2, 3, 4, 6, 8, 12, 26 and 52 weeks after baseline. Participants answered web-based questionnaires at baseline (week 0), 12, 26 and 52 weeks, while questions were sent by mobile text messages (SMS) at weeks 1, 2, 3, 4, 6 and 8. In addition, they answered some questions in collaboration with the physiotherapist at baseline and 12 weeks of follow-up. The patients received a reminder if they did not fill out the questionnaires. The software for the SMS data collection was provided by SMS-Track ApS, Denmark , high school, up to 4 years of higher education and more than 4 years of higher education.Pain intensity was assessed with the question “How would you rate the pain that you have had during the past week”, rated on a numeric rating scale from 0 (no pain) to 10 (as bad as it could be) . FunctioOther variables registered by questionnaires at baseline was number of pain locations (up to 10 marked on a body chart) , pain duSample size calculation was not performed for this study as we utilized previously collected data to explore and describe the clinical course and prognosis.In addition to the MSK diagnosis groups, participants were classified into five different phenotypes based on LCA; developed and validated in a previous study . To deriLinear mixed models were used to estimate mean scores for pain and function (PSFS) at the different time-points. The models were adjusted for age, sex, and education, and stratified for MSK diagnosis and LCA phenotypes. These models were also used to estimate change in pain and PSFS scores at the different time-points. Percentage of participants that recovered was calculated at the different time-points, both for the diagnosis groups and the LCA phenotypes. Recovery was defined as a pain score of 3 or less and/or a PSFS score of 8 or more .The analyses were done using STATA 14 .Recruitment of study participants and follow-up rates are given i Fig. Recovery trajectories for the MSK diagnoses and phenotypes based on the linear mixed models are shown in Fig. The courses of pain intensity and function showed different trajectories for the five LCA phenotypes and appeared visually more dispersed across the phenotype classes than the MSK diagnoses Fig. b, d. TheFigure Recovery in the phenotype classes showed an orderly and clearly decreasing proportion of recovered patients from LCA class 1 to 5 Fig. . PatientParticipants with missing information at 52 weeks of follow-up were somewhat younger (mean age 43 [SD 15] vs 47 [SD 16]) and more likely to be men (33% vs 22%) than those responding. Baseline scores for pain intensity and function were similar for those responding and those not responding . Pain duration, education level and distribution between the LCA classes were also similar between those responding and not, while the diagnoses varied a bit. Participants not responding had to a larger degree neck pain (38% vs 19%) and less back pain (14% vs 27%) and complex pain (15% vs 22%) than those responding.We explored one-year clinical course and recovery trajectories for function and pain in patients seeking primary care physiotherapy for common MSK complaints. All patients were classified by their phenotype (prognostic factors) as well as their MSK diagnosis (pain location). A general improvement in function was observed throughout the year of follow-up for the MSK groups, with smaller changes in pain intensity. Noticeably, we found that within each MSK diagnostic group , the patients were spread across all phenotype classes. Expressing course and recovery trajectories by diagnosis did not reflect the actual variation in prognosis within the diagnostic groups. The phenotype classes showed a clearly decreasing rate of recovery from class 1 to class 5.The variation in improvement between the prognostic subgroups is in line with previous research demonstrating large differences in recovery patterns within the same diagnostic group, like low back pain and neck pain –24. RelaPatients in the MSK groups were distributed throughout all five phenotype classes, except for shoulder pain patients who were not represented in phenotype class 5. The MSK diagnoses neck, shoulder and low back pain showed similar dispersion across the five phenotype classes, although the majority were clustered in the lower three phenotype classes. Patients with complex pain were mainly clustered in phenotype class 4 and 5, with low recovery rates, but surprisingly, 15% of the patients were classified in phenotype class 1 and 2 with the highest recovery rates. Contrary, while most neck pain patients were classified in the lower three phenotype classes with the highest recovery rates, 33% of the patients were classified in phenotype class 4 and 5 with the lowest recovery rates. This underscores that large variations in recovery rates exist among individuals within the same MSK group, and that on the individual level, phenotyping will provide higher precision on likely course. This information is important in clinical practice when setting up achievable goals, realistic timeframes and addressing the patients’ expectations. For patients with phenotypes with a less positive course therapists could, instead of focusing on pain location and intensity only, include a broader aspect of factors of importance for recovery early on, e.g., active coping for restoring function and activity despite pain. In addition, information about phenotypes could inform the clinician about expected amount of resources needed for treatment.In compliance with previous studies , 27–29, Drawing attention to prognostic factors in musculoskeletal pain research is not new. We acknowledge that prior research has pointed out several important prognostic factors in MSK pain conditions –32, and For interpretation of the different phenotypes we refer to our previous study . In summOne strength of this study was the repeated collection of data for pain and function from baseline and up to 52 weeks. There are also some limitations. Firstly, function is difficult to measure. A strength of the PSFS is that patients could report on functional activities that were important for them to improve. But this also means that the type of functional activities reported varied between patients, and that the scores could be similar between patients despite very different functional activities. Nevertheless, the PSFS have shown to be a sensitive measure of change . FurtherClassifying MSK patients in prognostic phenotypes rather than traditional diagnostic groups was superior in reflecting patient variation in clinical course and recovery among patients with common MSK pain complaints. For clinical practice it may be more informative to subclassify patients according to prognostic factors rather than site-specific MSK diagnostic groups, as prognostic phenotyping provided more precise information of individual patients’ potential for recovery. Future studies should evaluate stratified treatment based on the prognostic phenotype classes.Additional file 1:Online Table 1. Estimated mean change in Patient specific functional scale (PSFS) from baseline. Online Table 2. Estimated mean change in pain from baseline.


Previous studies have demonstrated the efficacy of duloxetine in reducing postoperative pain and opioid consumption. However, the effect of duloxetine on total hip arthroplasty (THA) remains unclear. The objective of this study was to assess the efficacy of oral duloxetine in THA.We enrolled 96 patients in this randomized controlled trial. These patients were randomized  to either the duloxetine group or the placebo group and received daily doses of 60 mg duloxetine or placebo, respectively, from 2 d pre-operation to 14 d after surgery. The primary outcome was pain severity upon movement measured by a visual analogue scale (VAS). The secondary outcomes included VAS scores for resting pain, morphine consumption, Harris Hip Score, patient satisfaction at discharge, length of postoperative hospital stay, and adverse events.p < 0.05) while none of the differences met the minimum clinically important difference (MCID). Moreover, patients in the duloxetine group performed better in terms of resting pain (in 3 weeks after surgery), morphine requirements, and satisfaction level at discharge . There was no difference between groups in the prevalence of adverse events.Patients in the duloxetine group had significantly lower pain severity scores upon movement within 3 postoperative weeks (Although it did not result in a clinically meaning reduction in pain after total hip arthroplasty, perioperative administration of 60 mg of duloxetine daily significantly alleviated pain in the postoperative 3 weeks and morphine requirements during the postoperative 48 h. Therefore, duloxetine still shows promise in optimizing the multimodal pain-management protocols in total hip arthroplasty.ChiCTR2000033606, 06/06/2020.Chinese Clinical Trial Registry,  Total hip arthroplasty (THA) is a common surgical procedure used to successfully, economically, and safely treat end-stage joint diseases that may cause deformities, lower the quality of life, and lead to bodily dysfunction . DespiteApproximately 7 to 23% of THA patients suffer postoperative pain, which is one of the most significant unfavorable outcomes related to this procedure . PostopeSevere postoperative pain exacerbates opioid usage and subsequent opioid-related deaths . In 2017Duloxetine  is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), approved by the Food and Drug Administration (FDA) for the treatment of depression, generalized anxiety disorder, and chronic musculoskeletal pain  , 12. DulHowever, as far as we know, all previous studies investigating the effects of duloxetine on pain following arthroplasty are focused on total knee arthroplasty (TKA) , 14, 15.A prospective study, in the form of a single-center , randomized, double-blinded, parallel-arm, placebo-controlled clinical trial, was conducted. In this study, we enrolled 153 patients who were scheduled for THA from June 2020 to September 2020. The study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University  and registered at the Chinese Clinical Trial Registry . Informed consent and research authorizations were obtained from all participants. The research report met unified clinical trial reporting standards and conformed with the Declaration of Helsinki .Eligible patients who were over 18 years of age; classified under American Society of Anesthesiologists (ASA) status I, II, or III; and scheduled to undergo primary THA for end-stage hip joint diseases, were screened using the Hamilton Depression Scale (HAMD) and the Hamilton Anxiety Scale (HAMA). Subjects whose HAMD and HAMA scores were both < 7 were included. The exclusion criteria were as follows: a known allergy to any of the studied drugs, previous exposure to SNRIs or selective serotonin reuptake inhibitors; known psychiatric disorders; alcohol or opioid abuse; acute infections of the hip joint; recent treatment for malignant diseases; major previous ipsilateral hip arthroplasty or open surgery; peripheral or central nerve impairment; cognitive dysfunction; history of peptic ulcers or bleeding tendency; impaired liver and/or renal function; and poor physical condition indicating the lack of ability to tolerate surgery.Sample size estimation was determined based on previous studies , 17. A sParticipants were randomized  to either the duloxetine group or the placebo group. Randomization was concealed from researchers as well as from the patients, by way of sealed envelopes delivered following hospitalization. A sealed, opaque envelope, containing the randomized grouping plan was prepared in advance. After an eligible patient was assigned a sickbed and excluded from surgical contraindications, an independent researcher opened the randomized envelope in the order in which the patients were enrolled to determine the grouping of that patient. Neither the participants nor the primary investigator was aware of the grouping status until the data analysis stage at the end of the study. The hospital pharmacy prepared two types of indistinguishable capsules containing either 60 mg of duloxetine or a placebo (starch) for daily oral administration starting from 2 d pre-surgeryto 14 d post-surgery. Surgery was performed by the same senior doctor, an experienced surgeon who had performed over 300 THA annually. All participants accepted a multimodal and standardized analgesic strategy. From preoperative day 2 to the day before surgery, every patient was given celecoxib 200 mg twice a day (one dose after breakfast and one dose after dinner) for preemptive analgesia. During the operation, all patients received general anesthesia, which was composed of an induction of sufentanil 0.5 μg/kg, midazolam 0.04 mg/kg, propofol 1–2 mg/kg and cistracurium 2 μg/kg intravenously, and a following continuous intravenous infusion of 0.1–0.3 μg/(kg•min) of remifentanil, 2–5 mg/(kg•h) of propofol and inhalation of sevoflurane to maintain anesthesia. Besides, all patients were treated with an 80 mL periarticular injection of 0.25% ropivacaine for local infiltration analgesia. Since postoperative day 1, every patient restarted oral administration of celecoxib (200 mg twice a day) until 2 weeks after the surgery. When acute pain was unbearable or VAS was > 6, morphine (5 mg intravenously) was used as a rescue analgesic . In the The pain severity score upon movement  was considered as the primary outcome, because movement-evoked pain during the postoperative period is more severe, more frequent, and exerts a greater influence on postoperative functional rehabilitation compared with pain at rest . Secondap < 0.05.All data management and statistical analyses were conducted using IBM, SPSS version 22.0 software. Whereas the independent t-test was used to analyze differences between continuous variables, such as body mass index (BMI) and age, the chi-square test or Fisher’s exact test was used to analyze categorical variables. The significance level was set at p > 0.05).A total of 153 patients with end-stage joint diseases were scheduled to undergo a primary unilateral THA procedure during the recruitment period (June 2020 to September 2020) at our department. Among these 153 patients, 49 did not satisfy the inclusion criteria and 8 declined to participate in the study. Thus, 96 eligible patients were included in the study. These patients were randomly assigned to either the duloxetine group or the placebo group. Specific information regarding patient flow is plotted . However, none of the between-group differences exceeds the MCID, and there was no significant difference between the pain severity scores upon movement in patients of the duloxetine and placebo groups after 3 months of surgery.The pain severity scores upon movement within the 3 postoperative weeks in patients in the duloxetine group were significantly lower compared to those in the placebo group (Table p < 0.05). There were no significant differences between the VAS scores for resting pain of the 2 groups after 3 months of surgery. Postoperative morphine consumption and HSS until 24 h, 72 h, and 1w after surgery are shown in Table p = 0.011). No significant difference was observed between the lengths of postoperative hospital stay between the two groups. There was no significant difference in the adverse event between groups (Table p > 0.05).Similar results were obtained for resting pain, wherein the post-operative movement-evoked pain level in patients of the duloxetine group was significantly lower than those in the placebo group until postoperative week 3 , and the difference for the VAS score of 1.9 offered improved pain control [In this study, we found that perioperative administration of duloxetine effectively relieved movement-evoked pain and resting pain 3 weeks post-surgery. These results are partially substantiated by a previously conducted randomized controlled trial, in which 80 patients scheduled for TKA, who were treated with duloxetine, achieved a better analgesic effect during the postoperative period from 2 to 12 weeks , 15, 28. control .The findings of our study indicated that duloxetine reduced morphine consumption within 1 w post-THA. Two previous randomized controlled trials that enrolled 106 and 50 participants, respectively, also showed similar results , 15. In The decision to use 60 mg of duloxetine as the daily dose in our study was based on the reports of previous studies , 15, 28.Our study had a few limitations. First, the 3-month follow-up time may obscure the long-term safety of duloxetine. However, the biological half-life of duloxetine is approximately 10–12 h, and maximum plasma concentration is attained approximately 6 h after dosing . PatientIn conclusion, the perioperative daily administration of 60 mg duloxetine to patients undergoing primary unilateral total hip arthroplasty alleviated movement-evoked pain 3 weeks post-surgery, although it did not result in a clinically meaning reduction in postoperative pain. Duloxetine also alleviated resting pain within 3 postoperative weeks, reduced morphine requirements following surgery, and improved satisfaction levels at discharge, without increasing the incidence of adverse events. Considering the positive results of the current study, it may be concluded that duloxetine shows potential as a novel therapeutic agent and could likely be used to optimize multimodal pain management protocols in total hip arthroplasty.


Background and objectives: To assess the pain relief of bipolar RFA combined or not with vertebroplasty in patients with painful vertebral metastases and to evaluate the feasibility and tolerance of the RFA procedure performed under local anesthesia. Materials and Methods: 25 patients  with refractory painful vertebral metastasis were consecutively included between 2012 and 2019. A total of 29 radiofrequency ablation (RFA) procedures were performed under CT guidance, local anesthesia and nitrous oxide inhalation, including 16 procedures combined with vertebroplasty for bone consolidation purposes. Pain efficacy was clinically evaluated using the visual analogue scale (VAS) at day 1, 1 month, 3 months, 6 months and 12 months, and the tolerance of the procedure was evaluated. Results: Procedure tolerance was graded as either not painful or tolerable in 97% of cases. Follow-up postprocedure mean VAS score decrease was 74% at day 1: 6.6 (p < 0.001), 79% at 1 month: 6.6 (p < 0.001), 79% at 3 months: 6.5 (p < 0.001), 77% at 6 months, and 79% at 12 months: 6.6 (p < 0.001). Conclusions: Bipolar RFA, with or without combined vertebroplasty, appears to be an effective and reliable technique for the treatment of refractory vertebral metastases in patients in the palliative care setting. It is a feasible procedure under local anesthesia which is well tolerated by patients therefore allowing to broaden the indications of such procedures. Field of study: interventional radiology. Bone is one of the most common metastatic sites, and 50% of pain experienced by cancer patients originates from bone metastases ,2,3,4. ADue to the short life expectancy of affected patients, treatment regimens are most often palliative rather than curative. Therefore, quick pain relief has become a priority in these patients suffering from refractory bone pain.Several conventional treatment options have been described including opioids, hormone therapy, chemotherapy, radiotherapy and surgery, which all have side effects and contraindications. Radiotherapy remains the gold standard, but up to 20% of patients are nonresponders, and the reported maximum benefit is obtained with a delay of 5–20 weeks after completion of treatment ,9,10.In these two past decades, interventional percutaneous image-guided techniques have emerged with satisfactory results in the management of vertebral metastasis such as vertebroplasty ,12, radiMost studies to date have assessed the effectiveness and safety of RFA with the use RF monopolar systems  and were mainly performed either under general anesthesia or conscious sedation ,19,20.The objective of this study was to assess the pain relief of bipolar RFA combined or not with vertebroplasty in patients with painful vertebral metastases and to evaluate the feasibility and tolerance of the RFA procedures performed under local anesthesia and nitrous oxide ventilation.Twenty-five consecutive patients  were recruited between 2012 and 2019. All included patients presented painful spinal metastases refractory to all previously attempted conventional therapies, including opioids and radiotherapy, and the decision to undergo ablation was decided in a multidisciplinary meeting. The decision to perform adjunct vertebroplasty was made based on the location, type and extent of the lesion, and the Kostuik score  was usedExclusion criteria were as follows: patients with tolerable pain (VAS < 5), locoregional or systemic infection at the time of inclusion, coagulation disorders.Procedures were performed during a short hospital stay. CT guidance was used for targeting lesions.Needle pathway local anesthetic injection (a mixture of fast- and slow-acting anesthetic (lidocaine hydrochloride 1% (1/3) and ropivacaine hydrochloride 0.25% (2/3): from skin entry point to tumor, associated to an intratumoral block with the same mixture. Quantities of injectant depended on both tumor size and patient’s tolerance, without exceeding dose limits .Inhalation of nitrous oxide throughout the procedure.IV administration of paracetamol (1 g) started 5 min prior to procedure. IV injection of nalbuphin (20 mg) could be added on demand in case of persisting pain.Strict local anesthetic protocol was followed as previsoulsy described  and inclStrict aseptic technique was assured during the procedure. From one to two bipolar RF needles  were introduced coaxially through a 13 gauge biopsy needle . Technical success was defined as the ability to successfully place the RFA probe in the center of the lesion in case of a unique lesion, and at least 1.5 cm distance between probes in case of several needles, and to perform RFA . DuratioMultiple RFA cycles and/or multiple needle approaches were performed for large lesions (>4 cm) see . In caseVisual analogue scale scoring was used to assess procedure effectiveness: before procedure, at day 1, 1st month, 3rd month, 6th month, and 12th month. A 50% pain decrease at one month on VAS was considered as a positive response. Intraprocedural pain and tolerance to the procedure was measured on a 0–2 scale: 0 = no pain, 1 = tolerable pain, 2 = intolerable pain.p < 0.05 was considered significant.Continuous variables were expressed as mean +/− SD. The Shapiro–Wilk test was used to determine whether variables came from a normally distributed population. A Friedmann’s variance analysis and Student’s t test on paired samples were performed between the groups. A value of The technical success rate was 100%. The average duration RFA procedure was 23 +/− 9.9 min. A thermocouple was used in 17 cases, 12 cases of radicular nerve monitoring, and 5 cases of epidural monitoring. Multiples needles were performed in: seven cases with two needles and two cases with three needles. No clinical complications were noted during or after procedure. Analysis of postprocedural CT did not reveal the immediate procedure related complications.Vertebroplasty was performed in seven cases of pathological fracture and nine cases of fracture prevention. In these cases of vertebroplasty, 11 of 16 postprocedural CT showed minor cement leakage with no clinical expression .Constant oral contact was made with the patient during the whole procedure especially during the ablation phase, and the patient was told to alert, in case of pain radiation in the legs. Moreover, every minute, sensitive and motor testing was performed in order to ensure the lack of neurological damage.The per procedure tolerance was rated as follows: 0 for 16 procedures , 1 for 12  and 2 for 1 procedure .One patient was lost to follow up at 12 months. Mean VAS before the procedure was 8.4/10. A significant reduction in pain was obtained in 24/29 (83%) procedures at 1 month. Details are summarized in Therapeutic failures on pain palliation were observed in three procedures with an advanced stage of disease. In each case, lesions were very large with significant prevertebral soft tissue and foraminal invasion. In five other patients, a pain decrease of less than 50% was noted: at 1 month (one patient), at 3 months (two patients), at 6 months (two patients) and at 1 year (two patients). Significant tumor lesion growth or new lesions were observed in these patients.Many therapeutic options are available for patient suffering from spinal metastasis.. Specific medication may lead to well-known side effects, gastrointestinal , neurological  or intolerance. Chemotherapy has systemic toxic effects and a delayed action. External beam radiotherapy remains the treatment of choice for the palliative treatment of metastatic bone tumors but is not effective in 20–30% cases (10 patients in our series). Furthermore, its analgesic effect is delayed 12–20 weeks . SurgeryThe results of our study are consistent with those of the recent literature . Indeed,The anxiolytic effect of visual, auditory and tactile distraction techniques was constantly performed by operators and technicians, as already demonstrated in other surgical fields , which iFinally, the absence of general anesthesia may broaden indications to patients for which general anesthesia may be contraindicated due to a frail condition. This is probably the most important added value of local anesthesia as it has been shown that palliative radiotherapy should be performed in patients with a short life expectancy . TherefoOur study however has several limitations. The results are retrospective based on consultation data. The study relies on a small study sample, with a lack of uniformity of the included lesions (size and type). Finally, no data were available on pain therapy modifications after the procedure, which may have introduced an outcome bias.Bipolar RFA is a safe and effective treatment of painful refractory vertebral metastases in patients in palliative care. It is well tolerated under local anesthesia with nitrous oxide inhalation. This approach allows for a regular intraprocedural clinical examination and may help avoid possible surrounding neural damage, such as cord injury. Immediate pain relief is observed, improving the patient’s quality of live, which is desirable in patients with a limited life expectancy. Such results are a priority in pain palliation patients.Further studies comparing RF alone versus RF combined with vertebroplasty are needed to establish the benefit of a combining RF and vertebroplasty.


In an anatomic shoulder replacement (aTSR) good results have been reported with the use of a stemless humeral prosthesis. In vitro a ceramic articulation with polyethylene has been shown to produce less polyethylene wear particles than with metal. This study aims to evaluate clinical and radiographic results of a stemless aTSR with a ceramic head articulating with a polyethylene glenoid component, with mid-term follow-up.n = 92) in this prospective study had an aTSR utilizing a stemless humeral component with a ceramic head and a cemented double pegged cemented polyethylene glenoid component for glenohumeral osteoarthritis. Pre- and postoperative clinical evaluations at 2 years were performed using the ASES score, Constant score, SPADI score, DASH score, VAS pain score, patient satisfaction and range of motion. There was a 5-year evaluation of SPADI, ASES, pain, and satisfaction, plus radiographic assessment of glenoid component radiolucent lines and humeral osteolysis.All patients (p < 0.001). Further improvement was identified with the ASES from 41.6 to 94.3, the SPADI from 62.9 to 4.3, VAS pain from 5.6 to 0.4 (0–10), and satisfaction levels were at 96%. Sixty-two cases had no glenoid radiolucent lines with a maximum Lazarus score of 2 in one patient. Constant scores, available up to 2 years, improved significantly from 30.3 to 77.9 (p < 0.001). There was one case that required revision for glenoid loosening.Seventy-four cases (68.1 ± 7.1 years) had a five-year follow-up and demonstrated active elevation improvement from 91.3° preoperatively to 151.1° . If symptomatic glenohumeral osteoarthritis of the shoulder fails to respond to conservative measures, and patients have an intact functioning rotator cuff, they could be suitable for an anatomic total shoulder replacement .There has been development over the past decade in anatomic components for both the humerus and the glenoid , 3. The The prosthesis used in the current study is the most common elective stemless aTSR used in the UK . A 2-yeaThe study was a prospective clinical, multicentre study with a 5-year follow-up.The current study is a continuation of the 2-year follow-up study published in 2014, with greater numbers and longer follow up . The priFive senior orthopaedic surgeons performed the surgical procedures in this study. All shoulders were replaced with an anatomic TSR, the stemless Affinis® Short  humeral component and a double pegged cemented all polyethylene glenoid component made of standard, not cross-linked, polyethylene.The study received ethics approval from the Monash University  and was registered at the Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613001183774. The study was performed in accordance with the latest version of the Declaration of Helsinki.Consecutive patients with advanced primary osteoarthritis of the glenohumeral joint and an intact rotator cuff in a patient who has failed conservative measures and considered their symptoms were severe enough to have a replacement were eligible to be enrolled in this study. The exclusion criteria were age over 80 years, inability to replace the glenoid, severe osteoporosis, rotator cuff tear, post fracture/traumatic osteoarthritis or proximal humeral deformity, abnormal neurology, or inability to comply with the study requirements.The rotator cuff was assessed with a clinical examination. Additionally, radiological imaging including CT scans were obtained for all cases, which assisted assessing the rotator cuff. If there remained any doubt, a MRI scan was organized to confirm the rotator cuff integrity. If the rotator cuff was not intact, the patient was excluded. Glenoid assessment was carried out preoperatively with a CT scan in regards to version, bone loss and glenoid type. If the morphology of the glenoid was judged by the surgeon unsuitable for adequate implantation of the double pegged cemented all polyethylene glenoid component, the patient was deemed unsuitable for implantation of the stemless Affinis® Short  and hence excluded from the study. Osteoporosis assessment was carried out with pre-operative radiological imaging and intraoperatively after removal of the humeral head. However, there were no patients excluded from implantation of this prosthesis related to pre-operative radiology or intraoperative judgement of osteoporosis.The operations were performed in all cases through a deltopectoral approach with tenodesis of the biceps tendon and mobilization of the subscapularis with either a tenotomy or a lesser tuberosity osteotomy. Capsular release was then performed. The humeral head was resected anatomically using the provided guides .0 retroversion and > 80% glenoid component seating. The appropriate size glenoid prosthesis was then cemented into position with pressure injected cement. The proximal humerus was then prepared. After trial implantation the definitive stemless humeral prosthesis and ceramic head was then impacted into position. Finally, the shoulder was reduced and the subscapularis reattached with a solid transosseous suture repair. Movement range and stability of the replacement were then recorded. The deltopectoral interval and skin were then closed.Glenoid preparation was then performed in a standard manner for the Affinis® double pegged glenoid prosthesis. Glenoid reaming was planned visually by the surgeon using the patient’s preoperative computer tomography (CT) scan. The aim in a glenoid with retroversion  was to have less than 10All patients used a sling for 5 to 6 weeks outdoors. A physiotherapy supervised passive motion home exercise program commenced on the first postoperative day. Active ROM was started slowly after 10 weeks, but resisted subscapularis strengthening was deferred until 3 months postoperatively.Pre-operatively patients had the American shoulder and elbow surgeons (ASES) score , ConstanIf any patient, when contacted post operatively, reported an increase in pain or decreased satisfaction, or on X-Ray had a Lazarus score over 1, clinical re-evaluation was organized to elucidate the source of the pain or dissatisfaction. This occurred in 12 patients. Clinical parameters and PROMs including CS score, ASES, SPADI, DASH VAS and ROM were re-assessed after any treatment. Findings were then documented as the patient’s latest score.Eleven patients were re-assessed at 5 years and included in the 5 year cohort. Seven had received treatment for AC joint pain and 4 for neck pain or chronic pain syndrome. One patient underwent a revision at 4 years for glenoid loosening. This adverse event related to the medical product was reported to the product company and the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR).Radiological assessment occurred at 1-day post-surgery, 12 weeks, and yearly thereafter to minimum 5 years. For humeral and glenoid sided assessment, radiographs were taken according to a standardized protocol in multiple planes . Radiographs were assessed independently and separately by two orthopaedic surgeons (MJKS and SH) not involved in the patient surgeries. Disagreements were referred to a third independent experienced surgeon (HC) for final decision.A standard technique for the assessment of peri-humeral humeral component osteolysis, with assessment of five zones Fig. , was usewww.minitab.com)). Inter-rater reliability for radiograph assessment was evaluated using percentage agreement and Cohen’s kappa interpretation scales. In addition to the standard descriptive statistics of variables, both parametric  and non-parametric methods , were used to assess associations between variables. Non-parametric methods were mainly needed to deal with analyses involving the year 2 values of pain and patient satisfaction, as both of these variables were very highly skewed with a majority of values being 0 and 100%, respectively, but, for consistency, they were also used for all of preoperative to year 2 comparisons.The approach taken has been to consider the precision of the estimated probability of failure of the prosthesis over a specific period together with the possibility of recruiting the specified number of patients within a reasonable time (years). These considerations led to a sample size of about 80 being considered appropriate, and achievable. All analyses were conducted using the statistical package Minitab . State College, PA: Minitab, Inc. , 2 had developed cancer). Therefore 74 patients were available for evaluation at 5-year follow-up  patients available for assessment. Clinical scores  were assessed for 86 and radiologic evaluation on 89.Twelve patients, who reported a clinical deterioration post operatively or had a Lazarus of > 1, were clinically re-evaluated at 5 years with all PROMs, CS, ROM and the results rescored as the latest clinical assessment. In 11 of those 12 patients clinically, there was no evidence of pain related to the prosthesis and radiology confirmed this. Clinical assessment demonstrated that in 7 of the 11 patients the pain was related to the AC joint. In 3 of the 11 patients the pain was assessed as neck pain or chronic pain syndrome. One of the eleven patients had no pain or loss of movement but had a Lazarus score of 2. One patient of the twelve had a serious adverse event and required revision of the prosthesis because of glenoid loosening of the medical device.The progress of the patients and reasons for incomplete follow up in some are documented in Fig. p < 0.001) (Table p < 0.001) and satisfaction levels remained on average over 95% at the 5-year follow-up  out of 74 with a Lazarus score of 2 (≤ 2 mm around one peg only), 11 (14.9%), with a Lazarus score of one, leaving 62 (83.8%) with a zero score. The one patient with Lazarus score of 2 had a significant fall upwards boarding a train, with humeral pain and bruising and sternal injury more than 4 years after surgery. It is unclear whether this contributed in the increase of score from 1 on previous annual X-ray to 2 post fall. This score was stable at 5 years. There were no cases with a Lazarus score of 3 or 4.Radiological assessment of the humeral prosthesis demonstrated at the 5-year follow-up that there were no radiolucent lines identified around the humeral stem component for all zones Fig. . At 5 yep < 0.001)).No associations were found in the 5-year postoperative PROMs between age, gender, or arm dominance. Higher satisfaction levels with the aTSR were significantly correlated with lesser pain scores at the 5-year follow-up  with non-prosthesis related postoperative issues, and the one (1.08%) with issues involving the prosthesis, were identified and recorded Table . There wOf the other 4 cases (4.3%), one had Lazarus 2, but had no pain and good function. Three others (3.2%) had diffuse pain not related to the prosthesis, and were thought to have pain of neck origin, perhaps with a chronic pain problem.There was one cases (1.08%) requiring revision due to early glenoid loosening Table . After 3This 5-year mid-term follow-up evaluated clinical and radiographic results of this anatomic stemless total shoulder replacement demonstrated that 12 out of 74 cases had a minor radiolucency around the glenoid component (11 - Lazarus 1 and one - Lazarus 2) and significantly improved clinical scores at 5-year follow-up.n = 12) had slightly lower external rotation (ER) 40.3° ± 13.9° and active elevation (AE) 126.2° ± 28.5° than the presented cases of our current study , there were no radiolucent lines visible. Only one case (1.3%) had a Lazarus score of 2 (≤ 2 mm around one peg only), eleven patients (14.9%) had a Lazarus score of one, and only one of these eleven cases required revision for glenoid component loosening. Computer tomography can be more sensitive in assessing radiolucent lines around a cemented pegged glenoid component [The radiographic assessment of the glenoid component demonstrates excellent results after 5 years. In the majority of cases  of complete humeral radiolucent lines in one of the 3 humeral grading zones, including the critical zone, for their humeral stemless prosthesis type . There wIn a study of the same prosthesis as in this current study, Jordan et al. report the results in 279 patients . They haIn a previous study by Bell et al., a direct comparison of the same glenoid component as in the current study was examined in which the glenoid component articulated with a metal-head long-stem prosthesis in 39 shoulders versus the same ceramic stemless humeral prosthesis as in this current study in 23 shoulders . With thThe stemless concept enables improved positioning of the humeral component on the humerus, and also creates different stress on the humeral bone. The data by Mueller et al.  identifiIn the future, further reduction of osteolysis can potentially be achieved with other glenoid materials such as vitamin E-enhanced cross-linked polyethylene which has been shown in vitro to result in less polyethylene wear of the glenoid component . Such a A limitation of the study is that there is no control arm, such as the use of the same stem with a metal head. However, following the results of previous studies , 7, we cThis study demonstrates that a stemless aTSR with a ceramic head and pegged cemented polyethylene glenoid component resulted in at 5 year follow up overall good clinical scores, little osteolysis, and few complications.


Median hospital stay for both groups was 1.0 day. The pregabalin group had significantly lower consumption of total opioids during admission  compared to the control group  . Although pain scores in the treatment group (3.21 ± 2.03) were lower than in the control group (3.71 ± 2.95), the difference was not statistically significant . DISCUSSION/SIGNIFICANCE OF IMPACT: Based on the results, a one-time preoperative oral dose of pregabalin before orthognathic surgery in patients with cleft lip and palate reduced total opioid consumption during admission. However, there was no difference in length of stay or pain scores within the two groups. A single preemptive oral dose of pregabalin should be considered an effective adjunct to pain management protocols in patients undergoing orthognathic surgery.OBJECTIVES/GOALS: The current opioid epidemic has placed post-operative pain management under scrutiny. Limiting post-operative pain can decrease overall opioid usage in the recovery period, especially after orthognathic surgery. Several studies have illustrated the efficacy of pregabalin in decreasing postoperative pain and opioid usage in adults undergoing orthognathic surgery. We aim to study the effects of a single dose of preoperative pregabalin on postoperative pain and total opioid consumption after orthognathic surgery in individuals with cleft lip and palate. METHODS/STUDY POPULATION: This was a retrospective cohort study of consecutive patients who received Le Fort I midface advancement between June 2012 and July 2019 by one of two surgeons at a single institution. We took advantage of our institution’s implementation, beginning in 2016, of a one-time dose of preoperative pregabalin for LeFort I midface advancement. All patients had diagnosed cleft lip and palate. The treatment group received a one-time preoperative dose of pregabalin. The control group did not receive pregabalin. Total morphine milligram equivalents (MME) consumption was calculated by adding intraoperative opioid administration and postoperative opioid consumption during admission. Postoperative pain control during admission consisted of oral oxycodone and intravenous (IV) hydromorphone or morphine. Duration of hospitalization and pain intensity assessed with the numeric pain rating scale (0-10) were also recorded. The mean postoperative pain assessment scores during admission was calculated for each patient. The median of these individual mean pain assessment scores for each group was subsequently computed. RESULTS/ANTICIPATED RESULTS: Twenty-three patients  were included in this study; 12 patients received pregabalin . Mean age (years) at operation of the pregabalin (18.3 ± 1.9) and control groups (17.8 ± 1.9) were also equivalent (


Total hip arthroplasty (THA) is reported to be one of the most painful surgical procedures. Perioperative management and rehabilitation patterns are of great importance for the success of the procedure. The aim of this cohort study was the evaluation of function, mobilization and pain scores during the inpatient stay (6 days postoperatively) and 4 weeks after fast-track THA.A total of 102 consecutive patients were included in this retrospective cohort trial after minimally invasive cementless total hip arthroplasty under spinal anesthesia in a fast-track setup. The extent of mobilization under full-weight-bearing with crutches  and pain values using a numerical rating scale (NRS) were measured. Function was evaluated measuring the range of motion (ROM) and the ability of sitting on a chair, walking and personal hygiene. Furthermore, circumferences of thighs were measured to evaluate the extent of postoperative swelling. The widespread Harris Hip Score (HHS) was used to compare results pre- and 4 weeks postoperatively.p < 0.001), at rest (p < 0.001) and at night (p < 0.001). All patients were able to mobilize on the day of surgery. In addition, there was a significant improvement in independent activities within the first 6 days postoperatively: sitting on a chair (p < 0.001), walking (p < 0.001) and personal hygiene (p < 0.001). There was no significant difference between the measured preoperative and postoperative (day 6 after surgery) thigh circumferences above the knee joint. Compared to preoperatively, there was a significant (p < 0.001) improvement of the HHS 4 weeks after surgery. In 100% of the cases, the operation was reported to be successful and all of the treated patients would choose a fast-track setup again.Evaluation of pain scores in the postoperative course showed a constant decrease in the first postoperative week (days 1–6 postoperatively). The pain scores before surgery were significantly higher than surgery (day 6), during mobilization (Application of a fast-track scheme is effective regarding function and mobilization of patients. Low pain values and rapid improvement of walking distance confirms the success of the fast-track concept in the immediate postoperative course. Future prospective studies have to confirm the results comparing a conventional and a fast-track pathway. Fast-track total hip arthroplasty (THA) is a well-established concept including optimized logistics and evidence-based treatment options. Focusing on minimizing surgical stress and improved postoperative recovery leads to lower mortality and morbidity as well as high patient satisfaction . In geneIn the USA and most European countries more than 200 total hip arthroplasties are implanted per 100,000 inhabitants every year. Numbers of up to 300/100,000 were reported (in Germany) in November 2019, published by the Organization for Economic Co-operation and Development (OECD) –6. Less Furthermore, patients express concern about pain and dependence upon other persons during the postoperative and rehabilitation period after the surgical procedure . TherefoThe aim of this study was to evaluate the incidence and intensity of postoperative pain, the mobility and the function at the early and 4‑week follow-up after fast-track THA.In the present study, 102 consecutive patients were retrospectively evaluated. Inclusion criteria were all patients after primary cementless THA with spinal anesthesia within a newly established fast-track pathway. Exclusion criteria were the existence of chronic pain syndrome preoperatively, except the reported pain of the hip joint arthritis. Furthermore, intraoperative change to general anesthesia was an exclusion criterion in order to prevent possible bias by the anesthetic method used. The interventions were performed between mid 2018 and mid 2019 after a fast-track implementation phase in early 2018. The fast-track scheme was initially performed parallel to a conventional pathway in order to enable a smooth transition.General data (age and sex) were recorded as well as the ASA risk classification (American Society of Anesthesiologists). The fast-track scheme was performed as follows: preoperative multidisciplinary lecture and gait-training with crutches for all patients, pre-emptive NSAID  administration (etoricoxibe 90 mg once one hour before the intervention), minimally invasive anterolateral approach under spinal anesthesia (prilocaine 1% hyperbaric 4 ml = 80 mg and sufentanil 10 µg as standard), i.v. application of dexamethasone (8 mg), implantation of cementless hip arthroplasty components , use of local infiltration analgesia in the periacetabular and -femoral region as well as subcutaneous infiltration , administration of tranexamic acid , renunciation of suction drains, conventional wound closure stitching plus application of wound glue. A transparent wound dressing was applied. Full weight bearing was allowed and range of motion was not restricted. Mobilization started as soon as peripheral sensory and motoric skills were approved, usually 1–2 h after surgery. After cardiovascular stimulating and thrombosis prophylaxis exercises, first walking exercises with crutches were started under physiotherapeutic supervision. Target for the day of surgery was a walking distance of at least 50 m. Starting on postoperative day 1, a fast-track exercise circuit was used to extend exercise intensity; patients received additional physiotherapy twice a day. Physiotherapy included mobilization of the hip, muscle strengthening as well as thrombosis and pneumonia prophylaxis. The fast-track exercise circuit consisted of a walking course, various muscle strengthening exercises and tutorials to improve coordination. In addition, a mirror wall with a holding bar was used at the ward. Here, the patients were able to repeat the exercises several times a day, independently and with self-control, in order to reflect their gait pattern and correct possible errors themselves.A standardized pain management concept was applied regarding the WHO recommendations . At the In Germany, the direct discharge to a rehabilitation unit is usually planned after the 6th postoperative day. Upon discharge, patients had to be able to walk 100 m safely under full weight bearing, take stairs and take care of themselves independently.The patient’s independent activities per day in minutes , range of motion (in degrees) and the leg circumference (in centimeters) were evaluated preoperatively, on the day of surgery and from days one to six after the operation by specially trained physiotherapists. Range of motion was measured as passive and active range of motion: extension, flexion and abduction. A mean of active and passive range of motion was calculated per day for graphic representation. Furthermore, the maximum range of motion during the day was documented. The thigh circumference was measured 15 cm, 20 cm and 30 cm above the knee joint to objectify swelling, with regard to the method of the German employer’s liability insurance association. All these parameters allowed the study group to evaluate detailed information of mobilization and pain values in the immediate postoperative course during the first postoperative week.In addition, the Harris Hip Score (HHS)  was asseThe study was approved by the local ethics committee . The study was applied in accordance with the ethical standards of the 1975 Declaration of Helsinki.p-value < 0.05 was considered statistically significant.Statistical analysis was performed by using Excel . For descriptive analysis, absolute and relative frequencies or mean and standard deviation were stated. A t-test for paired samples was used for statistical evaluation. No imputation methods were used. A The cohort of 102 patients composed of 68 men (66.0%) and 35 women (34.0%) with an average age of 61.3 ± 10.9 years . None of the included 102 patients had a second surgical intervention due to a complication. The average duration of surgery was 63.6 (±11.9) min with a minimum of 44 min and a maximum of 110 min. Furthermore, 28.4% had an ASA score of one, 64.7% an ASA score of two and 6.9% an ASA score of three; none of the patients had a higher ASA score. The average ASA score was 1.8 (±0.6).p < 0.001, respectively).Fig. p = 0.5) and 6 days postoperatively (p = 0.5): Mean pain value for men was 6.3 ± 2.0 preoperatively and for women 6.4 ± 2.2, while it decreased to a mean pain value 6 days postoperatively for men (2 ± 1.6) and for women (2 ± 1.5).There was no significant difference regarding pain values between men and women preoperatively (p < 0.001) and passive abduction (p < 0.001). Active flexion (p = 0.9) and active abduction (p = 0.5) showed no significant difference.Fig. p = 0.34), 20 cm (p = 0.05) and 30 cm (p = 0.09) above the knee joint.Fig. p < 0.001, respectively). In Figs. Fig. p < 0.001) improvement in the Harris Hip Score (HHS) comparing preoperatively and four weeks after surgery (Table There was a significant (ry Table . In 100%p = 0.5) and 6 days postoperatively (p = 0.5). This finding is contrary to the results by Wiesenfeld-Hallin. Wiesenfeld-Hallin postulates that the male sex is less sensitive to pain than the female [In the study at hand, more men (66.0%) than women (34.0%) underwent total hip arthroplasty (THA). This observation correlates with the results of the 10 included studies (9936 cases) in the systematic review of Zhu et al. . Our stue female . Numeroue female –23. Othee female , the cauA major risk factor for the occurrence of joint disease is age in general. The prevalence of hip arthritis increases with age; in the 7th life decade it reaches a plateau . The aveThere are numerous studies demonstrating a highly significant decrease in NRS from preoperatively to 6 to 12 months after THA , 28. Witp < 0.001) and passive abduction (p < 0.001). Temporiti et al. [Bandholm et al.  attributi et al.  concludep < 0.001), go for a walk (p < 0.001) and personal hygiene (p < 0.001). On average, German men need 24.6 min and women 28.1 min in the bathroom [Klapwijk et al.  showed tbathroom . In addibathroom . This rep = 0.34), 20 cm (p = 0.05) and 30 cm (p = 0.09) above the knee joint. The fast-track setup without using wound drains with application of tranexamic acid and under early mobilization apparently did not lead to swelling or relevant hematoma. Unfortunately, no study evaluating pre- and postoperative thigh circumferences was found whose results could have been compared to ours. However, the measuring technique is widely spread.Bandholm et al.  describeWe demonstrated that patients can get up, get dressed and do personal hygiene completely independently on the 2nd postoperative day. On the one hand, this relieves the burden on the nursing staff, and an earlier discharge time is enabled. Larsen et al.  defined Patient-reported outcome after fast-track hip arthroplasty measured with the Harris Hip Score (HHS) showed significant improvement (54.0 vs 74.4) comparing preoperatively and four weeks after surgery. Fast-track surgery (56.20 vs 95.36) combined with a clinical nursing pathway can significantly improve the patient-reported and functional outcome of patients undergoing THA (58.09 vs 89.39) measured with Harris Hip Score before surgery and 3 weeks after . In addiLimitations to be mentioned are the retrospective study design, with its restriction on explanatory power. Furthermore, possible selection bias within the selected cases is possible because fast-track procedures were only performed if the individual surgeon was convinced that it would succeed—as the fast-track concept was recently established. Possibly, patients with severe comorbidities were not included in the study collective, and possibly, especially these patients may have a good benefit with regards to this specific procedure. Furthermore, reported pain course is restricted to 6 days postoperatively. Possible external influence factors on pain sensation in the postoperative period, e.g. family, daily routine and work, could therefore not be considered. Still, the standardized setup within this early postoperative period enables us to have bias-reduced insight into pain course which is clearly a strength of the study.In addition, results in our study are limited to pain evaluation, range of motion, thigh circumference above the knee joint, activities and the HHS preoperative and postoperative after total hip arthroplasty in fast-track scheme. Long-term results such as behavior in everyday life, work and sports would also be interesting. Randomized controlled group analysis to compare fast track with a conventional rehabilitation pathway should be performed in the future to point out dedicated differences; to date and to our knowledge, none has been published.However, the evaluation with a comparison group was not the target of this work. In the specific fast-track setting as described in this study, patients can expect early postoperative mobilization with good function, early drop of pain levels and regain of independent activities without relevant swelling. This information can be either used to improve patient education preoperatively and/or to improve the pain protocol to prevent an increase of NRS.p < 0.001, respectively). Most patients achieved their independence on day 2 after surgery. There was no significant difference between the preoperative and postoperative (day 6 after surgery) thigh circumferences 15 cm (p = 0.34), 20 cm (p = 0.05) and 30 cm (p = 0.09) above the knee joint; therefore no relevant postoperative swelling could be stated. There was a significant (p < 0.001) improvement of the HHS four weeks after surgery compared to preoperatively, meaning a “good result” with regard to the HHS value interpretation. In 100% of the cases, the operation was reported to be successful and all of the treated patients would choose a fast-track setup again, underlining the success when using a fast-track setup. Orthopedic surgeons have to take these findings into account when planning to establish a fast-track scheme. The occurrence of pain values and rapid improvement of range of motion and independent activities should be clearly explained to patients. Future prospective studies have to confirm the results, ideally with comparison of a conventional and a fast-track pathway.The present single center study demonstrates pain course, range of motion, activities and circumference of the thighs to objectify swelling after primary cementless hip arthroplasty in a fast-track setup: preoperatively and within the first 6 days postoperatively. The pain scores after the operation (day 6) were significantly lower than preoperatively. Pain levels decreased steadily on the days after surgery during the hospital stay—even on the day of surgery, pain levels were lower than preoperatively. All patients were able to mobilize on the day of surgery. There was also a significant improvement in independent activities within the first 6 days postoperatively: sitting on a chair, walking and personal hygiene (


The nutritional hallmark of chronic critical illness (CCI) after sepsis is persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which results in global resistance to the anabolic effect of nutritional supplements. This ultimately leaves these patients in a downward phenotypic spiral characterized by cachexia with profound weakness, decreased capacity for rehabilitation, and immunosuppression with the propensity for sepsis recidivism. The persistent catabolism is driven by a pathologic low-grade inflammation with the inability to return to homeostasis and by ongoing increased energy expenditure. Better critical care support systems and advances in technology have led to increased intensive care unit (ICU) survival, but CCI due to PICS with poor long-term outcomes has emerged as a frequent phenotype among ICU sepsis survivors. Unfortunately, therapies to mitigate or reverse PICS-CCI are limited, and recent evidence supports that these patients fail to respond to early ICU evidence-based nutrition protocols. A lack of randomized controlled trials has limited strong recommendations for nutrition adjuncts in these patients. However, based on experience in other conditions characterized by a similar phenotype, immunonutrients aimed at counteracting inflammation, immunosuppression, and catabolism may be important for improving outcomes in PICS-CCI patients. This manuscript intends to review several immunonutrients as adjunctive therapies in treating PICS-CCI. Advances in intensive care unit (ICU) technology, support systems, care bundles, and evidence-based protocols have improved ICU survival by largely preventing early deaths . Girard In 2020, Rosenthal et al., published an analysis of CCI patients from the UF SCIRC sepsis database in which it was found that, despite receiving adequate macronutrients starting early in the ICU, CCI patients did not respond the way RAP patients did. Rather, they experienced a persistent acute phase response  and failed to become anabolic . These dOver the past few decades, guideline recommendations for ICU protein supplementation have increased from 0.8 g/kg/day up to as high as 2 g/kg/day  in an attempt to offset catabolism and anabolic resistance . The empAdding to the rationale for higher protein supplementation in PICS-CCI was another recent publication from a Protein Summit that recommended protein prescription in the range of 1.2–2.5 g/kg/day in the ICU setting to optimize nutrition, to preserve muscle mass, and to decrease mortality . FinallyArginine is a conditional amino acid with a wide range of bioactive impact but under states of physiologic stress and ongoing inflammation becomes depleted. Barbul and colleagues were early champions of arginine metabolism and reported its importance in wound healing and as an immunologic regulator ,50,51,52Branched-chain amino acids  are another group of amino acids that, when supplemented, have demonstrated decreased muscle catabolism and hypertrophic muscle growth through increased protein synthesis . Frank CGlutamine supplementation may prove to be important as its pluripotent ability to serve as an antioxidant, in gluconeogenesis, and to enhance immune function is lost during times of great stress. Skeletal muscle generates the majority of endogenous glutamine, but during major catabolic insults, demand for glutamine becomes far greater than supply. This phenomenon results in glutamine becoming a conditional amino acid. Glutamine serves as the primary oxidative fuel for rapidly dividing tissues, such as small bowel mucosa, proliferating lymphocytes, and macrophages . GlutamiLipids remain a crucial macronutrient and mainstay nutritional therapy for the critically ill and surgical populations, but controversy still exists regarding the digestion, absorption, and oxidation of lipids in hyperdynamic states . While uAn advanced understanding of the bioactive nature of omega 3 FAs (EPA/DHA) has shown us that there is an even greater endogenous byproduct of lipid metabolism called Specialized Pro-Resolving Mediator (SPMs) . These hICU care, as advanced as it may seem, has limitations, which has generated research interests for a better understanding of what a healthy, diverse microbiome can provide a host during critical illness. Since 1907, when the Nobel Laureate Elie Metchnikoff first described the concept of probiotics, the overarching opinion has been that probiotics are safe and have a role in treating gastrointestinal diseases, but the use has not been supported by the literature . InsightSupplementing the critically ill and post-surgical patients with both pre- and probiotics has proven beneficial in many settings, but evidence lacks as to which specific species are superior to improve the dysbiosis and can they be beneficial to PICS-CCI? Despite the amounting research that has shown benefit, supplementing probiotics is still not considered the standard of care in all ICU settings. Nevertheless, the idea is that ‘bioecological control’ has blossomed in critically illness and polytrauma patients: to supply viable beneficial bacteria or a substrate that enhances these specific beneficial bacteria instead of trying to eliminate the pathogen ,109. CouAnton et al. performed a meta-analysis to identify nutritional and pharmacologic interventions targeting chronic low-grade inflammation in older adults. In this analysis, he identified probiotics as having the largest impact on decreasing the serum biomarkers of inflammation (IL-6 and CRP). Angiotensin II receptor blockers and omega 3 fatty acids also significantly reduced these biomarkers but to a lesser extent compared to probiotics . Other cAnabolic and anti-catabolic agents may be beneficial in mitigating persistent muscle breakdown, a pillar of PICS-CCI. Herndon and colleagues described numerous adjuncts to mitigate catabolism in the pediatric burn population that may be of value in the PICS-CCI population, including (a) growth hormone , (b) intPICS-CCI is the high cost of ICU survival and the new, dominant chronic MOF phenotype in ICUs and LTACs. The underlying pathobiology contributing to this increasingly common CCI phenotype are being unraveled. We now know that evidence-based, gold standard nutritional protocols fail to have much of an effect on the PICS-CCI phenotype as this patient population continues to exhibit a cachexia-like response to our nutritional strategies. Commencing therapeutic strategies early in critical illness may mitigate progression into CCI. When PICS-CCI is established, combatting the pillars will likely require multiple modalities. Nutritional strategies such as the use of various immunonutrients are forthcoming and are one modality to hopefully alter the clinical trajectory of PICS-CCI. Among these strategies, the ones that hold the highest potential are protein concentration ≈2 g/kg/d, specific immuno-amino acids, omega 3 fatty acids, specialized pro-resolving mediators, probiotics, and anabolic agents.


Intractable chronic occipital neuralgia (ON) is an uncommon type of headache often experienced by patients in outpatient neurological clinics. Among patients unresponsive to oral neuralgia medications, needling or injections with several drugs were suggested alternatives for treating chronic ON. This study aimed to determine the effectiveness and safety of botulinum toxin type-A (BTX-A) injection treatments, where eight patients with unilateral chronic ON received BTX-A injections at the pain sites. The pain relief effect was observed 2 weeks after receiving the injections, gradually showing improvements up to 12 weeks after injection. There were no adverse events or changes from baseline in serologic studies and vital signs in any of the participants. The treatment’s pain-relieving effects were confirmed through regular, 12-week follow-ups, confirming the safety and effectiveness of BTX-A on chronic ON and suggesting that this method is an effective, novel alternative option for chronic ON treatment. Chronic occipital neuralgia (ON) is a refractory headache characterized by sudden, sharp, and pounding pain in the branches of the occipital nerves. Specifically, ON can be described as bilateral or unilateral, typically accompanied by paresthesia around the occipital nerve . During After screening and providing their informed consent, nine patients participated in this study. However, one patient was excluded after a baseline serologic examination showed a hemoglobin level of 9 g/dL, reducing the total number of participants to eight individuals  with an average age of 46.3 ± 7.8 years. The pre-clinical serologic findings did not show any notable findings in the study participants, and no differences in the serologic findings before and after injecting the BTX-A were observed.p = 0.011, F = 125.49; The primary efficacy variable was the change in the pain visual analog scale (VAS), evaluated by the investigator before and thrice on the 2nd, 4th, and 12th week after administration. Based on the clinical trial’s results, pain relief was continuously observed after the 2nd week, showing statistical significance  diagnostic criteria. All participants fully understood the aims of this study and voluntarily agreed. This study was conducted following the Declaration of Helsinki, and the protocols were approved by the appropriate ethics review board (#IS19MIST0008). All participants gave their consent before participating in the study.However, this study contained more extensive exclusion criteria. In general, those who received BTX-A injections into the occipital region within the year; those whose masses were touched in the occipital region; and those diagnosed with severe muscular asthenia, Eaton-Lamberton syndrome, amyotrophic lateral sclerosis, motor neuropathy, or similar diseases were excluded. In addition, participants who had taken aminoglycoside antibiotics, curare-like agents, or drugs that inhibit neuromuscular functions  four weeks before screening or who were allergic or sensitive to investigational drugs or their ingredients were also excluded. Among women, those who were pregnant, lactating, likely pregnant, or who did not agree to use medically accepted contraception during the trial period were excluded from the study as well. The study’s investigators also excluded those whom they deemed unsuitable for this clinical trial. These included patients who participated in other clinical trials up to 30 days before screening or took drugs that had not exceeded 5 times their half-life during the clinical trial.According to the International Classification of Headache Disorders (ICHD-3), ON belongs to the same family as cranial neuralgias, central and primary facial pain, and other headaches. The diagnostic criteria include paroxysmal stabbing pain, with or without persistent aching between paroxysms, in the distribution of the greater, lesser, or third occipital nerve, tenderness over the affected nerve, and pain that was eased temporarily by locally blocking the nerve with anesthetics.® single bottle of 50 U was diluted in 3 mL of 0.9% physiological saline. Lastly, a 27 G needle was inserted into the patient until the end of the bone touched the occipital ridge’s posterior along the nape at a 90° angle toward the occipital region  was first used to dissolve the lyophilized investigational drug. Next, Botulaxl region . InjectiThe great occipital nerve (GON) is located at the third point of the virtual line connecting the external occipital protuberance (inion) and the mastoid process. The injection sites are as follows: at a third of the virtual line connecting the mastoid process and inion, a point in the shape of an inverted triangle set around 3 cm from the first site, and the other 2 points are the vertices of the inverted triangle. Finally, BTX-A was injected into 4 points (red dots) around GON, where 5 U of BTX-A was administered for each point .p-value of less than 0.05 was considered statistically significant. All analyses were conducted using IBM Statistics SPSS .All values obtained in this study are presented as mean ± standard deviations. The difference between the mean values of the VAS and QOL baseline variables and the 2-week, 4-week, and 12-week treatments were analyzed using repeated measures ANOVA. A