The Perioperative Pain Management Bundle was introduced in 10 Serbian PAIN OUT network hospitals to improve the quality of postoperative pain management. The Bundle consists of 4 elements: informing patients about postoperative pain treatment options; administering a full daily dose of 1–2 non-opioid analgesics; administering regional blocks and/or surgical wound infiltration; and assessing pain after surgery. In this study, we aimed to assess the cost-effectiveness of the Bundle during the initial 24 h after surgery.The assessment of cost-effectiveness was carried out by comparing patients before and after Bundle implementation and by comparing patients who received all Bundle elements to those with no Bundle element. Costs of postoperative pain management included costs of the analgesic medications, costs of labor for administering these medications, and related disposable materials. A multidimensional Pain Composite Score (PCS), the effectiveness measurement, was obtained by averaging variables from the International Pain Outcomes questionnaire evaluating pain intensity, interference of pain with activities and emotions, and side effects of analgesic medications. The incremental cost-effectiveness ratio (ICER) was calculated as the incremental change in costs divided by the incremental change in PCS and plotted on the cost-effectiveness plane along with the economic preference analysis.The ICER value calculated when comparing patients before and after Bundle implementation was 181.89 RSD (1.55 EUR) with plotted ICERs located in the northeast and southeast quadrants of the cost-effectiveness plane. However, when comparing patients with no Bundle elements and those with all four Bundle elements, the calculated ICER was −800.63 RSD (−6.82 EUR) with plotted ICERs located in the southeast quadrant of the cost-effectiveness plane. ICER values differ across surgical disciplines.The proposed perioperative pain management Bundle is cost-effective. The cost-effectiveness varies depending on the number of implemented Bundle elements and fluctuates across surgical disciplines. While aIn an effort to improve the efficacy of the acute perioperative pain management in Serbia, a Perioperative Pain Management Bundle was introduced . A “BundThe most common method for evaluating the effectiveness of pain management in adults is through the use of a Numeric Rating Scale (NRS). This 11-point Likert scale is often employed to measure a single pain-related outcome such as pain intensity during periods of rest or movement , 22. HowIn this study, we aimed to evaluate the cost-effectiveness of the Perioperative Pain Management Bundle. In the first step of the analysis, we compared patients treated before the Bundle implementation to patients treated after the Bundle implementation. In the second step, patients in whom all Bundle elements were applied were compared to those without any Bundle elements. The PCS was used as a measure of effectiveness. We hypothesize that the Bundle is a cost-effective strategy of improving the quality of acute postoperative pain management.2.2.1.ClinicalTrials.gov, NCT02083835) was used to collect the data evaluated in the current study (The PAIN OUT methodology for auditing perioperative pain on the first postoperative day (nt study . The SerPatients were enrolled if they fulfilled the following inclusion criteria: (1) were ≥18 years old; 2) were on the first postoperative day and returned to the ward from surgery for at least 6 h; (3) consented to take part in the study. Data from patients who underwent surgical procedures registered ≤10 times in the whole data set were excluded. For further analysis, surgical procedures were grouped according to similar expected pain levels , 2. were on In each participating hospital, trained surveyors obtained the study data during the first 24 h after surgery. In Phase 1 (January–May 2018), baseline data were collected before the introduction of the Bundle. In Phase 2 (April–December 2019), the Bundle was introduced, and another set of data was acquired.2.2.Costs of postoperative pain management included: (1) costs of the analgesic medications, (2) costs of staff labor needed for administering the analgesic medications, and (3) costs of related disposable materials. Costs of hospitalization and staff fees were considered fixed.The costs of the analgesic medications were calculated by multiplying the number of vials of each medication used in the recovery room and ward with the unitary price of the vial. The number of vials used was derived from the cumulative dose of the medication, as recorded per PAIN OUT protocol, divided by the dose of that medication in the vial. If the medication was available in vials containing various doses, the price of the vial containing the larger dose was used. If the medication was administered in a dose smaller than that in a vial, the price for the whole vial was utilized.The costs of labor needed for administering the analgesic medications were calculated as follows. For the intravenous, intramuscular, or subcutaneous route of administration, the costs of labor were calculated by multiplying the number of used vials with the price of labor for the intravenous, intramuscular, or subcutaneous administration of medications. A unitary price was adopted for costing of neuraxial or peripheral nerve block administration.Costs of disposable materials related to analgesic therapy were estimated assuming “ideal consumption” whereby disposable materials are used without waste.All prices were obtained from the official price list of the Republic of Serbia National Health Insurance Fund.2.3.intensity , the extent it interferes with activities , sleep and emotions (anxiety and feeling of helplessness), side effects of analgesic medications , and how they perceive the care they receive, on an 11-point Numerical Rating Likert scales . The IPO-Q asks patients to evaluate their postoperative pain in terms of its t scales , 29.IPO-Q’s pain intensity, interference and side effects domains . The ICER was calculated as the incremental change in median costs divided by the incremental change in the median PCS . It willIn the first step of our analysis, we calculated ICER by dividing the difference in median costs of postoperative pain management by the difference in median PCS between Phase 2 and Phase 1 of the PAIN OUT study . With thIn the second step of the cost-effectiveness analysis, we compared patients in whom all four Bundle elements were applied with those in whom no Bundle elements were applied .The cost-effectiveness was also presented graphically on the cost-effectiveness plane using the method described by Bang and Zhao  along wiCosts and, consequently, ICERs were calculated in Republic of Serbia Dinars (RSD) and then converted to Euros (EUR) according to the middle exchange rate published by the National Bank of Serbia on the day the price list was downloaded .2.5.U test. The ICEinfer package in R for Windows was used to obtain graphical representation of the cost-effectiveness analysis. This package makes head-to-head treatment comparisons by generating bivariate bootstrap resampling distribution of ICE for a specified value of the shadow price of health and lambda, forms ICE confidence region with specified confidence fraction, color bootstrap outcomes within confidence wedge from ICE map with specified values of lambda, beta and gamma. Parameters lambda = 0.26, gamma = 1 and beta = 1 were used in the calculations  and R 3.4.2 . Results are presented as count and median with 25th – 75th percentile or 95% Confidence intervals. Groups of patients were compared using the Mann–Whitney ulations , 31. p v3.The cost-effectiveness analysis was performed on 2,216 patients after excluding data from 138 patients who underwent infrequent surgical procedures.3.1.When evaluating the complete cohort, costs of postoperative pain management were significantly higher and PCS lower in Phase 2 compared to Phase 1 patients. However, the resulting ICER was positive since the median costs of postoperative pain management in Phase 2 were lower than in Phase 1 .Costs were significantly higher in Phase 2 patients undergoing thyroidectomy, breast, cardiac and major abdominal surgery, and urological procedures other than nephrectomy. However, only in patients who underwent cardiac and major abdominal surgery costs increased in parallel with a significant decrease in the PCS, resulting in negative ICER values. In patients with thyroidectomy and breast surgery, higher costs of postoperative pain management in Phase 2, together with similar values of PCS between phases, were observed. Costs did not differ between the two project phases for laparoscopic cholecystectomy patients, but the PCS values were significantly reduced in Phase 2. Interestingly, in patients undergoing appendectomy, costs were lower in Phase 2, with no difference in PCS between the phases. There were no significant changes in costs and PCS between Phase 1 and Phase 2 for patients undergoing inguinal hernia repair, nephrectomy and other urological procedures, Cesarean section and other gynecological procedures, fracture fixation and hip/knee replacement .Plotted ICERs are positioned in the northeast and southeast quadrants of the cost-effectiveness plane , consist3.2.Results of the cost-effectiveness analysis that compared patients with no Bundle elements to those receiving all four Bundle elements are presented in Implementing all four Bundle elements resulted in significantly higher costs of postoperative pain management in patients undergoing thyroidectomy, breast, cardiac and major abdominal surgery, and nephrectomy. However, PCS scores were lower only in cardiac surgery patients .Plotted ICERs were almost entirely concentrated in the southeast quadrant of the cost-effectiveness plane , suggest4.Our results show that the proposed four-element Perioperative Pain Management Bundle is cost-effective and that the cost-effectiveness varies depending on the number of implemented Bundle elements and across surgical disciplines.The Perioperative Pain Management Bundle described in our study is the first example of using a Bundle approach to improve the efficacy of acute postoperative pain management across multiple surgical disciplines. Earlier cost-effectiveness studies in acute postoperative pain focused on individual surgical procedures or analgesic medications, making the results challenging to extrapolate to other settings. McDowell et al.  assessedEvaluating the costs of perioperative pain management is a highly complex task. Unlike the prices of medications and disposables, which are usually readily available and, therefore, easily comparable in different economic settings, the price of labor varies significantly not only between developed and developing countries  but alsoHowever, the results of the cost-effectiveness analysis might be affected by parameters not addressed in this paper such as medications used for treating side-effects of anesthesia and analgesic medications, comorbidities, duration of hospital stay or selection of pain medications administered to patients. This study was performed using registry data so introduction of new variables is not feasible. The lack of information about the costs of medications for treating medication-related adverse events is the limitation of our study, given that these costs can influence the cost-effectiveness of acute postoperative pain management . Our resThis is the first cost-effectiveness analysis in the field of acute postoperative pain that uses PCS as a measure of effectiveness. We calculated PCS as an average value of 12 IPO-Q variables since there is no evidence that one variable or a set of variables describes the overall experience of pain more closely than other variables. In recent studies, however, PCS was calculated as a weighted score, with some variables contributing more than others , 25, 27.ICER is generally accepted in pharmacoeconomics as the preferred analytical tool for cost-effectiveness analysis. It is usually calculated using mean values of costs and effectiveness outcome. However, when dealing with skewed data, such as in this study, a median is considered a more appropriate measure of central tendency. The difference in ICER values derived from the same dataset using mean and median values can often be very different, impacting statistical inference .This difference in ICER values and the location of plotted ICERs in two steps of the analysis may be explained by the implementation of all four Bundle elements only achieved in 17.28% patients. In contrast, other patients received one, two or three Bundle elements. Therefore, the cost-effectiveness of the Bundle may depend on the number of Bundle elements implemented, and our findings indicate that implementing all four elements is the most favorable. However, the continuation of this analysis would infer a “threshold ICER” defined by the amount that society is willing to pay to treat acute postoperative pain. Serbian National Health Insurance Fund has yet to define this sum. Willingness-to-pay sum defined by patients , 35 depeOur results show that ICER values vary across surgical disciplines suggesting different cost-effectiveness of the Bundle after different surgical procedures. A possible explanation could be in procedure-specific differences in postoperative pain intensity  and the As discussed above, future cost-effectiveness evaluation of the Perioperative Pain Management Bundle should include data on analgesic medication-related adverse events and compare alternate PCS calculations. We propose to investigate the Bundle in surgical procedures not included here, in patients with countries and settings with different socioeconomic backgrounds and referring to data collected during the entire hospital stay of a patient.5.This study evaluated the cost-effectiveness of the four-element Perioperative Pain Management Bundle. Our results suggest that the implementation of the Bundle is a cost-effective strategy for improving the quality of perioperative pain management.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by (1) Uzice Health Center, General hospital Prijepolje - Ethical approval for this study  was provided by the Ethical Committee of Uzice Health Center, Uzice, Serbia (Chairperson Dr. Sladjana Pavic) on 13 July 2017. (2) Cardiovascular Institute Dedinje - Ethical approval  was provided by the Ethical Committee of Institute for Cardiovascular diseases Dedinje, Belgrade, Serbia (Chairperson Prof. Dr. Dragan Sagic) on 21 Sept 2017. (3) Oncology Institute of Vojvodina - Ethical approval for this study  was provided by the Ethical Committee of Oncology Institute of Vojvodina, Sremska Kamenica, Serbia (Chairperson Prof S. Knežević Ušaj) on 17 July 2017. (4) Department of Anesthesia, Urology Clinic, Faculty of Medicine, University of Belgrade - Ethical approval  was provided by the Ethical Committee of Clinical Centre of Serbia, Belgrade, Serbia (Chairperson Prof. Dr. Branislav Stefanovic) on 13 July 2017. [*] (5) Military Medical Academy Department of Anesthesiology and Intensive Care - Ethical approval for this study  was provided by the Ethical Committee Military Medical Academy, Belgrade, Serbia  on 3 November 2017. (6) Clinical Hospital Centre Bezanijska kosa- Belgrade - Ethical approval for this study  was provided by the Ethical Committee Clinical Hospital Centre Bezanijska Kosa (Chairperson Dr. Mirjana Cvetkovic) on 8 September 2017. (7) Clinical Centre Nis - Ethical approval for this study  was provided by Ethical Committee of the University of Nis, Clinical Centre Nis, Serbia (Chairperson: Dr. Steva Stanisic) on 5 September 2017. (8) National Cancer Research Center of Serbia, Belgrade - Ethical approval for this study  was provided by the Ethical Committee of the National Cancer Research Center of Serbia  on November 14th, 2017. (9) Centre for Anesthesiology, Resuscitation and Intensive Care. University Clinical Centre of Serbia; Department of Anesthesia, Clinic for Digestive Surgery - Ethical approval for this study  was provided by the Ethical Committee of University Clinical Center of Serbia, Belgrade, Pasterova 2, Serbia (Chairperson Prof B Stefanović) on 13 July 2017. (10) Clinical Centre of Serbia, Clinic for Physical and Rehabilitation Medicine, Faculty of Medicine, University of Belgrade - Ethical approval  was provided by the Ethical Committee of Clinical Centre of Serbia, Belgrade, Serbia (Chairperson Prof. Dr. Branislav Stefanovic) on 13 July 2017. [*]. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.SB and DS: conception and design. SB, DS, NL, IP, and IL-L: acquisition of the data. SB and IS: analysis or interpretation of data. SB, DS, and RZ: drafting of the article. IS and PB: statistical analysis. SB, NL, IP, IS, IL-L, WM, RZ, US, PB, and DS: critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.PAIN OUT was developed with funding from the European Community’s Seventh Framework Program FP7/2007-2013 under Grant Agreement No. 223590. The European Pain Federation (EFIC) provided funding from its own resources to cover the costs of the project in Serbia. Funding included: (i) the annual subscription to PAIN OUT for 10 hospitals over a 2-year period; (ii) two half-day face-to-face meetings so that the Principal Investigator and one research surveyor from each hospital could review the findings and (iii) partial remuneration to hospitals for datasets collected. The funds were transferred to the Serbian Pain Association, which then contacted each of the participating hospitals. Neither funding body received or requested the trial protocol, analysis plan, analysis itself or any drafts of the manuscript prior to submission for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In the post hoc analysis with Bonferroni correction, the pain scores of the chest, neck, and axilla were significantly lower in the deep neuromuscular block group on postoperative day one compared to the moderate neuromuscular block group . This study demonstrated that deep neuromuscular block could reduce postoperative pain after robot-assisted transaxillary thyroidectomy. However, it could not demonstrate that deep neuromuscular block reduces paresthesia or hypoesthesia after the surgery.The occurrence of significant pain and paresthesia after robot-assisted transaxillary thyroidectomy has been reported, and some patients experience chronic symptoms even three months after surgery. This study scrutinized the effects of deep neuromuscular block during robot-assisted transaxillary thyroidectomy on postoperative pain and sensory changes. In this single-blinded, prospective, randomized, controlled trial, 88 patients who underwent robot-assisted transaxillary thyroidectomy were enrolled and randomly allocated to either the moderate or deep neuromuscular block groups. Study endpoints included postoperative pain, paresthesia, and sensory change after surgery. The linear mixed models for numeric rating scale pain scores in the chest, neck, and axilla all showed significant intergroup differences over time ( Robot-assisted transaxillary thyroidectomy (RATT) has gained popularity in recent years and offers many advantages over conventional open surgery, including improved cosmetic satisfaction without any difference in cancer control or safety ,2,3. HowThe surgical procedure for RATT includes chest skin flap elevation by using an external retractor system to form a working space ,8,9 Fig. During ClinicalTrials.gov (NCT03871387) on 12 March 2019. We obtained written, informed consent from all participants. The study was conducted in accordance with the Declaration of Helsinki.This study was designed as a single-blinded, prospective, randomized, controlled trial. The Institutional Review Board and Hospital Research Ethics Committee of the Severance Hospital at Yonsei University College of Medicine approved this study on 27 November 2018 (#4-2018-0963). It was registered at 2; (5) pregnant or lactating women; (6) those with a history of liver or renal failure; (7) those with a history of allergic reaction to rocuronium or sugammadex; (8) those who already had chronic pain or paresthesia; (9) those who could not understand the consent form, such as people with low levels of literacy or foreigners.We included patients aged 20–70 years who underwent RATT and had an American Society of Anesthesiologists physical status of I–III. The following patients were excluded: (1) patients scheduled for radical neck node dissection; (2) those undergoing simultaneous surgeries for other organs; (3) those with other accompanying cancers; (4) those with a BMI > 30 kg/mThe enrolled patients were randomly allocated to the moderate NMB group or the deep NMB group. Group allocation was performed via a predetermined randomization sequence, which was created by a computer-generated random table without any block or stratification. The random sequence was kept enclosed in an envelope. A predetermined investigator was responsible for random sequence security and group assignment, and that investigator did not participate in the subsequent research process. The patients, surgeons, and investigators who evaluated the outcomes were blinded to the group allocation. However, assignment results were disclosed to the attending anesthesiologists to control the level of NMB according to groups.® SX  was attached to the patient’s wrist. Glycopyrrolate 0.1 mg was administered intravenously before induction. Continuous remifentanil infusion was initiated at a rate of 0.05 to 0.2 μg/kg/min, and 1.5 to 2 mg/kg of propofol was administered intravenously. The TOF-Watch® SX was calibrated when the patient became unconscious. After calibrating the device, 0.6 mg/kg of rocuronium was administered to the patient, and endotracheal intubation was performed. Anesthesia was maintained with desflurane and a continuous infusion of remifentanil. All surgeries were performed by three experienced surgeons  who were blinded to the group allocation.When the patient arrived in the operation room, non-invasive blood pressure, electrocardiography, pulse oximetry, and bispectral index  monitoring were initiated. A TOF-Watch® SX on the patient’s wrist was used to monitor the TOF and post-tetanic count [Rocuronium was continuously infused during surgery, and the infusion rate was adjusted differently for each group. For the moderate NMB group, the rate of rocuronium infusion was adjusted to maintain one to two responses in the train-of-four (TOF). For the deep NMB group, the infusion rate was adjusted to maintain zero responses in the TOF and one to two responses in the post-tetanic count . The TOFic count . The attBefore the end of the surgery, 1 g of propacetamol and 0.075 mg of palonosetron were administered. When the surgery was completed, sugammadex was administered intravenously , and the investigator measured the time from sugammadex injection to a TOF ratio of 0.9. After the time was measured, desflurane and remifentanil were discontinued, and the endotracheal tube was removed when spontaneous respiration recovered. Patients who complained of pain at the post-anesthesia care unit (PACU) were administered 50 mg of tramadol, and those who complained of nausea were administered 0.3 mg of ramosetron. Pain control in the ward was conducted following the routine protocol of our hospital. On the day of surgery, 400 mg of ibuprofen was administered intravenously twice a day. From postoperative day (POD) 1 to POD 3, 200 mg of ibuprofen was routinely administered orally thrice daily. For patients requiring additional analgesia, 1 g of acetaminophen or 400 mg of ibuprofen was additionally administered intravenously.The primary endpoint was the numeric rating scale (NRS) scores for pain on POD 1. The secondary endpoints included (1) NRS scores for postoperative pain until three months after surgery, (2) postoperative paresthesia, (3) postoperative sensory changes, (4) postoperative nausea and vomiting, (5) time from sugammadex injection to TOF ratio of 0.9, and (6) postoperative complications.Postoperative pain was evaluated by using an NRS score of 0–10  with a single measurement. The pain scores were separately evaluated for the neck, chest, and axilla and were evaluated at PACU, POD 1, POD 3, and 3 months after surgery (POD 90). Paresthesia of the neck and chest was evaluated on a scale of 0–7  by using a questionnaire on POD 1, POD 3, and POD 90 . AdditioIn the PACU, endpoints were evaluated after being admitted to the PACU and measuring vital signs. On POD 1 and POD 3, endpoints were measured in the morning just before administration of routine oral analgesics. On POD 90, endpoints were measured when the patient visited the outpatient clinic for follow-up. All endpoint measurements were performed by investigators who were blinded to the group allocation.A previous study reported a visual analogue scale pain score of 3.04 ± 1.28 on POD 1 after RATT . Under tWe used SAS software version 9.4  and IBM SPSS Statistics version 25.0  for statistical analysis. We performed the independent t-test or Mann–Whitney U test in comparing the continuous variables, and we conducted chi-square test or Fisher’s exact test in comparing the categorical variables. The NRS pain score, paresthesia score, and degree of remnant sensation were analyzed by using linear mixed models, and post hoc analysis was conducted with Bonferroni correction.In total, 88 patients were enrolled in the current study, and the patients were evenly allocated to the moderate NMB group (n = 44) or the deep NMB group (n = 44). Two cases of postoperative bleeding occurred in the deep NMB group; one of them underwent reoperation and was dropped from the study, and the other patient received only conservative management and was included in the analysis. Finally, 87 patients were included in the analysis . There wp < 0.001; sugammadex, 121 vs. 244 mg, p < 0.001). The vital signs and peak airway pressure did not show significant intergroup differences, except for the heat rate when the robot was undocked. The time from sugammadex injection to TOF ratio of 0.9 was significantly longer in the deep NMB group than that in the moderate NMB group . PACU time and length of hospital stay did not significantly differ between the two groups. There was no significant difference in the number of patients who received rescue analgesics between the two groups. No patients experienced respiratory failure or desaturation after surgery . The deep NMB group also showed significantly lower NRS pain scores of the neck and axilla on POD 1 compared to that in the moderate NMB group (p = 0.039). Additionally, the number of patients complaining of severe axilla pain on POD 1 was significantly higher in the moderate NMB group than that in the deep NMB group  (The deep NMB group showed significantly lower NRS pain scores of the chest than that in the moderate NMB group immediately after surgery (in PACU) and on POD 1 and POD 3  .p = 0.003 in the chest; p = 0.001 in the neck; p = 0.002 in the axilla). Post hoc analysis with Bonferroni correction revealed that the NRS pain scores of the chest, neck, and axilla on POD 1 were significantly lower in the deep NMB group compared to those in the moderate NMB group   .p = 0.049)  .This was the first investigation on the effects of deep NMB in RATT. This study demonstrated that deep NMB could reduce postoperative pain after RATT; however, it could not demonstrate that deep NMB reduces paresthesia or hypoesthesia after surgery.The mechanisms underlying pain and sensory changes after RATT remain unknown. However, some researchers have argued that the retractor system may be involved ,10. RATTThe benefits of deep NMB have been demonstrated in a variety of surgeries. According to a meta-analysis  on the eWe could not demonstrate that deep NMB reduces paresthesia or hypoesthesia after RATT. Considering that the deep NMB group showed a trend of less paresthesia and sensory change, significant results may be obtained if a larger number of participants were investigated, or a longer follow-up was conducted.This study also demonstrated that deep NMB could be safely maintained during RATT without severe complications or intensive care unit admission. Nevertheless, two cases of postoperative bleeding occurred in the deep NMB group, including the dropped patient. Although we did not observe significant intergroup differences in the incidence of postoperative bleeding, it is noteworthy that the bleeding events occurred only in the deep NMB group. Some studies have reported that sugammadex increases bleeding tendency by prolonging the activated partial thromboplastin time and prothrombin time ,29,30. GThis study had several limitations. First, most outcomes in this study were subjective indicators. Pain was measured by using the NRS, and paresthesia was assessed by using a questionnaire. The pinprick test relied on the subjective expression of the degree of remnant sensation by patients. Future studies should aim to confirm the effects of deep NMB through more objective indicators. Second, POD 90 data had missing values in 18 patients; hence, more participants are necessary to investigate the effects of deep NMB on chronic pain and sensory changes three months after the surgery. Larger- and longer-scale studies would provide a more accurate evaluation of the effects of deep NMB on chronic symptoms after RATT. Third, we did not measure retractor pressure during surgery. Considering that deep NMB reduced postoperative pain in this study, it could be expected that the retractor pressure would decrease, but we could not prove it. Fourth, we evaluated pain scores as a single assessment. Indicators calculated from repeated pain measurements, such as the sum of pain intensity difference or maximum total pain relief, can be more accurate than single assessments. However, we measured pain scores a total of four times  during the study period and analyzed their changes by using a linear mixed model.Deep NMB showed a significant effect in reducing NRS pain scores after RATT compared to moderate NMB. However, this study could not demonstrate that deep NMB reduces paresthesia or sensory changes after the surgery. Deep NMB may be beneficial in reducing postoperative pain in RATT.


Despite commonly investigated predictable smooth-pursuit neck-torsion tasks (SPNT) in neck pain patients, unpredictable conditions have been seldom investigated but are indicative of preserved oculomotor functions during neck torsion. Although not previously studied, some speculations about compensatory cognitive mechanisms such as increased phasic alertness during unpredictable tasks were suggested. The aim of this study was to investigate eye movement accuracy and pupillometric responses during predictable and unpredictable SPNT test in neck pain patients and asymptomatic controls. Eye movements (gain and SPNT-difference) and pupillometry indicative of tonic (average and relative pupil diameter) and phasic (index of cognitive activity-ICA) alertness were measured in 28 idiopathic neck pain patients and 30 asymptomatic individuals using infrared video-oculography during predictable and unpredictable SPNT test. Gain in unpredictable SPNT test was lower as compared to predictable tasks and presented with similar levels in neutral and neck torsion positions, but not in the predictable SPNT test. ICA was lower during neutral position in all tasks in patients as compared to control group but increased during neck torsion positions in unpredictable tasks. Relative pupil diameters presented with no differences between the groups or neck positions, but the opposite was observed for average pupil diameter. Higher ICA indicates an increase in phasic alertness in neck pain patients despite no alterations in oculomotor control during SPNT test. This is the first study to indicate cognitive deficits in oculomotor task in neck pain patients. The latter could negatively affect other tasks where additional cognitive resources must be involved. Patients with neck pain disorders commonly present with disturbances in the oculomotor system  was used to measure eye movements during SPNT test and left eye pupillary diameter , (ii) tracking a sinusoidal target movement with changing target movement amplitude ranging from 30° to 50° amplitude at constant velocity of 30°s−1 SPNT test (unpredictably changing amplitude), (iii) tracking a sinusoidal target movement with changing target movement velocity ranging from 20 to 40°s−1 at a constant target movement amplitude of 30° (unpredictably changing velocity) and (iv) a sinusoidal target movement with changing of amplitude (from 30° to 50° amplitude) and velocity (from 20 to 40°s−1) (unpredictably changing amplitude and velocity—unpredictable task).Testing protocol consisted of four horizontal SPNT tests of which characteristics were based on previous studies  neutral position with the trunk and head facing forward, (ii) torsion of the neck for 45° to the left (rotation of the trunk underneath the stationary head to the right) and (iii) torsion of the neck for 45° to the right (rotation of the trunk underneath the stationary head to the left). The order of neck torsions was pseudo-randomized across subjects.Subjects were required to track 10 cycles of sinusoidal target movements followed by 60 s rest with all tasks performed in random order.Eye movement data were filtered for blinks, saccades and fixations using Tobii Pro Lab software . Square waves  were removed from eye movement data using custom-written software in MATLAB . Eye movement data were fitted with a corresponding reference sinusoid. Each fitted sinusoid consisted of 10 cycles with corresponding amplitude (converted from angular degrees to pixels) and frequency matching the profile for each individual condition. Horizontal eye movements were analysed using gain, calculated as the ratio between fitted eye velocity amplitude and visual target velocity amplitude as described by Tjell et al. . Gain toEquation : gain nePupil size data were analysed using two approaches. The index of cognitive activity (ICA) was derived from the pupil size data using a procedure described in Marshall . This prp < 0.05.Statistical analysis was performed in SPSS . Shapiro–Wilk test, skewness and kurtosis were calculated to analyse data distribution for each parameter. Median and interquartile range were calculated for both groups in each test and neck position. Due to non-normality of data distribution in some parameters, Friedman’s test was used to analyse differences between the neck positions in each SPNT tasks for each group separately and for differences between tests for each position and group separately. Post-hoc sign rank test was used for pairwise comparisons. Differences between groups were analysed using Sign test for each neck position and each SPNT test separately. Cohen d was calculated for each post-hoc test. Statistical significance was set at p = 0.046; d = 0.203). In the neck pain group cervical spine magnetic imaging assessment presented disc protrusions or herniations at levels from C4 to Th1 in 23 patients, seven patients presented with facet joint osteoarthritis at the levels from C5 to Th1, six patients with low-grade spondylolisthesis and seven patients with cervical spinal stenosis. Nineteen patients had a combination of at least two types of structural deformity, but only one was present in nine patients. Average pain duration in the patient’s group was 11.3 ± 6.9 months and average VAS score was 4.9 ± 1.8. Control group presented with no pain.Twenty-eight patients and thirty controls were recruited for the study. Twenty-one women and seven men were included in the patient group and nineteen women and eleven men in the control group. The mean age of the patient’s group was 42.1 ± 4.6 years (age range 27–51 years) and the mean age of the control group 39.3 ± 5.7 years (age range 23–50 years). The control group was statistically significantly older as compared to the patient group  in neck pain patients and asymptomatic individuals. Additionally, possible changes in tonic and phasic alertness were assessed during all SPNT tests for both studied groups. Neck pain patients presented with decreased precision (decreased gain) to follow a moving target in all SPNT tests as compared to asymptomatic individuals. Moreover, during predictable target movements patients presented with decreased gain (higher SPNTdiff) in neck torsion positions as compared to the neutral position, which was not observed in unpredictable target movement tasks (lower SPNTdiff). Higher ICA presented with an increase in alertness under neck torsion manoeuvre as compared to the neutral position in neck pain patients. This was evident for unpredictable and unpredictable SPNT test with varying amplitude  but not predictable SPNT test. Although similar trend was observed for predictable SPNT test, it could be speculated that this was due to its lesser challenge to the cognitive system. On the contrary, asymptomatic individuals presented with similar alertness in the neutral and neck torsion positions. Comparisons between the two groups presented with statistically significant differences in ICA but only during tasks in the neutral position. Tonic alertness presented with statistically significant differences between groups for all observed tasks and neck positions when observing the average pupil diameter, but not for the relative pupil diameter. Moreover, no differences between neck positions were observed for both parameters of alertness for either of the groups.Although previous studies investigating predictable eye movement tasks indicate that amplitude and velocity might play an important role in the accuracy of eye movements  was used, with all additional sources of information omitted from the visual field. On the contrary, tonic alertness described by an average pupil diameter was statistically significantly lower in neck pain patients as compared to asymptomatic individuals in all studied tasks and neck positions. This suggests possible impairments of tonic alertness in neck pain patients as compared to asymptomatic individuals.Although our results indicate alertness alterations in neck pain patients, more studies are needed to confirm our observations. An important limitation of our study was that it is unclear to what extent the pupil diameter could have been affected by posturally modulated activity of locus coeruleus. Changes in neck position have been shown to influence the activity of locus coeruleus in animals (Pompeiano et al. An additional limitation of this study was that the intake of stimulants such as coffee was not controlled. This could have influenced alertness in some participants and consequently added towards increased variability between the two groups. However, it is not possible to hypothesize whether use of stimulants would affect differences between neck torsion and neutral position and three different SPNT tasks in either of groups.The results of our study confirm previous results showing that neck pain patients are able to compensate for oculomotor deficits in neck torsion position during unpredictable smooth pursuit eye movement tasks using higher order cognitive and oculomotor control processes. Both tonic and phasic alertness have been shown to be altered during smooth pursuit eye movement tasks, however, phasic alertness was the primary compensatory mechanisms which enables neck pain patients to preserve precision of oculomotor control during neck torsion positions. These results help to better understand the wider effect of neck pain on other aspects of patient’s daily activities and consequently help to better understand the interconnection between different signs and symptoms.


Playing Related Musculoskeletal Disorders (PRMD) belong to the most prevalent medical ailments affecting musicians' health and career. This study documents the effect of a physiotherapeutic treatment as well as functional impairments of PRMD on the musculoskeletal system. In total, 32 music students suffering from PRMD were examined in Hanover Medical School (MHH) before and after they received twelve physiotherapeutic treatments, which were carried out over 20 min each over 6 weeks. Additionally, 32 healthy music students, matched by age and gender, were examined at one time point in the MHH to explore which musculoskeletal restrictions are associated with PRMD. The examination included the evaluation of the pain on the Visual Analogue Scale for pain (VAS), a body composition, and body posture measurement, the finger-to-floor distance, the range of motion of the cervical spine, the pressure pain and muscular hypertension examination, the temporomandibular joint-test, the Beighton score screening test, and the testing of the widespread pain score (WSP). After analyzing the data of the patient group (PG) a significant reduction of pain level on the VAS from an average pain of 5.33 to 3.35 was found (large effect). Additionally, a significant reduction of the pressure pain of the M. levator scapulae, the M. rhomboideus, the M. sternocleidomastoideus on the left side and the paravertebral muscles of the cervical spine on the right side after the treatment of the patients could be detected. Regarding the WSP, the positive testing significantly differed, showing a 28% positive testing in the patient group vs. a positive testing of 9% in the control group (CG). As hypermobility is a common phenomenon in musicians, the percentage of those being diagnosed with generalized hypermobility by using the Beighton score in both groups  was remarkably higher compared to previous studies. In this study, a short course of manual therapy, client tailored for each musician's specific problem, was shown to reduce pain levels in musicians with PRMD. When experienced by non-musicians, listening to music frequently arouses emotions and physical reactions of wellbeing and relaxation. In contrast, when a person plays an instrument professionally, the activity can often lead to discomfort and painful muscle maladjustments, such as Playing Related Musculoskeletal Disorder (PRMD). The lifetime prevalence of musculoskeletal complaints in professional musicians ranges from between 62% and 93% and therefore represents a huge health restriction for musicians –5. HowevRegarding the percentage of musicians affected by PRMD, it should be mentioned that the definition of PRMD is not consistently used. Zaza, Charles, and Muszynski provide a well-established description of PRMD as “pain, weakness, lack of control, numbness, tingling, or other symptoms that interfere with your ability to play your instrument at the level you are accustomed to” . Since mEven though PRMD is very common among musicians, to date, little research has been conducted to investigate whether preventive strategies and therapy for PRMD exist. Zaza examined 281 classically trained professionals and university student musicians. They identified warming up before and taking breaks during practice sessions as preventive factors of PRMD . AdditioSince the majority of previous studies investigating musculoskeletal dysfunctions in musicians have used questionnaires , 23, thiThis study aimed to explore musculoskeletal restrictions correlating with PRMD by using a detailed physical examination. The results were not only compared before and after a 12-session physiotherapeutic treatment but also a healthy control group of music students not suffering from PRMD. Specifically, this study aimed to explore the effects of Manual Therapy by comparing bodily exams before and after a physiotherapeutic treatment.The study is a prospective cohort study with an uncontrolled trial and an effective experimental design. It was conducted at the Hanover Medical School (MHH) in cooperation with the Institute of Music Physiology and Musicians' Medicine (IMMM) of the Hanover University of Music, Drama, and Media. It is part of a cooperation study divided into psychological factors influencing the development of PRMD (IMMM), as part of which this study focuses on the somatic factors that determine the origin of PRMD. Data on the psychological impact of PRMD will be published elsewhere .In total, 32 music students  suffering from PRMD  were physically examined before a closely spaced twelve session physiotherapeutic treatment (timepoint T1), which included a 20 min treatment per session specific to the participants' main symptoms carried out by two expert physiotherapists from a physiotherapy clinic that specializes in musicians and directed by co-author Stephan Faßnacht-Lenz. The participants were asked to finish the treatment within 6 weeks.The detailed examination included the evaluation of pain on the Visual Analogue Scale (VAS), a body composition- and body posture measurement, the finger to floor distance, the range of motion of the cervical spine, pressure pain and muscular hypertension examination, the temporomandibular joint-test, the Beighton score screening test, and a Widespread Pain Score (WSP) was calculated.The same parameters and examinations were collected after the therapy (timepoint T2) to show the effectiveness of the physiotherapeutic treatment.This study aimed to answer the question, and was concerned with the musculoskeletal restrictions of PRMD and predisposing factors such as hypermobility linked to the development of PRMD. Therefore the control group (CG), which consisted of music students not suffering from PRMD, underwent a physical examination identical to the patients' group.All subjects provided written informed consent and the study protocol received ethics approval from the ethics committee at Hanover Medical School (MHH) (study number 2865-2015). The study was conducted in accordance with the principles of the Declaration of Helsinki.Participants were recruited by the IMMM, either by being asked during a PRMD appointment in the musician's clinic or by a call asking them to participate in the study based on patient records indicating that they suffered from PRMD. We also placed notices inside the Hanover University of Music, Drama and Media building. After a screening examination to verify the diagnosis of PMRD, an appointment at the MHH was made for a detailed bodily examination.The healthy subjects in the control group were also recruited in the IMMM and, after we had ascertained that they did not have PRMD (based on the previously outlined criteria), they were sent to the MHH to be examined the same way as the patient group cf. . The pat➢–suffering from PRMD –aged 18 to 30 years old–a pain intensity of three or more on the Visual Analogue Scale (VAS) during the last week–not previously exposed to physiotherapeutic treatment for PRMDInclusion criteria:➢Exclusion criteria:Diseases like cancer, heart failure, major depressive disorder, acute and inflammatory diseases, injury, diabetes, autoimmune and infection diseases, joint and spine diseases, as well as pregnant and breast-feeding females, or only temporary pain (<3 weeks).The following parameters were set up as inclusion and exclusion criteria for the patient group:The inclusion and exclusion criteria stayed the same for the control group with the exception that the control group participants must be free from relevant pain.To explore musculoskeletal restrictions correlating with PRMD, a detailed physical examination was performed by two experienced physicians at the MHH. For the examination, 45 min were scheduled per patient, and individual extra time was given for filling in the questionnaire. First, the probands had to mark their estimated pain in two separate visual analogue scales (VAS). The first scale represented the average pain felt during the last week (VAS1), and the second one requested the average pain felt after playing their instrument during the last week (VAS2).Participant’s body composition  was measured using the InBody machine .–Body posture examination, which included the examination of the symmetry of the shoulders (shoulder elevation measured in cm), the detection of spine scoliosis via visual diagnosis and palpation of the spine, the assessment of the waist triangle , and the examination of the pelvic position .–Finger-floor-distance , the dis–Range of motion of the cervical spine, measured using CROM 3 : with a –Pressure pain and increased muscle tension of the hyoid muscles, the M. sternocleidomastoideus, M. scaleni, M. trapezius, M. levator scapulae, M. rhomboideus, M. pectoralis, paravertebral muscles of the cervical-, thoracic-, and the lumbar spine and the M. quadratus lumborum were examined by manual palpation carried out by one of the experienced physicians. The depth of the manual palpation was initially calibrated with a Tissue Tensiometer so that the examination was comparable. The variables are dichotomous . Increased muscle tension was determined by the examiner when an increased resistance of the muscles was palpable. A positive tenderness was recorded as soon as a patient expressed pain on palpation.–temporomandibular joint test (developed by a study group of dentists of the MHH for detection of temporomandibular disorders) cf .–Beighton score screening test of hypermobility . A summa–Testing of the 18 tender points for assessing widespread pain (WSP) . A score of 12 or more positive tender points led to a positive WSP testing.To be able to detect any physical anomalies that might be related to PRMD, the following examinations and tests were carried out:Twelve sessions of physiotherapy were prescribed per patient, carried out by two experienced physiotherapists specializing in the treatment of musicians. The treatment was adapted to the individual symptoms of the musicians, dependent on the results of the physical examination. The therapy included a postural stabilization at the beginning of the treatment, followed by individual treatments . To identify the specific risk factors induced by postural workload or lack of mobility patients were asked to bring their musical instrument. Thereby, therapists could better adapt exercises to patients' problems. After the treatment was completed, a treatment report for every patient was created by the physiotherapists .The study was a sub-study as part of a main study exploring the correlation between BDNF (brain-derived neurotrophic factor) and PRMD. The negative outcome of BDNF analysis (no correlation with pain or therapy) will be reported elsewhere. Additional to these studies, the IMMM examined in another sub-study the psychological factors that influence PRMD. According to the main study the sample size was calculated based on a study by Laske et al. . Based op < 0.05.The statistical analysis of the body examination (T1 and T2) was evaluated by STATA Version 16 using Shapiro-Wilk-Test for detecting a normal distribution, so analysis continued with ANOVA or Kruskal-Wallies-Test chi-squared, or chi-squared with ties. Significance is set at From the initial 42 examined patients, ten had to be excluded. Two participants were not eligible due to the inclusion and exclusion criteria, six of the participants did not reach the requested VAS, one had to be excluded since the data collection could not be finished due to the patient's schedule, and one had to be excluded since the matched healthy control participant did not fulfill the criteria of being free from pain. Furthermore, two of the healthy subjects were excluded after going through the examination, since they could not be matched cf. .The body measurement represented a good match within the control and the patient group, as there was no significant difference in the captured parameters including height, bodyweight, muscle mass, the fatty tissue of the body in kg, as well as the BMI cf. , 3. The d = 5.94) and the difference is significant at p < 0.01  VAS1 was 5.33 (8.24) compared with the average VAS1 for healthy subjects of 0.56. The effect is large (Cohen's 0.01 cf. .d = 1.10/0.92), left and right M. scaleni (Cohens’ d = 1.15/1.02), left M. trapezius (Cohens’ d = 0.98), left and right M. levator scapulae (Cohens’ d = 1.34/1.60), left and right M. rhomboideus (Cohens’ d = 1.62/1.26), left and right paravertebral muscles of the cervical spine (Cohens’ d = 1.01/1.01) and the left M. quadratus lumborum (Cohens’ d = 0.81).This was reflected in the examination of the pressure pain of the different muscle groups. The patients were characterized by being significantly more affected in all examined muscles except the left paravertebral muscles of the lumbar spine compared to the healthy control group. A large effect could be identified in the left and right M. sternocleidomastoideus (Cohens’ d = 0.45) as well as the joint muscles with a medium effect (Cohens’ d = 0.67) could be described.There was a significant difference in the pressure pain of the temporomandibular joint with a small effect (Cohens’ p = 0.0001), both sides showing a large effect size (Cohens’ d = 1.38 vs. 1.16).As shown in p = 0.0001). Whereas the patient group scored three times as high as the healthy subjects with 9.4, the healthy control only scored around 3 points .The widespread pain score showed a significant difference between the groups  with a medium effect size .Consistent with the result of existing moderate hypermobility in both groups, we provide a higher mobility of the cervical spine in both groups compared to the normal range of inclination of 45° . The meaSince both groups were diagnosed with moderate hypermobility, as expected, no relevant differences could be detected by measuring the finger to floor distance between the patients and the control group.For estimating the effectiveness of the physiotherapeutic therapy, a second examination of the patient group was carried out after the treatment.p < 0.0001) and the effect was large (Cohens’ d = 1.42). The maximum pain was declared at 8.2 in T1, and 7.2 in T2.The VAS1 of the musicians suffering from PRMD declined significantly from the initial 5.3 (T1) on average to 3.4 (T2) (p < 0.0001). In T1, the average VAS2 was 6.28, in T2 the VAS2 was measured at 3.58 on average, which means a reduction of 57%, after twelve sessions of therapy, which resembles a large effect (Cohens’ d = 1.19). The VAS2 was significantly reduced (p < 0.0116), showing a medium effect (Cohens’ d = 0.66). The pressure pain of the M. rhomboideus was reduced from 69% in T1 to 38% on average in T2 on the right side, and from 72% (T1) to 44% (T2) on the left side . Interestingly, the pressure pain examination of the M. sternocleidomastoideus only showed a significant reduction of the left side  . The pressure pain of the paravertebral muscles of the cervical spine was also only significantly reduced on the right side . The detailed examination of the pressure pain in T2 showed a significant reduction, with an average of 33% of patients having less pressure pain in the M. levator scapulae on both sides than before the therapy (d = 0.66) proven. On average, 73% of the patients had hypertension of the muscle, whereas in T2 only 59,3% of patients on average were still suffering from hypertension. No other significant reduction of hypertensive muscles could be detected.Concerning the M. quadratus lumborum, no significant reduction of the pressure pain was achieved, but concerning hypertension, a significant decrease was only seen on the right side with a medium effect (Cohens’ d = 0.78) and the difference was significant at p < 0.0005. On average, the patients had 9.4 positive tender points in T1 (T1WSPP), and 28% scored a positive WSP-testing since they had twelve or more positive tender points. The percentage of the positively tested WSP patients in T2 decreased to 9%. In comparison, the healthy probands had on average, 3 positive tender points, and none of them scored a positive WSP-testing , and the probands were examined by two experienced examiners. We documented a correlation to other often with musician associated syndromes, such as hypermobility. Furthermore, our sample, though relatively small, was also characterized by an excellent matching of the control group by age and gender.The patients received therapy from highly qualified physiotherapists with long-term experience in the therapy of musicians and PRMD.The main weakness of the study is the case-control follow-up design, documenting improvements due to manual therapy. However, this could also be the effect of spontaneous recovery. We would like to emphasize that during ongoing music studies and under the stress of the approaching exams at the end of the semester, PRMDs usually increase and do not improve spontaneously. Indeed, we first planned a prospective randomized trial, applying the intervention and a sham intervention in PRMD students. However, due to the high level of suffering and the high pressure to be able to perform for those being concerned, we decided not to implement a control group. Since the study participants were music students at the beginning of their careers, we did not want to risk a chronification of prolonged pain and the distress this might cause. To be able to detect the influence of the placebo effect more studies are needed, which might examine a different group of study participants.Since the study does not distinguish between the different instruments, which often need a typical posture, more specific muscular patterns for each instrument should be investigated. This may help to develop standardized therapy concepts to avoid chronic pain as a result of the instrument played. Because of the difficulties in time management experienced by music students, the therapy was not always carried out over six weeks, twice per week, as recommended. A potentially stronger effect might be achieved through stricter timing of the therapies. Furthermore, we might further discuss how musicians tend to rate their health more positively , and furWhen PRMDs are detected at an early stage, physiotherapeutic treatments provide the opportunity to reduce pain significantly. A reduction in muscle tension can additionally be achieved by therapy, which can help to regain the normal range of motion that is required to play the instrument. For developing specific therapies, more studies are needed, including different kinds of instrumentalists and an enlarging of the study population. More controlled trials are needed to find the most effective evidence-based therapy to keep those making music for others physically healthy, and contributing to the well-being of people who experience their music.


Fibromyalgia (FM) is a condition characterized by musculoskeletal pain and multiple comorbidities. Our study aimed to identify four clusters of FM patients according to their core clinical symptoms and neuropsychological comorbidities to identify possible therapeutic targets in the condition. We performed a population-based cohort study on 251 adult FM patients referred to primary care according to the 2010 ACR case criteria. Patients were aggregated in clusters by a K-medians hierarchical cluster analysis based on physical and emotional symptoms and neuropsychological variables. Four different clusters were identified in the FM population. Global cluster analysis reported a four-cluster profile . The second analysis on clinical symptoms revealed three distinct subgroups . The third analysis of neuropsychological variables provided two opposed subgroups . These empirical results support models that assume an interaction between neurobiological, psychological and social factors beyond the classical biomedical model. A detailed assessment of such risk and protective factors is critical to differentiate FM subtypes, allowing for further identification of their specific needs and designing tailored personalized therapeutic interventions. Fibromyalgia (FM) is a chronic complex condition of unknown etiology, considered multifactorial and combining genetic and epigenetic factors that condition a persistent alteration in pain regulation mechanisms . The diaFibromyalgia is one of the leading health problems worldwide due to its high prevalence causing significant clinical and social burden, which may further exacerbate the patients’ level of disability , chronicThe prevalence of FM in Spain according to the EPISER study is high and has been estimated as approximately 2.4% of the general population over 20 years of age, representing approximately 700,000 people affected ,13. It aIt is important to note that heterogeneity and variability have been found in people with FM, both in clinical symptoms  and in dIn the present work, our study aimed to identify subgroups of FM patients using a hierarchical cluster analysis based on clinical and neuropsychological variables. Thus, clinical variables such as pain, fatigue, sleep quality, stiffness, anxiety, depression and disability at work with physical and emotional impact were studied. The psychological variables explored were acceptance, mindfulness, positive affect and negative affect, catastrophizing, surrender and perceived injustice in the FM population.We included 251 FM patients from the primary care health center of Aragon region, Spain , and selected those patients who met the following inclusion criteria: patients diagnosed with FM according to the 2010 ACR case criteria [Patients were contacted by telephone to explain the characteristics of the study protocol. Subsequently, the patients were randomly summoned by a psychologist in postgraduate training in order to carry out the clinical interview and complete the protocols in person. In the personal interview, the conditions and completion of questionnaires, study aims, research conditions and the confidentiality of the process and data were explained. After obtaining informed consent, the tests and interviews were administered, lasting approximately one and a half hours per person. The study followed the norms of the Helsinki Convention and its subsequent modifications and the Madrid Declaration of the World Psychiatric Association. Informed consent was requested from all patients before being included in the study and voluntary and informed participation was guaranteed. At any time, the patient could decline to participate or answer any questions he/she considered appropriate, as well as revoke the previously signed informed consent.This study is part of a project financially supported by the Health National Institute Carlos III in Madrid, Spain (grant number PI09/90301) and the data collection took place between July 2011 and May 2014.Sociodemographic variables such as age, sex, place of residence, marital status, educational level, cohabitation, employment status and comorbidity were recorded. A general survey was also performed on each participant.Physical impact variables of FM: pain, fatigue, sleep quality, stiffness and difficulty at work. The Spanish consensus version of the Fibromyalgia Impact Questionnaire (FIQ) was used. The Spanish FIQ version was used in this study . The FIQVariables of Emotional Impact or Distress, Anxiety and Depression. The Hospital Anxiety and Depression Scale (HADS), a self-reported measure, was used to detect anxiety and depression in people with medical illnesses. It comprises 14 items that are scored on a 4-point Likert scale. It includes two subscales—anxiety (7 items) and depression (7 items)—which are scored independently; the higher the score, the greater the anxiety or depression. The HADS has been validated in Spanish. It is recommended by the SER as an instrument to assess the emotional state or impact of patients with FM . The Spanish version has shown adequate test–retest reliability and a Cronbach’s alpha of 0.69 .Acceptance: It is measured with the Chronic Pain Acceptance Questionnaire (CPAQ). The Spanish validation of the questionnaire was used in this study. It measures pain acceptance as a predictor of well-being in patients with chronic pain. It is an abbreviated version of the CPCI-42 that maintains its psychometric properties. It analyzes 2 subscales: willingness to perform activities of daily living and acceptance of pain. It is composed of a list of 20 self-administered items, assessed on a rating scale from 0 (never true) to 6 . The result of the two subscales is summed directly and the range is between 0 and 120. The higher the score, the greater the acceptance of pain and/or availability to perform the activities. The Spanish version has shown adequate test–retest reliability, internal consistency and construct validity .Mindfulness: It is measured with the Mindful Attention Awareness Scale (MAAS) validated in Spanish. The mindfulness scale is composed of 15 items, which measure the construct of “being aware”, focused on the present and without judging the situations being experienced. The correctness of the items is from 1  to 6 , summed directly. There is only one factor, which is the total of the scale. The range is between 15 (minimum mindfulness) and 90 (maximum mindfulness). In an attempt to control for socially desirable responses, participants are asked to respond according to what actually reflects their experience and not what they think it should be. Cognition, emotions, physical, interpersonal and general domains are assessed. The original MAAS had high internal consistency  .Positive and Negative Affectivity : Most studies on the structure of affect agree that affect is made up of two dimensions or factors: positive and negative affect. The PANAS scales have proven to be a valid and reliable measure to assess the presence and degree of positive and negative affect in clinical and normal populations of adolescents, adults and older adults, validated in Spanish. The PANAS is characterized by an internal consistency with alphas of 0.86 to 0.90 for positive affect and 0.84 to 0.87 for negative affect. The correlation between the two is invariably low, ranging from −0.12 to −0.23, which reinforces the idea that they are independent domains of affective well-being. Currently, this scale has an abbreviated version of 10 items that have proven to be cross-culturally reliable. PANAS consists of two mood scales with 10 items each for the assessment of positive and negative affectivity. The score for each range of the scale goes from 0 to 50. A positive affect is obtained by adding the odd-numbered items and negative affect by adding the even-numbered items. The scores for both affects are obtained by adding the numbers assigned to the 10 items that make up each of the two scales. The mean positive PANAS for a sample of young students was 32 and the mean negative PANAS was 23. People with scores above 38 for positive and below 16 for negative are characterized by an extremely positive affect balance. People with scores below 25 in positive and above 30 in negative give an extremely negative affect balance . Catastrophizing: It is measured with the Spain-validated Pain Catastrophizing Scale (PCS). It consists of 13 items divided into three subscales that analyze rumination or meditation doubt (4 items), magnification or exaggeration (3 items) and hopelessness or helplessness (6 items), and its design focuses on feelings and thoughts related to pain, valuing them on a scale from 0  to 4 . The 3 subscales are summed and the range is between 0 and 52. A higher score would correspond to a higher frequency and intensity of negative thinking and feelings regarding pain. The maximum total score is 52, such that a higher score would correspond to a higher frequency and intensity of negative thinking and feelings regarding pain .Surrender: The Spanish version of the Pain Self Perception Scale was used. It is composed of 24 items that measure the self-processing of thoughts and feelings that can be experienced during an episode of severe pain. It is a self-administered questionnaire, where responses are measured using a 5-point scale between 0 (minimum intensity) and 4 (maximum intensity). There is only one factor, which is the global factor of the scale, and there are no subfactors. It is scored between 0 and 96 .Psychological inflexibility: It is measured by the self-reported Psychological Inflexibility of Pain Scale, which contains 12 items, with two main subscales: avoidance (8 items) and cognitive fusion (4 items); both measure the inability to maintain our values in the presence of unpleasant thoughts, emotions and physical symptoms. The statements are scored on a Likert-type scale ranging from 1 (never true) to 7 . Total 12-item scores can range from 12 to 84. Higher scores would indicate greater psychological inflexibility in the face of pain. Its psychometric properties are considered adequate .Perceived injustice: This construct is measured by a questionnaire that reliably measures how a traumatic situation affects people’s lives validated in Spanish. It contains 12 items, with 2 subscales of severity/irreparability (6 items) and guilt/injustice (6 items) on a 5-point scale, from not at all (0) to all the time (4). The total scale scores range from 0 to 48. The psychometric properties of the injustice experiences questionnaire (IEQ) are considered adequate for use in the study ,29.SPSS version 21 was used to perform cluster analysis, which is a multivariate technique that seeks to group variables to achieve maximum homogeneity in each group and the greatest difference between groups. We will rely on cumulative hierarchical algorithms, i.e., the method that forms groups by making larger and larger clusters. In our study, three cluster analyses were performed using the hierarchical clustering method , as discussed below. First of all, we can say that the distance considered is the Euclidean distance . In addition, in order to compare the distances, the distances are standardized into Z-scores. The linkage technique is the inter-group average. Three cluster analyses were performed and the objective consisted first of all in grouping all the individuals into non-predefined subgroups and classifying or organizing them according to the 14 variables studied in order to obtain similar profiles with respect to psychological and clinical variables. From the result obtained, two other cluster analyses were performed, one with psychological variables  and another cluster analysis with respect to clinical variables .Global cluster 1 analysis included pain, fatigue, sleep quality, stiffness, difficulty at work, anxiety/depression, surrender, injustice, mindfulness, catastrophizing, acceptance, positive affect and negative affect. These variables have been analyzed from a sample collected from 251 patients; 96.8% are valid cases and 3.2% are missing values. In our study, the matrix of distances between the different clinical and psychological variables mentioned above was performed and below we present the average (inter-group) linkage of the psychological constructs and clinical variables mentioned above .The dendrogram shows the formation of the clusters, as well as the distances between them. It can be seen, for example, that the variables (observations) closest to each other were pain (FIQ_5); fatigue (FIQ_6); sleep quality (FIQ_7); stiffness (FIQ_8); anxiety ; depression ; and difficulty at work (FIQ_4), which form the first group (distance closest to 0) and were the closest to each other. These are joined with injustice, catastrophizing (CATAST), negative affect (PANAS_negative) and positive affect (PANAS_positive). On the other hand, it was joined by proximity acceptance (CPAQ) and mindfulness and, finally, a fourth cluster with the variable surrender .The summary of the subgroups obtained from the global analysis was as follows: cluster 1: FM patients with pain, fatigue, sleep quality, stiffness, anxiety, depression and difficulty at work; cluster 2: FM patients with injustice, catastrophizing, negative affect and positive affect; cluster 3: FM patients with mindfulness and acceptance; cluster 4: FM patients with surrender.Cluster 2 analysis: pain, sleep quality, fatigue, stiffness, anxiety, depression and difficulty at work. Of the sample of 251 patients, 100% were valid cases. Below, we present the distance matrix of the variables analyzed .The cluster analysis showed the following: in the first stage, fatigue was clustered with work difficulty. In the second, anxiety was clustered with depression. In the third stage, sleep quality was clustered with rigidity. In the fourth stage, fatigue, work difficulty, sleep quality and stiffness were clustered. In the fifth, pain was combined with fatigue, work difficulty, sleep quality and stiffness. In the sixth, pain, fatigue, work difficulty, sleep quality and stiffness were combined with anxiety/depression .The dendrogram shows the grouping orders according to intensity: fatigue (FIQ_6) and work difficulty (FIQ_4) were the closest. Anxiety and depression were strongly linked and so on, as were sleep quality and stiffness (FIQ_7 and FIQ_8), (FIQ6 + FIQ4) with (FIQ_7 and FIQ_8) and this group with pain (FIQ_5) .Cluster 1 consisted of patients with fatigue, work difficulty, sleep quality, stiffness and pain; however, a separate group with pain was identified in cluster 2 and anxiety and depression were linked in cluster 3. The interpretation of the combination scale indicates that the relationship between the variables anxiety and depression and functional disability (assessed using FIQ) was 25 times less relevant than the stronger relationship between fatigue and work difficulty or between anxiety and depression symptoms.Cluster 3 analysis: The variables analyzed were: catastrophizing, surrender, mindfulness, acceptance, injustice, positive affect and negative affect. Of the sample of 251 patients, 96.8% were valid cases and 3.2% were missing values. In our study, a matrix of distances between the different psychological variables mentioned was performed .In addition, we present the average (inter-group) linkage of the aforementioned psychological domains .According to the clustering history under the criterion of proximity, they were grouped as follows: in the first stage, surrender and injustice are united in clusters. In the second stage, catastrophizing was united with surrender and injustice. In the third stage, acceptance and positive affect were clustered together. In the fourth stage, catastrophizing, surrender and injustice were clustered together with negative affect. In the fifth, mindfulness was joined with acceptance and positive affect, and, in the sixth, mindfulness, acceptance and positive affect were joined with catastrophizing, surrender, injustice and negative affect. The result of the previous process is represented by a graph called a dendrogram in the form of an inverted tree, where, on the vertical axis, the variables (and groupings) are placed and on the horizontal axis a relative measure of intensity is represented, rescaled inversely in distance.The dendrogram shows the formation of the clusters, as well as the distances between them. It can be seen, for example, that the variables (observations) closest to each other are surrender and injustice, which form the first group (distance closest to 0). These two are joined with catastrophizing and then these three with negative affect, forming a relatively cohesive cluster. On the other hand, acceptance and positive affect were joined by proximity, and this cluster is joined in turn by mindfulness, forming the second cluster .The observations that are most similar to each other in the first cluster are surrender, injustice and catastrophizing, and the last to be incorporated is negative affect. In the second cluster, the most similar and close variables are acceptance and positive affect and the most different is mindfulness. The two large clusters above are obviously part of a set of variables, which is the final total cluster .The following cluster classification was then obtained from the third cluster analysis: cluster 1: FM patients with high scores of surrender, unfairness, catastrophizing and negative affect; and cluster 2: FM patients with high scores of acceptance, positive affect and mindfulness.Our research has revealed that, by using cluster analysis on clinical data and psychological variables, we can identify different FM subgroups. In the first cluster analysis, which included clinical variables, anxiety and depression components and psychological domains, four subgroups were defined: cluster 1 displayed high scores in pain, fatigue, poor sleep quality, rigidity, anxiety/depression and difficulties at work; cluster 2 displayed high scores in injustice, catastrophizing, negative affect and positive affect; cluster 3 displayed high scores in mindfulness and acceptance; and, finally, cluster 4 displayed high scores in surrender. In the second cluster analysis, which included clinical variables and anxiety/depression components, three subgroups were defined: cluster 1 reported high fatigue scores, sleep quality, stiffness and difficulties at work; cluster 2 displayed high pain scores; and cluster 3 displayed high anxiety/depression scores. In the second cluster analysis, the objective of which was to group individuals into predefined subgroups and classify or organize them according to similar profiles with respect to the variables of pain, fatigue, sleep quality, stiffness, anxiety, depression and difficulty at work, fatigue, difficulty at work, sleep quality and stiffness appeared to be linked. It is important to highlight that difficulty at work does not appear associated or linked to pain .In the third cluster analysis that included psychological constructs, a first subgroup was defined, with high scores in surrender, injustice, catastrophizing and negative affect, and a second subgroup with high scores in acceptance, positive affect and mindfulness.Our study has empirically demonstrated that the psychological and clinical factors studied could be partly responsible for both the explanation of the health outcomes of these FM patients and their chronification, supporting models that assume an interaction between biological, psychological and social factors .A systematic review in the scientific literature identified different subgroups of FM according to criteria of patients without concomitant disease (FM type I), patients with rheumatic and autoimmune diseases (FM type II), with severe psychiatric disturbance (FM type III) and FM simulator patients (FM type IV) . In this line, D’Souza et al.  identifiOur data agree with these studies, as they suggest the diagnostic heterogeneity that characterizes FM patients and that could be due to anxiety and depression symptomatology. These differences could be interpreted as being associated with one type of patients and not with others presenting with levels of pain, fatigue and joint stiffness .Our study confirms the existence of clearly distinct patient profiles, which have also been described in previous studies ,32. HoweMuch of the multifactorial research on the biopsychosocial approach to FM shows significantly more psychological problems than healthy controls and also more than patients with chronic pain disorders, such as those with rheumatoid arthritis. Differences have been found in active coping strategies and, in the case of patients with FM, they present worse physical functioning, greater pain, poor coping strategies for their pain and a more limited support network than the healthy controls studied .On the other hand, Fietta et al.  indicateStudies have shown that there is a correlation between symptoms of psychopathology with the duration of the disease and pain . Other fIn order to analyze the causes of the variability in depressive disorders, researchers have studied various patient subgroups. A study conducted by Broderick et al.  found thThere is great heterogeneity in relation to the presence of anxiety and depression disorders in the population affected with FM and although their prevalence is high, it cannot be established that these disorders are causal in nature or intrinsic to FM. However, there is scientific evidence that people with a higher level of anxiety and depression have a worse prognosis and their disease progresses negatively; it is also necessary to highlight a greater negative impact on their daily lives and a poorer quality of life. The subgroups of the study by Hasset et al.  was baseBoersma and Linton’s study  pointed This type of multidisciplinary intervention is usually applied in accredited hospital units and with people affected by FM with a degree of severity or severity much higher than that of patients with FM who are usually treated in primary care, the level of care where the present study was carried out. Given that there is scientific consensus on the high explanatory value of the psychosocial model in FM, and that the empirical data also support it, all this leads us to think of the importance of the application of cognitive and behavioral interventions. It is crucial to highlight the significance of introducing these multidimensional treatments for FM in primary care and making them accessible to all individuals with FM. This approach aims to enhance their overall health status, improve their quality of life and reduce the social and health burden and other costs derived from disability and sick leave in individuals with fibromyalgia.To the best of our knowledge, only a few previous reports used cluster analysis to explore clinical and neuropsychological symptoms in the Spanish FM population. Moreover, we took into account the comorbid health conditions and clinical and neuropsychological domains in our analysis, allowing for a wide extension of our outcomes in routine clinical practice. However, several limitations need to be addressed. The main limitation is the cross-sectional study design, correlational in nature, where the type of sampling was performed in primary care; this limits the generalization of the results and may affect the risk of over-adjustment of the clusters found. Therefore, experimental and longitudinal study designs are more appropriate to better understand the differentiating profile of FM patients and their subsequent classification into various subgroups. However, the high effect sizes indicate that these results reflect the intergroup differences found. On the other hand, the potential to combine machine/deep learning to further enhance the performance and extend the application scenarios of the proposed methods is foreseen as a valuable tool for future studies ,43. The psychological  and clinical  factors studied are partially responsible for both the explanation for the health outcomes of these FM patients and their chronification. These empirical results support models that assume an interaction between biological, psychological and social factors. In the assessment of the FM patient, it is very important to use clinical variables, such as pain, fatigue, disability or difficulty working, sleep quality and stiffness, as well as other psychological variables related to anxiety, depression and other psychological constructs, in order to define the presence of subgroups and to consider the therapeutic approach in each of them.


While fear of movement is an important predictor of pain and disability in osteoarthritis (OA), its impact on patients with hip OA remains uncertain. This study aimed to determine whether fear of movement, evaluated by the Tampa Scale for Kinesiophobia (TSK)-11, and pain catastrophizing, evaluated by the Pain Catastrophizing Scale (PCS), were associated with quality of life (QOL) in patients with hip OA.This cross-sectional study was conducted between November 2017 and December 2018. Ninety-one consecutively enrolled patients with severe hip OA were scheduled for primary unilateral total hip arthroplasty. The EuroQOL-5 Dimensions questionnaire was used to measure general QOL. The Japanese Orthopedic Association Hip Disease Evaluation Questionnaire was used to assess disease-specific QOL. The covariates included age, sex, body mass index (BMI), pain intensity, high pain catastrophizing (PCS ≥ 30), and high kinesiophobia (TSK-11 ≥ 25). Variables were subjected to multivariate analysis using each QOL scale.In multiple regression analysis, pain intensity, high pain catastrophizing, and BMI were independently correlated with the disease-specific QOL scale. High pain catastrophizing, pain intensity, and high kinesiophobia were independently correlated with the general QOL scale.High pain catastrophizing (PCS ≥ 30) was independently associated with disease and general QOL scales. High kinesiophobia (TSK-11 ≥ 25) was independently associated with the general QOL scale in preoperative patients with severe hip OA. Osteoarthritis (OA) is a common chronic disease that causes pain, functional limitations, and a reduced quality of life (QOL) among adults worldwide , 2. The Recent studies reported that pain catastrophizing in knee OA is associated with daily physical activity , 6, walkThis study aimed to investigate the effect of fear of movement with the Tampa Scale for Kinesiophobia (TSK)-11 and pain catastrophizing with the Pain Catastrophizing Scale (PCS) on both general and disease-specific QOL scales in patients with severe hip OA.This cross-sectional study was approved by the institutional review board of the University of Tokyo Hospital, with the ethical approval number: 11,725-(1), and was conducted in accordance with the World Medical Association Declaration of Helsinki. We included 105 patients with hip OA, who were scheduled to undergo primary unilateral total hip arthroplasty (THA) at our institution from November 2017 to December 2018. Written informed consent for all procedures was obtained from all patients at hospital admission. The inclusion criteria were: (1) diagnosis of hip OA by an orthopedic surgeon through clinical examinations and radiographic findings using the American College of Rheumatology criteria; (2) radiographic hip OA > grade 3 using radiographic images on the Kellgren–Lawrence criteria; and (3) presence of hip pain for at least six months and functional limitations in ADL that required THA. We excluded 14 patients for the following reasons: inability to obtain informed consent (n = 3); incomplete response to the questionnaires (n = 5); complications of psychiatric disorders such as schizophrenia (n = 4); and presence of severe knee OA compatible with hip pain severity (n = 2). Finally, 91 patients with severe hip OA were evaluated in this study.We investigated patients’ demographic data, including age, sex, body mass index (BMI), and smoking history. Validated questionnaires were completed by each participant after admission, before surgery.Pain intensity was measured using a visual analog scale (VAS), which is a component of the Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ) . VAS, a Pain catastrophizing was assessed with the 13-item PCS, a validated and widely used instrument for measuring pain-related catastrophic thinking , 24. ParFear of movement was assessed using the Japanese version of the previously validated TSK-11 . TSK-11 QOL was assessed with two patient-record outcome measures. The EuroQOL-5 Dimensions (EQ-5D)-3 L is a generic health-related QOL instrument tool with available local Japanese set value . This quThe JHEQ was used to evaluate disease-specific QOL in patients with hip joint disease. This questionnaire included questions related to movements specific to the Asian lifestyle, such as the use of a Japanese-style toilet and getting up from the floor. As such, JHEQ is a useful tool for evaluating Japanese patients with hip disease. This questionnaire has also been reported as reliable and valid . JHEQ coThe sample size was estimated using G*Power 3.1.9.6 for Mac  . More spP < 0.05. Statistical analyses were performed using the JMP software .Demographic variables were presented as medians and interquartile ranges (IQR). Patients were stratified into groups based on a predefined cut-off scores for PCS and TSK-11. Fisher’s exact test was used to compare categorical parameters, and the Wilcoxon rank-sum test was used to compare continuous parameters between the groups. Correlation of QOL scores (EQ-5D and JHEQ) with each variable was analyzed using the Spearman’s rank correlation coefficient test. Factors affecting QOL scores were determined. Each QOL score (EQ-5D and JHEQ) was set as a dependent variable. VAS score; high pain catastrophizing (PCS ≥ 30), of which association with QOL was previously reported ; high kiP = 0.003, P = 0.035, P = 0.001, and P = 0.009, respectively). There was no significant difference in VAS score between two groups. Patients with high pain catastrophizing had significantly lower JHEQ total, JHEQ pain, JHEQ movement, JHEQ mental, and EQ-5D scores than those with low pain catastrophizing . VAS and TSK-11 scores in patients with high pain catastrophizing were significantly higher than those with low pain catastrophizing (P < 0.005 for both). Correlations between each QOL scale showed a significant difference in VAS, TSK-11, and PCS scores     Table . EQ-5D sIn this study, high pain catastrophizing (PCS ≥ 30) was associated with both disease-specific and general QOL in patients with severe hip OA before THA. High kinesiophobia (TSK-11 score ≥ 25) was associated with the general QOL scale. High pain catastrophizing had the worst or second-worst QOL, followed by pain intensity, depending on the scale used. High kinesiophobia had the third-worst general QOL after pain intensity and pain catastrophizing. High pain catastrophizing and high kinesiophobia were associated factors for QOL in patients with severe hip OA.A cross-sectional study on severe hip OA reported that pain catastrophizing was independently associated with disease-specific and general QOL scales . HoweverTwo studies evaluated kinesiophobia in patients who underwent THA. One study showed that patients with high kinesiophobia (TSK-13 ≥ 40) had higher preoperative Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total and functional scores . In the Pain intensity was not significantly different between the high and low kinesiophobia groups in this study. Several studies reported an association between pain intensity and kinesiophobia. The intensity of activity-related and resting pain was associated with the TSK-17 score in patients with knee OA . HoweverBMI was associated with disease-specific QOL scores, followed by pain intensity and high pain catastrophizing in our study, suggesting that BMI is a factor that can impair QOL. Several studies reported an association between BMI and hip OA. In this regard, a retrospective cohort study reported that BMI had an independent, weak negative impact on health-related QOL in patients with hip OA . BMI wasHigh kinesiophobia and high pain catastrophizing were independent associated factors of QOL in this study. We suggested that efforts to increase QOL in patients with severe hip OA before THA may be enhanced by strategies aiming to reduce the fear of movement and pain catastrophizing. However, this was a cross-sectional study, and longitudinal studies are required to investigate the association of kinesiophobia, pain catastrophizing, and other psychological factors with QOL. There is evidence that specific pain neurophysiology education could reduce pain catastrophizing and increase knowledge about pain in people with chronic pain . There aThis study had several limitations. First, it included only a small number of patients from a single center; therefore, its generalizability remains unclear. Second, while we only analyzed pain catastrophizing and fear of movement, other psychological factors  have been evaluated in a systematic review of the outcomes of THA and total knee arthroplasty . Third, High kinesiophobia (TSK-11 ≥ 25) was associated only with general QOL in patients with preoperative severe hip OA. High pain catastrophizing (PCS ≥ 30) was associated with both, disease-specific and general QOL. This study suggested that screening for individual psychological factors, such as pain catastrophizing and fear of movement, should be considered, and therapeutic intervention should be assessed to improve QOL in patients with severe hip OA.