This study investigated the long-term effects (12 months post-rehabilitation) of a standard inpatient multidisciplinary rehabilitation program for patients with chronic low back pain (CLBP), in which a control group (CG) received pain competence training and an intervention group (IG) received combined pain competence and depression prevention training.n = 583 patients were included into per protocol analyses. To examine the effects of rehabilitation on depressive symptoms, pain self-efficacy, and work ability, patients were stratified in repeated-measures analyses of variance by treatment condition (IG vs. CG), level of depressive symptoms (low vs. high), and time of assessment . The impact of each treatment on pain-related days of sick leave  was determined separately by conducting non-parametric analyses. Multiple imputations (n = 1225) confirmed the results. Effects were interpreted if clinical significance was given.In this prospective control group study with cluster-block randomization, a total of Only patients with high levels of depressive symptoms showed long-term improvements in depressive symptoms and self-efficacy. Long-term improvements in work ability index and mental work ability item were restricted to the IG. Furthermore, long-term effects on pain-related DSL were ascertained by per protocol and multiple imputation analyses only for the IG.Patients with high levels of depressive symptoms showed improvements in depressive symptoms and self-efficacy, supporting the psychological effectiveness of both interventions. However, the beneficial long-term effects of rehabilitation on work ability and pain-related DSL among the IG support implementation of combined pain competence and depression prevention training.DRKS00015465 ; date of registration: 03.09.2018.The online version of this article (10.1186/s40359-019-0282-3) contains supplementary material, which is available to authorized users. Chronic low back pain (CLBP) is among the most common diseases in Western countries  and induHowever, based on the major impact of psychological processes in pain chronification , 6–9, psBased on this empirical evidence, Hampel et al. –16 develIn contrast, the module of depression prevention training comprised five guided 60-min group sessions and was based on Beck’s cognitive theory of depression . The intervention group (IG) was treated with both modules and compared to a control group, to whom the pain competence training was applied only. In sum, the IG showed significant sustainable psychological effects in orthopedic rehabilitation compared to pain competence training without prevention of depressive symptoms.In the present study, this training was optimized with regard to didactic methods and manualized for evaluation . The stuPrevious quantitative analyses revealed similar short- and mid-term effects on depressive symptoms, anxiety, and pain from the combined pain competence and depression prevention training compared to treatment-as-usual with pain competence training only . NeverthThe aim of this multi-center study was to analyze long-term effects of the modified combined cognitive-behavioral pain competence and depression prevention training in a different rehabilitation setting with different sample characteristics compared to the prior bi-center study. For this purpose, its effectiveness was investigated on depressive symptoms as a primary outcome. Moreover, self-efficacy was assessed as a secondary outcome, which is a core outcome of clinical trials , can be treatment condition and level of depressive symptoms as between-subjects factors and time of assessment as a within-subjects factor. The treatment condition consisted of the control group , who received pain competence training, and the intervention group , who received combined pain competence and depression prevention training. The level of depressive symptoms was assessed with the German version of the Center for Epidemiological Studies Depression Scale , post (t1), 6 months (t2), and 12 months (t3) after rehabilitation.A randomized controlled trial with cluster-block randomization was conducted. In the context of block randomization, the intervention condition was always carried out in two clinics and the control condition was simultaneously carried out in the other two clinics in order to control for seasonal effects. In addition, conditions were alternated every two months in terms of cluster randomization and an equal number of the two conditions were performed in each clinic . A 2x2x4 CG; n = 8, who re CG; n = 8, who red = .38 for the 24-month follow-up, a small effect size in the primary outcome measure “depressive symptoms” was assumed for the 24-month follow-up test between the IG and CG for the respective subgroups of depression. For this effect size, with an alpha level of .05, two-sided testing, and a desired power level of 1-β = 0.8, a prior power analysis using G*Power yielded a sample size of n = 176 for each of the four study groups. In the previous 24-month follow up-study, the dropout rate was 37%. Conservatively, a dropout rate of 40% and a response rate of 70% were calculated, so that a total sample of approximately n = 1173 patients enrolled at the time of measurement prior to rehabilitation was sought. For the present analysis, only data from the 12-month follow-up were analyzed, as in the 24-month follow-up correcting for missing data in the work ability score by multiple imputations (MI) failed due to extreme amount of missing data.On the basis of previous studies and our own preliminary study –16, whicPatients were informed about the study during the first physical consultation in the clinic and were allocated to the treatment condition according to the week of arrival in the clinic. Allocation of the four clinics to the sequence of treatment condition took place according to a randomized Latin square design to ensure a balanced design. The assignment was conducted by an independent doctoral student at the Europa-Universität of Flensburg. Thus, the physicians and nursing staff at the clinics were blinded to the patients’ group assignments. It was not applicable to blind the therapists and patients, as the amount and contents of the treatment revealed the allocation to the groups. Recruitment took place from October 2014 until December 2015 and was finished when the expected sample size was achieved.All data  were collected using questionnaires filled in by the participants. Informed consent was obtained from all participants included in the study. This study had received full approval of the ethical review board of the German Psychological Society (DGPs) and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments.n = 583 participants were recruited in four inpatient rehabilitation clinics in Germany and included in per protocol analyses. The age ranged from 28 to 64 with a mean age of 53.3 years (SD = 6.1), 81.8% were female, and the mean pain duration was 15.2 years , informed consent for participation, and German language skills. Patients were excluded if they underwent surgery or had had an accident in the last 6 months before rehabilitation, had somatic diseases inducing back pain, were pregnant, had infections, had cardiovascular or metabolic diseases affecting rehabilitation, or had a serious psychiatric disorder.The evaluation of the combined pain competence and depression prevention training was embedded in a standard inpatient multidisciplinary rehabilitation in four German clinics lasting three to four weeks. Four modules of pain competence training were delivered to both treatments, but the IG also received four modules of depression prevention training. All eight modules consisted of 75-min group interventions guided by a psychotherapist and a 25-min group workshop without a psychotherapist.not at all confident” to 6 = “completely confident”). A sum score was calculated with higher scores indicating higher self-efficacy (range 10–60), showing a good internal consistency (α = .94), similar to Mangels et al. , similar to the normative samples of Hautzinger et al. . The co et al.  and level of depressive symptoms  as between-subjects factors and time of assessment  as a within-subjects factor. For the WAI , only three sample points could be included into the univariate two-way repeated-measures ANOVA, as no post-assessment took place . Moreover, a multivariate repeated-measures ANOVA was performed for the two single WAI items assessing the physical and mental work ability. Additionally, pairwise comparisons corrected by Bonferroni were performed to detect mean differences.For the CES-D and PSEQ, univariate two-way repeated-measures analyses of variance (ANOVA) was conducted with Furthermore, non-parametric analyses were carried out; DSL were analyzed with Friedman’s ANOVA separately for the CG and IG, followed by Wilcoxon signed-rank tests.p < .05 for all calculations due to the explorative character of the analyses. The effect sizes of the ANOVAs were interpreted as small (η2 = .01), medium (η2 = .06), or large , medium (d = .50), or large (d = .80). Effect sizes for Pearson product-moment correlations (r) were interpreted as small (r = .10), medium (r = .30), and large . The two-tailed significance level was set at 2 = .14; ). For thr = .50; ).n = 1225). The 10 imputations substituted single missing values as well as missing data due to dropout from the study. Due to a significant result on Little’s Missing Completely at Random (MCAR) test and as the power of testing increased with multiple imputations, these analyses were considered only as validation of the PP results. In addition, only results with at least a small effect size were interpreted .PP results were validated by calculations after MI  = 0.22, p = .639). However, the patients who dropped out were more often male, not married, and reporting more than 14 DSL and were less often employed. Additionally, they were younger, reported a shorter pain duration, had lower scores in the PSEQ and WAI, and reported a higher average pain intensity.Dropout rates did not depend on treatment condition . Regarding the mental work ability item, the IG improved significantly in the long-term with a medium effect size , while the CG did not show a clinically significant enhancement in mental work ability.Simple interactions were ascertained for the WAI  and mental work ability . All effects reported above were confirmed by MI analyses  = 45.79, p < .001). A subsequent Wilcoxon test showed a significant long-term effect (Table 2(2) = 76.55, p < .001; Additional file Friedman’s ANOVA revealed a significant change in pain-related DSL over time in the IG  = 4.36, p = .113; Table 2(2) = 22.92, p = .002) as well as a significant long-term effect on the Wilcoxon test  = 5.69, p = .017).Descriptive analyses of the PP results indicated that especially the distributions 12 months after rehabilitation differed by treatment condition: More participants in the IG than in the CG improved (30.2% vs. 20.8%), and fewer worsened (7.8% vs. 14.6%) from pre-rehabilitation until 12 months post-rehabilitation. Overall, MI analyses revealed significant effects for both conditions, but effect sizes in the IG were larger than in the CG and PP analyses were not significant for the CG. Further descriptive analyses with post hoc chiThis paper predominantly sought to evaluate the long-term effects of a combined cognitive-behavioral pain competence and depression prevention training on depressive symptoms, pain self-efficacy, work ability, and pain-related DSL. Patients with high levels of depressive symptoms improved more from the rehabilitation in depressive symptoms and pain self-efficacy, pointing to the significant influence of depressive symptoms on CLBP . Since pHowever, the IG had more favorable results compared to the CG in the long-term in general work ability (WAI), mental work ability, and pain-related DSL. The results for work ability are particularly of interest because the IG seems to have demonstrated a differential effect on mental work ability but not on physical work ability. These selective effects can be attributed to the content of the additional depression prevention training in the IG  is more effective in increasing  work ability and reducing pain-related DSL than a treatment-as-usual including pain competence training only. The preliminary results of the differential effects of level of education on psychological outcomes need to be replicated. Overall, the effectiveness of multidisciplinary treatments for CLBP applied by a multi-professional team was confirmed by the sustainable effects of both interventions on physical work ability among all patients and on depressive symptoms and pain self-efficacy among patients with high levels of depressive symptoms.Additional file 1:Table S1. Modules’ description of the pain competence and depression prevention training. Table S2. Means (M), standard deviations (SD), within-group effect sizes Cohen’s d (ES), and pairwise comparisons (p) for the interaction effect of level of depressive symptoms and time for depressive symptoms (CES-D) and the Pain Self-Efficacy Questionnaire (PSEQ). Table S3. Means (M), standard deviations (SD), within-group effect sizes Cohen’s d (ES), and pairwise comparisons (p) for the interaction effect of treatment condition and time for the Work Ability Index (WAI). Table S4. Repeated measures ANOVA results for main and interaction effects of treatment condition (TC), level of depressive symptoms (DS), and time of assessment (T) for pain self-efficacy and subjective work ability . Table S5. Observed and expected frequencies of days of sick leave because of pain dichotomized in up to and more than 2 weeks at the beginning (t0) as well as 6 months (t2) and 12 months (t3) after rehabilitation for both treatment conditions . (DOCX 60 kb)


The aim of the research was to further evaluate the analgesic effect of a synergistic low-dose ASA–PAR–CAF–CLF combination in the treatment of low back pain, in a parallel, multiple-dose, double-blind, active controlled clinical trial. A number of 89 patients with low back pain of at least moderate intensity were randomly assigned to receive Algopirin® (ALG), a combinational product containing 125 mg ASA, 75 mg PAR, 15 mg CAF, and 2 mg CLF, or PAR 500 mg, a drug recognized by American Pain Society as “safe and effective” in the treatment of low back pain. One tablet of the assigned product was administered three times a day for seven consecutive days. The patients evaluated their pain level using a Visual Analog Scale prior to administration, and at 1, 2, 4, and 6 h after the morning dose. Time course of effect was similar in structure and size for both treatments. Pain relief appeared rapidly and steadily increased over 4 h after drug administration. Differential pain curves of ALG and PAR were very similar and comparable with the previously determined ALG analgesia pattern in migraine. Differences between the daily mean pain scores were not statistically significant for the two treatments. Similar results were obtained for the Sum of Pain Intensity Differences (SPID) for 0–4 h and 0–6 h intervals as well as for the time course of the proportion of patients with at least 30% and at least 50% pain relief. In conclusion, in spite of very small doses of active components, ALG proved equally effective to the standard low back pain treatment and therefore a viable therapeutic alternative, mainly for patients with gastrointestinal and hepatic sensitivity.The present paper continues a more complex research related to the increased synergism in terms of both anti-inflammatory and analgesic effect obtained by the addition of chlorpheniramine (CLF) to the common acetylsalicylic acid (ASA), acetaminophen (PAR), and caffeine (CAF) combination. This synergistic effect was previously highlighted both Trial Registration:www.ClinicalTrials.gov, identifier EudraCT No.: 2015–002314–74. Low back pain (LBP) affects a large number of people in developed countries and, following the associated disability, has important consequences on the health system and economy . In factLBP is usually divided into acute LBP , sub-acute LBP , and chronic LBP  . In someThe common therapy to reduce pain, inflammation, and functional disability includes nonsteroidal anti-inflammatory drugs (NSAIDs), PAR, corticosteroids, and various opioids.NSAIDs are the most widely used drugs in the world and their use in the treatment of LBP makes no exception . In factA systematic review of the clinical trials with NSAIDs in LBP  analyzedIn a later report from 2000 , the anaMore recently, a meta-analysis  revealedN = 309).Four studies compared one or more types of NSAIDs with PAR, concluding that there is moderate evidence that NSAIDs are equally effective with PAR for acute LBP . HoweverIn LBP, PAR is considered safer than NSAIDs, since NSAIDs are often associated with upper gastrointestinal tract bleeding/perforation . HoweverASA was compared to other drugs in LBP in an old study on 45 patients admitted to a military hospital . 625 mg Combinations of ASA and other compounds in the LBP treatment were tested since the late 1980s. Hence, the following treatments were administered three times a day to groups of 40 patients each: i) mefenamic acid 500 mg; ii) chlormezanone 100 mg and paracetamol 450 mg; and iii) ethoheptazine 75 mg, meprobamate 150 mg, and ASA 250 mg. The number of patients reporting no pain after 1 and 7 days were i) 21, ii) 23, and iii) 20. The number of patients reporting adverse effects in the study was i) 9, ii) 10, and iii) 16 .Aside from the fact that treatments had approximately the same effect, it is important to note that “no pain” can rarely be achieved, only after several weeks of treatment, and only for patients with moderate initial pain. Therefore, pain relief to less than 70% or to less than 50% of the initial value could therefore be a more appropriate marker of effect.In all the above studies implying treatments longer than a few days, side effects that cannot be neglected also appeared .Synergistic drug combinations have been envisaged to be a promising approach to treat in pain treatment, since the complementary mechanism of action of the components lead to an effect that is superior to the additive effects of the individual constituents. In fact, the term “synergy” itself, originating from the Greek word meaning “working together,” perfectly resumes how “cooperation” between different active moieties leads to a combined boost in drug efficacy.ASA–PAR–CAF is a well-known and may be the most representative example of synergism . A meta-® in the US and Anadin Extra® in UK.Combinations containing less than 250 mg PAR, 250 mg ASA, and 50 mg CAF per dosage form were extensively studied as analgesics in migraine in the last 40 years . In 1993in vitro, in analgesia and carrageenan-induced rat paw inflammation models, as well as in vivo in the treatment of mild algic syndrome , an authorized combination of the four active containing 125 mg ASA, 75 mg PAR, 15 mg CAF, and 2 mg CLF  Good Clinical Practice regulations, as well as the Joint Clinical Practice Guideline from the American College of Physicians and the American Pain Society on the diagnosis and treatment of LBP .The study protocol (EudraCT number: 2015-002314-74) was approved by the National Agency for Medicines and Medical Devices  and the National Bioethics Committee for Medicines and Medical Devices . All participants gave written informed consent prior to study participation and were instructed by specialized personnel on how to record the characteristics of their back pain. All patients were allowed to terminate their participation in the trial at any time, without restrictions.A number of 89 male and female patients , aged between 18 and 65 years, were enrolled in the study by neurology or internal medicine specialists at the clinical facility. The enrolled subjects fulfilled the inclusion criteria specified in the protocol, having at least moderate pain intensity . Patients were excluded if they were under ongoing treatment with ASA-, PAR-, CAF-, or CLF-containing drugs as well any other prescription or nonprescription analgesics, antirheumatic, or anti-inflammatory drugs in the last 4 days or if they were under ongoing treatment with anticoagulant agents. Exclusion criteria also included special physiological conditions ; hypersensitivity to ASA, PAR, or CAF; alcohol or drug abuse; different diseases ; or any major neurological disorders.During the initial screening and in treatment days 1, 3, and 4, patients responded to the Roland–Morris Questionnaire (RMQ), a self-rated physical disability measure on a 24-point scale.® (ALG)  were provided by Polisano Pharmaceuticals S.R.L., Sibiu, Romania.All study medication, e.g., the PAR 500 mg tablets used as active comparator as well as the investigated drug AlgopirinThe double-blind character of the study was ensured by utilizing matched trial supplies, identical in both taste and appearance .The study was designed as a noninterventional, randomized, parallel, multiple-dose, double-blind, noninferiority clinical trial, comparing the effectiveness of ALG tablets  versus PAR 500 mg tablets, a drug recognized by the American Pain Society as “safe and effective” in the treatment of LBP.Each participant in the study received a tablet of the assigned product three times a day, for seven consecutive days. The patients evaluated their pain level using a Visual Analog Scale prior to administration, and at 1, 2, 4, and 6 h after the morning dose in the first five as well as in the last day of the study.No other drug intake was allowed in the first 4 h after study medication administration. Patients were allowed to use rescue medication (PAR 500 mg) only 4 h after the administration of the study medication and were not allowed to drink coffee or CAF-containing beverages within 2 h before and after administration of the trial medication.Pain intensity was assessed on a horizontal 100-mm Visual Analog Pain Intensity [VAS(PI)] scale labeled No Pain (0 mm) on the left end and Worst Pain Imaginable (100 mm) on the right end. In the screening visit, the investigator provided to each of the enrolled patients a standardized explanation on how to evaluate and record the VAS(PI) score, using a written explanatory text.Patients were required to record in a diary the date and time of drug administration and pain intensity on the VAS(PI) scale baseline immediately before each trial drug administration, as well as at 1, 2, 4, and 6 h after the morning dose on days 1, 2, 3, 4, 5, and 7 of the clinical trial. The investigator reviewed the completed diary with the patient in order to ensure that all the significant information, including safety and tolerability issues, had been documented.The primary endpoint of the trial was considered the mean pain intensity score evaluated on the VAS(PI) scale after five treatment days.Secondary endpoints were:Proportion of patients who achieved at least 50% pain relief at different intervals after administration [evaluated on VAS(PI) by linear interpolation between consecutive observation time points];Time-weighted Sum of Pain Intensity Differences (SPID) relative to baseline for 4 or 6 h after intake of the medication, evaluated on a daily basis;Hazard ratio of the percentage of patients with at least 50% pain relief as a function treatment duration;Safety assessment.0-4h and SPID0-6h values) were performed using Student’s t test. Differences were considered statistically significant when p values were <0.05.The statistical analyses as well as graphical representation of data were performed using GraphPad Prism 7  software. Statistical comparisons of different numerical data sets (such as daily mean pain scores as well as the SPIDp < 0.05).For the categorical variables, the comparisons were performed using chi-square test  evaluation .α = 0.10, for type II error β = 0.20, a coefficient of variation n = 81 subjects was obtained. Estimating a 10% proportion of outliers or premature withdrawals, the number of patients to be enrolled was set at 90.Considering the probability of type I error Of 97 patients assessed for eligibility, 89 patients were included in the study, 4 were excluded due to not meeting inclusion criteria, and 4 declined to participate. Of the 89 patients included, 45 were randomized to the PAR group and 44 were randomized to the ALG group.The flow diagram of the progress of the patients through the phases of the trial is presented in t test, p = 0.88), gender distribution , weight , as well as clinically relevant aspects such as the mean baseline pain intensity, expressed as VAS(PI) score .Patient characteristics were comparable between the study groups Table 1.In order to estimate a possible effect of age on the conclusion concerning equivalence of the two treatments, comparison of mean pain curves was performed separately for group of subjects under 50 years (52.5%) and group of subjects with age greater than 50 years (47.5%). The results were not significantly different from those for the whole group.t test led to the following results: Mean Pain Score Female vs. Male ALG (p = 0.49), Mean Pain Score Female ALG vs. PAR (p = 0.25), Mean Pain Score Male ALG vs. PAR (p = 0.74), and Mean Pain Score Female vs. Male PAR (p = 0.75); therefore, it was concluded that gender does not significantly influence the efficacy results.The gender analysis of the efficacy results using Effects of the two compared products were analyzed as functions of four variables:h = 0, 1, 2, 4, 6 represent the time in hours after the current administration; d = 1, 2, 3, 4, 5 represent the day since the beginning of the treatment; i = 1,…, trn represents the subjects within a treatment group; tr depicts the treatment .where The single-dose effect of the trial medication was evaluated from the data obtained after the first administration in the first day of the study. Pain relief relative to baseline was observed in both study groups. It is noteworthy that both ALG and PAR followed similar pain relief patterns: a more pronounced effect within the first 2 h after drug intake continued with a much slower decline  of the pain score for up to 6 h Figure 2Within the first 2 h, the pain relief followed a linear decrease model for both investigated products Figure 3t test (Comparison between the mean VAS(PI) score values for the two treatments before and at 1, 2, 4, and 6 h after drug intake was performed using Student’s t test Table 2.p = 0.37) difference of the baseline pain score disappeared within 1 h after the administration of the study medication. From this point onwards, the pain score values became practically equal . It should also be noted that the SD values were very consistent between the two treatments, suggesting no differences in variability.A small . Therefore, multiple-dose treatment is being required to achieve a clinically meaningful effect.An obvious decrease in the pain score values was obtained as treatment progressed Figure 4Daily individual curves obtained following averaging of all pain score values registered within the same day For further analysis, we evaluated the daily mean pain score for each treatment, by averaging all the pain score values obtained for all patients receiving the specified treatment within each day, An and Pn are, respectively, the number of patients who received ALG and PAR.where The corresponding mean daily pain curves are presented in p values between 0.64 in the 4th day and 0.92 on the 2nd day)  Table 3.Irrespective of the day, the difference between the mean pain scores was not clinically significant Figure 7A common alternative endpoint in the clinical efficacy evaluation of analgesic drugs is the time-weighted Sum of Pain Intensity Differences (SPID), where the pain intensity differences are calculated as the differences between the current pain level and pain at baseline, multiplied by the interval between measurements.When the length of measuring time intervals tends to zero, SPID becomes the integral of pain curve and equals area under complementary of pain curve that actually represents the effect curve. When time intervals between measuring points remain constant, the parameter becomes the mean of the pain values.0–4h) as well for the 0–6 h interval (SPID0–6h) were evaluated .Another common endpoint used for the efficacy evaluation of pain drugs is the time to onset of meaningful pain relief, with a value of 50% pain relief being the most utilized threshold (T50 was defined as the time (expressed in days) that contained the first moment when the pain passed the 50% threshold. By examining the daily mean pain scores expressed as percentage of the initial baseline (p = 0.13).T70) objective is more realistic and was achieved after approximately 2 days of treatment for both products (p = 0.48).A pain relief of at least 30% from the baseline value .In our case, Graphical representation of the two “pain survival curves” is depicted in Evaluation of the mean survival time of the pain for the two treatments led to the results presented in The mean survival time was estimated as the area under the survival curve. Non-parametric statistical tests to compare the two survival curves indicated that the difference between them is not significant Table 6.Thus, both the parametric and nonparametric comparison of pain curves indicate the equality of the analgesic effect of the two treatments.A series of recent studies  providedOver time, 75 parameters were discussed. But it is worth mentioning what Professor Douglas Altman reported at the 2016 meeting of the Core Outcome Measures in Efficiency Trials (COMET) “Trials should build on what’s already done; it’s not the place to be too novel; use a core outcome set if it exists; too much originality won’t help patients.”Hence, it was considered the usual endpoint in clinical trials concerning analgesic drugs: the pain reported by the patient. It is to note that, for the registration of new drug combinations, the current guidelines recommend efficacy evaluations to be performed against all the active components. However, in the particular case of the present drug combination, this approach would lead to a five-study-group clinical trial, which would clearly lack any clinical and ethical justification.On the other hand, as a result of the continuous efforts for increasing the certainty level of results, the regulatory biostatisticians consider as a gold standard testing the effect of a new drug by comparison against placebo , which iAs opposed to them, biostatisticians serving in Ethics Committees consider the use of placebo to be unethical, due to unacceptable risks for the patients receiving placebo treatments . FurtherNumerous guideline documents for the management of LBP in primary care have been published in various countries around the world . They alDespite a wide consensus regarding the clinical use of PAR, two recent clinical trials concluded that its effect was not superior to placebo. However, for these studies, some very “strange” aspects in terms of dose choice, comparator, duration, and goals have to be underlined. One study  concludeThe other study  concludeTaking into account all the above considerations, for the assessment of the clinical significance of the analgesic effect for the ASA–PAR–CAF–CLF combination, we considered the best comparator to be the standard analgesic clinical treatment for LBP, i.e., PAR. In fact, in one of our previous experiments , the eff®) cannot be extrapolated to LBP.The first question to be answered by this study was whether ALG has a significant clinical effect in LBP. It is obvious that the previously proven effect of an ALG single dose in migraine , ranging between 5.3% and 17.9% of the maximum daily dose of the active components    scores at moments kt−1 and kt, respectively.where The derivatives of the mean pain curves after the first dose of medication are presented in The time course of effect is naturally related to the release kinetics of the active ingredients from the tablets and, finally, to their pharmacokinetics. Pharmacokinetics were considered by analogy with available data on similar combinations in the literature. It is worth noting that, despite ASA and PAR being in therapy for a very long time, and their effect being both well known and well established, there are very few data with reference to their pharmacokinetic profile.The maximum analgesic effect of ALG in LBP occurred between 1 and 2 h  Figure. As a fuThe PAR effect occurred a little earlier than the ALG effect, but the ALG effect has been shown to be influenced by the dose. In a previous pilot clinical trial (data not published), two ALG tablets were administered to five subjects, and the maximum effect occurred at the first measurement point, demonstrating a faster coupling between plasma levels and effect. The maximum effect of two ALG tablets appeared visually greater than that of PAR, but the low number of patients administered with two ALG tablets could not allow a significant statistical analysis.An important risk of failure during the study was the relationship between pain and effort. After a significant decrease of the baseline pain after the study medication was administered, the patient might feel “healed” and be tempted to resume the physical effort that the pain has prevented him from having. Thus, following an initial pain relief, a sudden increase may occur, which, in fact, cannot be considered as a result of the treatment. An actual example obtained from one of the study patients is depicted in After the “expected” analgesic effect on the first day, on the second day, and on the third day of the study, due to the patient undertaking physical effort, a significant increase of the pain level occurred, unrelated to medication. In the next 2 days, the effect of the medication appeared again to be “expected,” and the pain was practically gone. The patient is therefore an “outlier.”The question of whether outlier values should be kept or dropped is very difficult, for sometimes their impact on the results of the analysis could be determinant for the conclusions of the study . FortunaA final discussion on the statistical methods to compare the effects of the two treatments should be made. There is still a never-ending debate among statisticians whether parametric or of nonparametric methods have greater suitability for data analysis. A recent paper on this subject  concludeComparison of the pain scores at different measurement points as well as pain curve parameters, such as SPID values, were performed on the assumption of a normal distribution of these parameters. On the other hand, because the distribution of proportions of patients with at least 50% pain relief is not known, and there are no arguments to assume a normal distribution, their comparison was performed using the log-rank test. Other authors used the same log-rank test in the statistical analysis of analgesic formulations . RegardlThe Roland–Morris Questionnaire (RMQ) is a self-rated physical disability measure on a 24-point scale . TestingThe score did not differ significantly between treatments, but after 4 days, there was a drop of half the initial value. ALG appears to have a greater efficacy, but the difference is not statistically significant . The same conclusion was drawn from comparing the daily sums of pain intensity differences SPID0–4h and SPID0–6h Daily proportions of patients with at least 50% pain relief revealed differences between the two treatments, but the differences were not statistically significant. Comparison of pain survival curves using the log-rank test indicated that the hazards rate is not significantly different from the unit (p = 0.06).The time course of the analgesic effect of ALG and PAR was very similar. The effect occurs quickly and increases continuously for 4 h. After this time, analgesia decreases up to 8 h, and the pain level is maintained below the baseline. Over a week of treatment, the mean daily pain decreased continuously, in a linear fashion over the first 3 days and asymptotically in the second interval. The mean pain values per hour after the first dose as well as the mean daily pain values were compared using Student’s An alternative treatment that starts with two ALG tablets following the administration schedule of two tablets at the first administration, on the first day, followed by one tablet every 8 h for the rest of the study period leads to significantly better effects (data not shown). Correlation with the pharmacokinetics of ASA has shown a delay of about half an hour between the maximum plasma level and the maximum effect. The pattern of derivatives of pain curves after the first dose administration of ALG and PAR was very similar and much more similar to the ALG differential model of migraine analgesia found in a previous study.As ASA, PAR, and CAF doses are very low in ALG, this combination should be considered as an alternative treatment for LBP, mainly for patients with gastrointestinal and hepatic sensitivity.The study protocol (EudraCT number: 2015-002314-74) was approved by the National Agency for Medicines and Medical Devices  and the National Bioethics Committee for Medicines and Medical Devices . All participants gave written informed consent prior to study participation and were instructed by specialized personnel on how to record the characteristics of their back pain. All patients were allowed to terminate their participation in the trial at any time, without restrictions.VV coordinated the entire project; CM elaborated the clinical trial design and performed the statistical analysis; CP, MJ, and VB were clinical investigators; RS and AC performed data collection, built and structured the clinical study results database, and performed statistical analysis; VA was responsible for the quality assurance and IM was responsible for production of the investigational drugs and study monitoring; CM, IM, and VA prepared the manuscript. All authors approved the manuscript.Finalization of this work was supported by the PNCDI II grant 139/2014 of the Romanian Ministry of Education and Research. Publication of this paper was financially supported by “Carol Davila” University of Medicine and Pharmacy through Contract no. 23PFE/17.10.2018 funded by the Ministry of Research and Innovation within PNCDI III, Program 1 – Development of the National RD system, Subprogram 1.2 – Institutional Performance – RDI excellence funding projects.AC was employed by CEBIS International, Bucharest. The company had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, and in the decision to publish the results.The remaining 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.


Management of chronic idiopathic testicular pain may be difficult because of problems identifying the causes. We evaluated “AUTOKLAV”, a novel endourological nephrolithotomy device to diagnose and treat chronic idiopathic testicular pain. We divided 103 patients to either scrotoscopy group  or open exploration group  between September 2014 and March 2017 at Zhongnan Hospital. Perioperative information, like operating time, length of incision, and wound infections, was carefully recorded during in hospital. Follow-up data, like pain scores improvement, satisfaction with penis appearance, and adverse event, were collected at one month postoperatively. Finally, both the operating time and length of incision showed better performance for SG . Though the pain improvement had no significant differences between the two groups , SG showed obvious advantages in incidence of wound infections and satisfaction with wound/scrotum appearance . In conclusion, scrotoscopy using the novel AUTOKLAV device is feasible, has an acceptable complication rate, and can be effective and safe in men with idiopathic chronic testicular pain. Etiologically, secondary inflammatory changes caused by the complete or incomplete torsion of testicular or epididymis appendices or by the existence of stones in the tunica sac might be responsible for the pain. Patients with chronic testicular pain who present with intermittent or constant unilateral or bilateral testicular pain persisting for >3 months are frequently encountered by urologists or general practitioners. This condition considerably interferes with the patient's daily activities . It can Chronic testicular pain can have well-defined testicular causes or even be idiopathic . UnfortuTo the best of our knowledge, no study has reported on the use of a scrotoscope to manage chronic idiopathic testicular pain. In this paper, we compared the safety and clinical efficacy between conventional open exploration and novel scrotoscopy using an endourological nephrolithotomy device named AUTOKLAV. In addition, the possible causes of chronic idiopathic testicular pain were explored.ChiCTR-INR-17012652.This trial was undertaken at Zhongnan Hospital, Wuhan University, Wuhan, China. Between September 2014 and February 2017, 103 patients aged between 19 and 65 years were enrolled. The patients had no history of surgery for scrotal contents and had chronic testicular pain persisting for >3 months. Patients with testicular pain owing to testicular causes, such as tumors, torsion, and trauma, were excluded after routine physical examination, ultrasound, or other diagnostic procedures. Patients with varicocele, inguinal hernia, intervertebral disc prolapse, or urinary stone disease were also excluded. Patients were given the freedom to choose between the two procedures: open exploration or scrotoscopy. However, the patients were sufficiently informed of the merits of the two methods before deciding on which one to choose. The study was performed in accordance with the ethical principles of the Declaration of Helsinki. All patients gave informed consent prior to being included. The study was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University. The registration ID of this clinical trial at Chinese Clinical Trial Registry was In the scrotoscopy group (SG), AUTOKLAV  was used for scrotoscopy because no specialized devices were available  8–10]. –10. 8–10The procedure was performed under sterile conditions, with the patient in a lithotomy position. Spinal anesthesia was administered because (1) it has a lower adverse reaction rate and (2) the patients could resume food intake and return to daily activity early (6 h after surgery). A minimal incision (5–10 mm) was made using a scalpel blade at the anterior inferior part of the lesion side of the scrotum, and layer-by-layer dissection was performed until entry into the tunica sac. After three Allis clamps were used to hold all the layers of the scrotal wall, a homemade working sheath was passed through the incision into the tunica sac and then steadily fixed to the scrotal wall using 2-0 sutures , allowinIn the open exploration group (OEG), the surgical position and anesthesia method were similar to those in SG. A 3–5-cm incision was made in the scrotal surface, and the scrotal wall was opened till the tunica sac. The testis and epididymis were removed through the incision, and all the contents were exposed and directly examined. All abnormalities were identified and treated before the incision was sutured layer by layer.After surgery, scrotal bandages were well fixed in both groups, and the first dressing change was performed within 24 h. The subsequent dressing changes were performed according to the extent of recovery of the wound. Surgical procedures in both groups were performed by a single surgeon (SXJ).Perioperative information, including duration of pain, operating time, length of incision, blood loss, incidences of scrotal hematoma and edema, number of testis and/or epididymis injuries, number of wound infections, and hospitalization days, was recorded during the procedure and before discharge. Duration of pain was defined as the duration from the beginning of pain to the recruitment time. Operating time was defined as the duration from the incision in the scrotum to the termination of suturing. Intraoperative blood loss was calculated based on the increase in weight of the standard gauze. The visible, suspected causes of chronic testicular pain were also recorded during the procedure.Patients were requested to visit our department for follow-up at 1 month after the surgery. Physical examination was performed with special attention to the external genitalia. A visual analog scale (VAS)  was used χ2 tests were used for discrete data. Statistical significance was defined as a P value of <0.05. All P values were two-sided. Two authors (LJH and GYM) conducted the statistical analysis independently, and any disagreements were resolved through discussion among the study group members.All the statistical analyses were performed using a statistical software package . Continuous variables are expressed as mean ± standard deviation (SD). Discrete variables are expressed as percentages. T test was used to compare continuous data, andThe TREND flowchart of the patients through each stage of the study was shown at All procedures were performed successfully in the 103 patients. The operating time in SG was much less than those in OEG . In SG, based on intraoperative observation, the blood loss was very little but could not be easily evaluated because of the continuous irrigation with isotonic crystalloid solution . The length of the incision in SG was significantly shorter than that in OEG . The incidence of scrotal edema  and hematoma  was less in SG than in OEG. In addition, SG had a shorter duration of hospitalization . Both types of surgeries did not result in any testis or epididymis injuries. Perioperative comparisons between the two groups are given in During the procedure, testicular or epididymis appendices were detected in all 103 cases, and scrotal stones were found in 32 cases (24 in SG and 8 in OEG). At the 1-month follow-up, complete data of 89 patients (55 in SG and 34 in OEG) were available, indicating a follow-up rate of 86.4%. Of the remaining 14 patients who were lost to follow-up, 8 patients refused to visit our department for further consultation until the closure of the study and 6 patients could not be contacted or provided incomplete data over telephone calls. At 1 month after the procedures, in the 89 patients with successful follow-up, the mean pain scores in SG and OEG were 1.82 ± 0.82 and 1.93 ± 0.92, respectively (P > 0.05). The improvement in pain scores in SG and OEG was 2.92 ± 0.99 and 2.14 ± 1.02, respectively (P > 0.05), which did not significantly differ between the groups. On the other hand, the pain scores before and after surgery were significantly different, both for SG (P < 0.05) and for OEG (P < 0.05). The blood flow was normal, and no testicular/epididymal ischemia or necrosis was detected by B ultrasound. In addition, no significant differences were noted with respect to the occurrence of hematoma (0% versus 0%) or edema (0% versus 0%). Nevertheless, patients in SG showed obvious advantages over those in OEG in terms of the incidence of wound infections and satisfaction with wound/scrotum appearance . The follow-up data at one month postoperatively are shown in Chronic testicular pain has multiple causes, such as testicular tumor, torsion, varicocele, and trauma, and management depends on the definite etiology of testicular pain. Unfortunately, despite using ultrasound, computed tomography, and magnetic resonance imaging, the etiology of chronic idiopathic testicular pain is not easily determined. Open exploratory operation can serve as an alternative, but the acceptability of this procedure is low among patients because of its invasiveness. Patients urgently require new methods to determine the etiology and treat their pain with procedures that are safe, effective, and minimally invasive.As described by Shafik et al.  and FranRecently, novel reports on the clinical application and progress of scrotoscopy have earned praise for innovation and commendable efforts. In 2014, Yan et al.  conducteUnfortunately, no studies have reported on the management of chronic testicular pain using scrotoscopy, and we presume that the limited application of scrotoscopy may result from an inappropriate use of instruments and the limited number of available cases. To the best of our knowledge, this is the first prospective trial to compare the effectiveness and safety between scrotoscopy and open exploration for the management of chronic idiopathic testicular pain. We used an AUTOKLAV , which iRegarding the primary endpoint, the improvement in pain scores at 1 month was higher in SG than in OEG, although without significant differences . Even so, either method, scrotoscopy or open exploration, could significantly relieve their pain (P < 0.05). The higher pain improvement might be related to the less impact of scrotoscopy on the scrotal contents due to the use of auxiliary tools, such as biopsy forceps and fiber optic lasers, for biopsy, excision, and vaporization throughout the examination and treatment procedures. Conversely, open exploration might more easily lead to damage, scars, or adhesions when exposing the testicle, epididymis, and spermatic cord outside the scrotum; furthermore, compared with using scrotoscopy, the anatomical structures of the scrotal contents were more severely damaged using this procedure. This finding can also explain why the incidences of scrotal edema  and hematoma (0% versus 5.1%) were significantly less in SG than in OEG. A comparison of our SG method with Yang's scrotoscopy method  revealedRegarding the etiology, our results are encouraging with respect to an indication of scrotoscopy for chronic testicular pain, particularly in cases where no definite cause is determined on routine examination. The findings of the 103 cases were finally confirmed by pathologic examination. Cystic masses with simple columnar or simple cuboidal epithelium were observed, with different degrees of inflammatory cell infiltration for most patients (94/103). They were considered to be testicular or epididymal appendices . In addiLike other studies, this study also has limitations. Given the rare nature of the disease, we were only able to include <100 eligible participants despite a 2.5-year recruitment period. Another limitation is that this was a nonrandomized study. Data obtained from multicenter randomized studies with longer follow-up period can further validate the clinical effects of this surgical procedure in men with chronic idiopathic testicular pain.In conclusion, scrotoscopy using the novel AUTOKLAV device is feasible, has an acceptable complication rate, and can be effective and safe in men with idiopathic chronic testicular pain. Secondary inflammatory changes caused by the complete or incomplete torsion of testicular or epididymis appendices or by the existence of stones in the tunica sac might be responsible for the chronic idiopathic testicular pain.


Patients were randomly assigned to one of the groups stratified for age, gender and BMI. Before starting of the active study period and collecting of the initial data on day 1, all patients received a pharmacological analgesic baseline therapy for one week. At the next study stage patients started their randomly assigned treatment protocol for 42 days and final follow-up was set on day 70. Patients recorded their pain intensity  using a standardized patient diary. The pain free walking time in min was recorded and range of motion was assessed. Results: Rescue medication intake was comparable between both groups on day 42 (p = 0.55) and day 70 (p = 0.35). After the active study period (day 42) pain scores decreased significantly in both groups . At follow up median pain scores further decreased in group 1 (p = 0.0002) and remained at a low level in group 2 (p = 0.001). Level of pain decreased in about 50% in both groups and was comparable during the study period. Total mean range of motion (ROM) increased in both groups . Group 1 had more improvement of mean total ROM compared to group 2 (p = 0.034). Pain-free walking time increased in both groups and was comparable between both groups (p = 0.31). Any adverse effects due to EAA or LFMECT were not observed. Conclusions: Data of the current study indicates that implementation of EAA or LFMECT seems to be beneficial to reduce knee pain and improve knee function in patients with knee osteoarthritis.Background: Knee osteoarthritis is a major cause of knee pain. Conservative therapy resources are limited due to adverse effects. Therefore, alternative non-invasive therapy approaches to reduce pain medications are gaining importance. The current study analyses if electrical auricular acupuncture (EAA) or low frequency modulated electric current therapy (LFMECT) could support analgesic treatment. Methods: In a randomized pilot trial patients with painful knee OA were treated with EAA (group 1) or LFMECT (group 2) additional to standard pharmacological analgesic treatment. In total 19 female and 10 male patients with a mean age of 59.1 years (standard deviation ± 13.6) and a mean BMI of 28.9 kg/m Knee osteoarthritis (OA) is a major cause of knee pain. Resources for pain reduction without causing adverse effects are limited and are needed for patients who are not suitable for surgery. Therefore, alternative approaches, such as acupuncture or acupressure, are gaining importance. Classical acupuncture points are located on the “meridians” or on the ears as described by Nogier et al. . Auricul®™ device  was developed to provide continuous EAA for several days. It uses special auricular needles, which are placed on selected acupuncture points, and are connected by wires to a microcontroller fixed behind the ear. It applies a defined periodical electrical stimulation followed by stimulation breaks to prevent tolerance or adaption. In patients with chronic cervical or low back pain electrical auricular acupuncture (EAA) using the P-Stim®™ device showed to be more effective than conventional auricular needle acupuncture [The P-Stimpuncture ,8,9.®™, Enerbalance GMBH, Vienna, Austria)  with the self-controlled energo-neuro adaptive regulation device (SCENARAustria) , which in relief . In compThe number of randomized controlled trials investigating needle acupuncture for knee osteoarthritis (OA) has increased in the last years ,12. In cThe current randomized pilot trial assessed patients with painful knee OA undergoing EAA or LFMECT additional to standard pharmacological analgesic treatment. The study was approved by the Institutional Review Board on the 5 April 2007 (EK 097/2007) and written informed consent was obtained from all participants.Patients were randomly assigned to two groups . In grouInclusion criteria were age of 18 years or older, a history of knee pain of at least three months, knee pain on most of the days of the past month, an average pain level of ≥3 out of 10 on a numerical rating scale , knee stiffness in the morning of maximal 30 min duration and radiological knee OA (grade >1 according to Kellgren and Lawrence ). ExclusFurther exclusion criteria were coagulopathy, contraindication for Metamizol or Tramadol intake, skin disorders (ear or knee) and pre-existing pain medication intake ).In total 31 patients were recruited at the outpatient pain centre. Patients were randomly assigned to one of the intervention groups (EAA or LFMECT) stratified for age, gender, and BMI. Randomization was performed as previously reported by Sator-Katzenschalger et al. using computer-generated randomization . Patient2 (± 5.2) were included.15 patients were randomized to the EAA group (group 1) and 16 patients to the LFMECT group (group 2). Two female patients in the LFMECT (group 2) were excluded due to incompliance. Finally, 19 female and 10 male patients with a mean age of 59.1 years (± 13.6) and a mean BMI of 28.9 kg/mBefore beginning of their assigned treatment protocol, patients received a pharmacological oral analgesic baseline treatment  for one week. After one-week patients were clinically evaluated and baseline data were collected. In the next study stage, all patients started their assigned treatment protocol (EAA or LFMECT). This time point was set as day 1. The active study period was six weeks (42 days). All patients received EAA or LFMECT on day 1, 7, 14, 21, 28, and 35. All clinical assessments were performed by three fourth year medical students, who were supervised by seven physicians at the outpatient pain center in the midmorning. The active study period ended on day 42 and final follow-up was set on day 70. Patients recorded their required daily rescue medication intake, pain intensity , psychological well-being, quality of sleep, nausea, emesis, and fatigue in a standardized patient diary. Clinical evaluation included knee effusion and active range of motion (ROM). All examiners were trained by an experienced orthopedic trauma surgeon and they trained on several patients with OA not related to the current study. Knee effusion was assessed with the patellar tap test and was rated as positive or negative. ROM was measured according to the neutral zero method with a goniometer using the greater trochanter, lateral femoral epicondyle, fibular head, and lateral malleolus as reference points. All measurements were performed three times and the means were recorded. Moreover, the pain free walking time in min was recorded under standardized conditions. Patients were asked to walk on a flat walking track of 400m length with a consistent walking speed of 3 km/h until they were suffering knee pain.®™ device  to identify the acupuncture points . Titan disposable auricular needles  were inserted in the acupuncture points at the dominant side and connected to the P-Stim®™ device. Patients in the auricular acupuncture group (group 1) received continuous low frequency EAA for 96 hours on an outpatient basis. The P-Stim®™ device and acupuncture needles were withdrawn by the patients 96 hours after insertion.In group 1 patients received additional to the standardized basic pharmacological analgesic therapy  electrical auricular acupuncture (EAA) using the P-Stim™ device . Before ®™ device . In the current study following acupuncture points were stimulated with the SCENAR®™ device: the body acupuncture meridians, bladder meridian, and Bachmann points.Participants in group 2 had in addition to the standardized basic pharmacological treatment low frequency modulated electric current therapy (LFMECT) using the SCENAR™ device . It is ap value < 0.05 was considered statistically significant.The primary outcome parameter was required daily intake of rescue medication. Comparisons between the two groups were performed using the nonparametric Wilcoxon rank sum test. Secondary outcome parameters were pain (NRS), ROM, and pain-free walking time. Continuous outcome variables are presented by mean (± standard deviation). For variables with skewed distribution the median (quartiles) was used. Due to the skewed distribution log-transformed values of the pain-free walking time were used. Analyses of covariance (ANCOVA) models were used for comparison of the outcome variables pain, ROM and pain-free walking time, between the two intervention groups, including the respective baseline values (day 1) as a covariate. Repeated measures analysis of variance (ANOVA) models were calculated to evaluate the secondary outcome variables pain and psychological well-being, compared to baseline values, additionally including follow-up values (day 70). The nonparametric Wilcoxon signed rank test was used to evaluate changes in the subjective outcome variable sleep, as it was not normally distributed. All statistical tests were two-sided and a p = 0.55) and day 70 (p = 0.35) , p = 0.0006). At follow up median pain scores further decreased in group 1  p = 0.0002) and remained at a low level in group 2 , p = 0.001). Level of pain decreased in both groups in about 50% (Rescue medication intake was comparable in both groups on day 42 ( = 0.35) . Pain scbout 50%  and painbout 50% .p = 0.0003; group 2 114° (± 19), p = 0.02). Group 1 showed more improvement of mean total ROM compared to group 2 (p = 0.034). The mean extension lag in group 1 decreased from 6° (± 10) at baseline assessment to 2° (± 4) at the end of treatment. In group 2 the mean extension lag improved from 3° (± 5) to 1° (± 3).On day 1 mean total ROM was in group 1 105° (± 21) and in group 2 101° (± 28). At the end of the treatment mean total ROM increased in both groups (group 1 126° (± 12), p = 0.0001, group 2 60 min , p = 0.0006). The improvement of the pain-free walking time was comparable (p = 0.31). Effusion was extremely rarely observed despite an increasing activity level during the study period.Pain-free walking time was after baseline therapy 30 min  in group 1 and 20 min  in group 2. At the end of the active study phase an increased pain-free walking time was recorded in both groups , p = 0.005) and improved further at final follow-up compared to baseline values (p < 0.0001). Also, an improvement of psychological well-being between the end of the active study period and final follow-up (p = 0.02) was observed in both groups . Quality of sleep improved in both groups at final follow-up (p = 0.03)  .Occurrence of nausea, emesis, and fatigue was caused mainly due to side effects of tramadol intake and was were analyzed together. Nausea was rarely reported during baseline therapy and occurrence of emesis was not recorded during the whole study period. Fatigue values were decreased during the study period and stayed at a low level at final follow-up.Adverse effects of EAA such as occurrence of auricular hematoma, local infection, or hypotension did not occur. Also, patients undergoing LFMECT did not report any adverse events.Implementation of EAA or LMFECT seems to be beneficial to support pain management in knee OA. Data of the current study indicates that these therapy modalities seems to be beneficial to reduce knee pain and improve knee function in patients with knee OA.Acupuncture for patients with OA or chronic pain seems to be a valuable additional treatment option for pain reduction and functional improvement ,15,16. TMavrommatis et al.  comparedNonetheless following limitations of the current study have to be considered: (1) Only a limited number of patients were analyzed, however, patients were prospectively and randomly allocated to the intervention groups. (2) An intra- and interobserver reliability analysis of evaluation of knee effusion and ROM measurement was not performed prior the study. (3) Patients were not controlled for level of physical activity, daily working hours or weight changes. (4) The pain free walking time test is not validated for knee osteoarthritis in the literature, however all measurement in the current study were performed under standardized, controlled and reproducible conditions. (5) A control group only receiving pharmacological analgesic treatment was not included. Further randomized trials comparing EAA and LFMECT with patients receiving stand-alone pharmacological analgesic treatment are needed.The current study indicates that implementation of EAA and LFMECT in conservative pain management of patients with knee osteoarthritis seems to be beneficial to reduce knee pain and improve knee function. Moreover, EAA and LFMECT showed a continuing effect and might be an additional treatment modality in particular for patients with severe medical comorbidities who are at high risk for complications in total joint replacement surgery.


Herpes zoster is characterized by acute neuritis and post-herpetic neuralgia. Currently, data concerning the zoster-associated impact on quality of life and healthcare resource utilization in Brazil are scarce. This study measured the zoster-associated burden in a Brazilian population.This was a prospective, observational, single-cohort study conducted in a primary hospital’s emergency room in São Paulo, Brazil. Patients enrolled at various timepoints during a zoster episode were followed over 180 days. The Zoster Brief Pain Inventory and the Initial Zoster Impact Questionnaire assessed zoster-associated pain. The EuroQoL assessed the impact of herpes zoster and/or zoster-associated pain on quality of life. Healthcare resource utilization was assessed by patient-reported questionnaires.p<0.001), followed by gradual improvements in quality of life over 180 days, with pre-herpes zoster quality of life achieved at the end of the observation period. The majority of patients purchased prescription medications (89.7%) and required doctor’s office visits (65.8%) for zoster episodes.One-hundred forty-six zoster patients were enrolled [mean (SD) age of 69.9 (10.9) years]. Mean (SD) worst pain scores decreased from 5.3 (3.5) at baseline to 1.9 (3.0) 180 days following rash onset. Mean (SD) EuroQoL scores significantly decreased from 0.9 (0.2) before rash appearance to 0.7 (0.2) after rash onset (Herpes zoster is associated with a significant disease burden, including zoster-associated pain, impaired quality of life and increased healthcare resource utilization in Brazil. These results support the implementation of early intervention and prevention programs such as vaccinations to reduce the herpes zoster-associated disease burden in Brazil. Herpes zoster (HZ), also known as shingles or zoster, is caused by the reactivation of the varicella-zoster virus (VZV) in sensory ganglia after a latency period following an initial infection with varicella The most significant features associated with HZ are a blistering dermatomal rash, pain, acute neuritis and, later, post-herpetic neuralgia (PHN) PHN is characterized by tender, burning, throbbing, stabbing, shooting and/or sharp pain persisting for months or years, which may lead to emotional distress. The manifestations may be constant or paroxysmal as minor stimuli to the affected skin may trigger allodynia. At least 90% of patients with PHN experience allodynia, and it is generally one of the most distressing and debilitating type of pain In the United States, the incidence of HZ has been reported to be 10-20% in the general population Currently, published data are limited concerning the clinical characteristics, disease severity and health care resource utilization (HCRU) related to HZ in Brazil. Given the aging Brazilian population, the HZ disease burden will increase in the near future. A thorough understanding of the Brazil-specific HZ burden and associated HCRU would help assess the potential impact of a HZ vaccination program in Brazil. The aim of this study was to measure the HZ disease burden, assess the impact on QoL and determine the HCRU due to HZ episodes in a Brazilian population.The present study is part of the international MASTER (Monitoring and Assessing Shingles Through Education and Research) study conducted in 8 countries  aimed to assess the disease burden associated with HZ and PHN Review board approval was obtained in compliance with local law. The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practices and the tenets of the Declaration of Helsinki. Eligible patients who provided written informed consent prior to cohort entry were included in the study.Patients were prospectively recruited between May 2008 and October 2009 and entered in the cohort at the time of presentation with HZ rash or ZAP symptoms.Up to 120 patients from a public primary hospital’s emergency room (ER) were planned to be recruited in the study. Patients were part of the nation’s Unified Health System, the ‘Sistema Único de Saúde’ (SUS). Incident cases were defined as patients recruited for a current HZ episode with a duration of less than 7 days. Prevalent cases were defined as subjects enrolled while visiting an investigator for a current HZ episode with a duration of more than 7 days and for which the rash onset had been recorded in the patient’s medical records. Disease onset was defined according to the HZ rash onset date.Patients were required to be at minimum of 50 years of age at the HZ rash onset date and to have a diagnosis of HZ rash or ZAP (acute pain or PHN) confirmed by a physician. Patients were further expected to have telephone contact and be capable of completing the patient questionnaires, understanding the trial and the content of the informed consent, participating in the study by signing the consent form and being available for the follow-up period of the study.Following the baseline assessment (day 0) conducted at the ER, nine additional assessments were performed on days 7, 14, 21, 30, 60, 90, 120, 150 and 180 following study enrollment. The follow-up period lasted six months, and the same schedule was followed for all patients regardless of their disease stage at enrollment. Data were obtained by telephone contact.Burden of disease due to HZ pain was assessed as a function of pain duration, and severity was measured by the Zoster Brief Pain Inventory (ZBPI) and by the Initial Zoster Impact Questionnaire (IZIQ) Patient-reported HCRU was assessed with the aid of a simple questionnaire administered at each visit. Patients provided information about the health care services utilized due to HZ rash or ZAP since their last visit. HCRU included visits to the ER and admission to a hospital, as well as the use of other health-related services, including use of an ambulance or nursing service, visits to a doctor’s office, physiotherapist/rehabilitation, psychiatrist/psychologist/counselor and visits to a specialist.Out-of-pocket expenses for health care, including fees for prescription, over-the-counter (OTC) and alternative medications were recorded in a healthcare cost questionnaire. The Work and Productivity questionnaire measured indirect costs, including the number of missed work days by patients or caregivers, duration of extended sick leave, and duration of disability from HZ or ZAP episodes since the last visit.Descriptive statistics were produced for all variables studied. For continuous variables, measures of central tendency (mean) and dispersion (standard deviation (SD)) were reported, and frequency distributions were produced for all categorical variables. A paired-samples Student’s t-test was used to assess the change in QoL from baseline following HZ rash appearance. The level of statistical significance was set to 0.05. All statistical analyses were performed using the Statistical Analysis Software .A total of 146 eligible patients were enrolled in the study. During the follow-up period, 139, 137, 138, 142, 146, 144, 143, 145 and 144 patients completed visits at days 7, 14, 21, 30, 60, 90, 120, 150 and 180, respectively.At baseline, 78.1% of patients presented with a HZ rash. The most common affected primary dermatome was the thoracic region (38.4%), followed by the cervical (15.1%) and lumbar (13.7%) regions. Nearly half of patients (48.6%) presented with 1 to 20 lesions in the primary and adjacent dermatomes .Prior to HZ rash onset, 54.1% of patients experienced ZAP, with mean (SD) worst and average IZIQ scores of 7.4 (2.5) and 5.8 (2.5), respectively. Following HZ rash onset, 91.1% of patients reported ZAP, with mean (SD) worst and average IZIQ scores of 8.6 (7.2) and 5.5 (2.5), respectively. Approximately half of patients (49.3%) experienced PHN. Among the 140 (95.9%) patients who received HZ treatment, the most frequently utilized medication types included analgesics (34.2%), antivirals (27.4%), topical treatments (21.2%) and other therapies (44.5%) .p<0.001) deterioration in QoL was observed prior to and immediately following rash onset, with mean (SD) EQ-5D index scores decreasing from 0.9 (0.2) to 0.7 (0.2), respectively. Furthermore, EQ-5D index scores significantly (p<0.05) improved between baseline and days 7 to 30. More specifically, mean (SD) index scores gradually increased from 0.7 (0.2) immediately following rash appearance to 0.7 (0.2) at day 7, 0.8 (0.2) at day 14, 0.8 (0.2) at day 21 and 0.8 (0.2) at day 30. Although QoL further improved between days 60 and 180, results were not significantly different, with baseline values prior to rash onset (p>0.05).This study assessed the disease burden, impact on QoL, and HCRU associated with HZ in Brazil. Limited HZ epidemiological findings have been reported in Brazil. However, in a Brazilian study conducted by Castro et al., where medical records of child and adult patients were obtained from a dermatology clinic, the reported incidence rate was 5.62 cases per 1.000 person-years between 1987 and 1989 To our knowledge, this is the first study to prospectively assess the disease burden related to HZ in Brazil. Overall, HZ was associated with significant impact on pain, QoL and HCRU. As reduced immunological activity may increase the risk of HZ development among individuals with latent VZV The study results show the considerable and rapid impact of HZ on patients’ QoL, as illustrated by the highest mean ZBPI pain scores and lowest EQ-5D QoL index scores immediately following HZ rash appearance. Although pain generally decreased over time, a negligible improvement of pain was reported during the first 14 days (days 0 to 14) following rash onset. Moreover, pain did not entirely subside at the end of the study, illustrating the long-term pain and lengthy recovery associated with HZ and PHN. The prolonged duration of pain is highlighted by the important subset of patients with PHN (49.3%), particularly as the mean (SD) pain duration of 143.1 (440.2) days was longer than the 90-day established threshold of PHN. Nonetheless, the large SD of the mean duration of pain illustrates the high degree of variability in the cohort with respect to the duration of ZAP.The gradual decrease in pain was correlated with an improvement in QoL during the 180-day observation period. Significant changes in EuroQoL scores were observed between baseline and all visits within the first 60 days following HZ onset. However, this significance was lost from days 60 to 180 when compared to pre-HZ values, indicating a normalization of QoL over time. The results of the present study are comparable to findings of previous studies in the literature from other countries. In the UK, Gater et al. reported worst and average ZBPI scores of 5.0 and 3.9 at baseline and of 4.0 and 3.0 between days 7 and 14, respectively. The improvement in pain coincided with a concurrent amelioration of QoL Patients reported substantial HCRU during the 180-day observation period, in agreement with the high levels of reported pain associated with HZ. As patients were recruited by the study investigator in an ER, a higher rate of ER visits as opposed to family doctor consultations (65.8%) was expected. Moreover, although only 20% of patients visited a specialist, the total number of visits were the highest observed in this study [mean (SD): 5.7 (12.1)]. This may be due to the high subset of patients with PHN under the assumption that patients with the most severe cases of HZ would require multiple consultations with specialists to alleviate their long-term symptoms. With respect to Latin America, unpublished surveys conducted by the Foundation for Infectious Diseases evaluating outpatient visits between 1993 and 2005 in Argentina reported a total of 803 HZ cases among 154,392 ambulatory consultations. Of the 302 patients with HZ between 2000 and 2005, complications arose in 20% of patients, and this rate was highest among those older than 50 years of age. Moreover, the most common complication was PHN, which was experienced by 13% of patients, followed by bacterial superinfection (5%) and ophthalmic complications (2%) Currently, HZ and PHN prophylaxis and treatment present an important unmet global need, and Brazil is no exception. While the preponderance of patients 95.9%) received HZ treatment, only 29.3% received antiviral therapy, the current standard of care in HZ management .9% receiOur study also highlights the importance of including work loss when assessing the economic value of any intervention aiming to control HZ. Among the 36 patients employed prior to HZ development, the vast majority [n=33 (91.7%)] reported any missed work days during the 180-day observation period.The present study had several limitations. Although HZ generally affects elderly populations, the patient population in the present study, which only included patients above 50 years of age who sought HZ care, may have omitted certain HZ patients. This may have introduced a selection bias, as older HZ patients generally report worse pain and QoL scores, higher rates of analgesic use and a higher risk of complications Overall, this study highlights the significant disease burden associated with HZ and PHN. The high levels of ZAP correlated with a substantial impact on QoL over time. Although pain was generally alleviated over time, an important subset of patients experienced long-term PHN. These findings, as well as the high rates of HCRU observed in the study, support the need for the implementation of early intervention and prevention programs such as vaccination to reduce the HZ-associated disease burden in Brazil.Toniolo-Neto J, Rockett TY, Johnson KD, Monsanto HA and Acosta CJ substantially contributed to the conception of the study and interpretation of the data, with significant contributions towards critical review of the manuscript’s content. Psaradellis E and Karellis A substantially contributed to the analysis and interpretation of the data, with significant contributions towards producing the draft and critical review of the content. Rampakakis E and Sampalis JS substantially contributed to the analysis and interpretation of the data, with significant contributions towards critical review of the manuscript’s content.Joao Toniolo-Neto has consulted for Support (DANONE), Ache, MSD and Apsen and has been a speaker for MSD. Eliofotisti Psaradellis, Angela Karellis, Emmanouil Rampakakis and John S. Sampalis are employees at JSS Medical Research Inc., which is a CRO. Talita Y. Rockett has no disclosures to declare. Kelly D. Johnson is an employee at Merck & Co. Homero A. Monsanto and Camilo J. Acosta are employees and stock shareholders of Merck & Co.


Groin pain is a common problem in athletes which results in loss of playing time. Moreover, it can be for the cause of athletic career termination. A common cause of groin pain in athletes is inguinal disruption; pain in the groin area near the pubic tubercle were no obvious other pathology exists to explain the symptoms. Aim of this study was to evaluate the effect of endoscopic totally extraperitoneal (TEP) hernia repair in athletes with inguinal disruption.Thirty-one athletes with chronic groin pain due to inguinal disruption, who had undergone conservative therapy without any effect, were included in this prospective cohort study. Prior to surgery patients were assessed by clinical examination, ultrasound of the inguinal region, x-ray and a radionuclide bone scan with single photon-emission computed tomography and CT (SPECT-CT). TEP hernia repair was performed and a lightweight polypropylene mesh was placed pre-peritoneally. Additionally the athletes’ perception about their groin disability was assessed preoperatively and 6 weeks postoperatively by means of the Hip and Groin Outcome Score (HAGOS). The HAGOS consists of six subscales: Pain, Symptoms, Physical function in daily living, Physical function in Sport and Recreation, Participation in Physical Activities, and hip and/or groin-related Quality of Life.No complications occurred during and after surgery. After six weeks patients improved in all the separate subscales of the Hip and Groin Outcome Score (HAGOS). Within 6 weeks of surgery, 26 patients (84%) returned to sports activities with no or less groin pain.This study showed that endoscopic totally extraperitoneal (TEP) hernia repair is an effective surgical treatment of inguinal disruption in athletes with chronic groin pain. Chronic groin pain, commonly seen in athletes, is a debilitating condition which often results in a reduced playing time. Moreover, it may cause the end of a professional athlete’s career. This condition is common in sports involving repetitive kicking movements and rapid directional changes because of the forces exerted around the pelvic area ,2. ThereNo diagnostic imaging modality with high sensitivity and/or specificity to diagnose inguinal disruption is available. Coexisting pathology and symptoms are often present in the groin . It is cInitial treatment usually starts with conservative treatment, consisting of refraining from sport, non-steroidal anti-inflammatory drugs, cortisone injections, shockwave and physiotherapy. Research has shown that physiotherapy should involve an active training program aimed at improving strength and coordination of the muscles around the pelvis and adductors ,10.Management of inguinal disruption by surgical exploration and mesh placement should be considered when non-operative treatment fails ,11,12. AHence, aim of this prospective cohort study was to evaluate the early recovery of athletes with inguinal disruption after endoscopic totally extraperitoneal (TEP) hernia repair in terms of physical functioning and quality of life.Athletes with undiagnosed chronic groin pain that were referred between 2013 and 2017 to the Medical Center of Leeuwarden, The Netherlands, were eligible for inclusion in the study. Inguinal disruption was defined, according to the Manchester Consensus Conference [Pinpoint tenderness over the pubic tubercle at the point of insertion of the conjoint tendon.Palpable tenderness over the deep inguinal ring.Pain and/or dilation of the external ring with no obvious hernia evident.Pain at the origin of the adductor longus tendon.Dull, diffused pain in the groin, often radiating to the perineum and inner thigh or across the midline.Patients eligible for inclusion were males between 18–65 years old who are limited in their sports participation because of their groin pain. Inclusion criteria included symptoms for at least 3 months and having received at least 10 weeks of active physiotherapy aimed at strength and coordination of the muscles acting on the pelvis, in particular the adductor muscles. Exclusion criteria were a history of previous surgery in the groin area or other causes for chronic groin pain diagnosed by physical examination or imaging . The study was approved by the medical ethics committee of the Medical Center Leeuwarden . Written informed consent was obtained from all participants.Physical examination was performed by a sports medicine physician and a surgeon, both experienced in groin pathology, according to the guidelines proposed by Hölmich et al. .Additional imaging  was performed to rule out other pathology causative of groin pain.Surgical treatment consisted of endoscopic totally extraperitoneal (TEP) hernia repair. Surgery was performed under general anesthesia. A 10 x 15 cm lightweight polypropylene mesh  was placed in a tension free manner without fixation. All operations were performed by two surgeons with extensive experience in endoscopic hernia surgery. Intra-operative findings were recorded. In case of a true inguinal hernia, classification according to Nyhus  was usedPatients were advised to take paracetamol in combination with non-steroidal anti-inflammatory drugs (NSAID’s) for the first postoperative days for pain management. No restrictions were given except for no strenuous activities in the first week postoperatively. Early return to sport was promoted. A  rehabilitation program under supervision of their physiotherapist was advised.Patients were contacted by telephone two weeks after surgery. The main purpose of this contact was to evaluate complaints, and to evaluate the rehabilitation program and return to sport. Resumption to sport activity was recorded in their electronic medical records.The athletes perception about their groin disability was assessed preoperatively and 6 weeks postoperatively by means of the Hip and Groin Outcome Score (HAGOS). Six weeks postoperatively, the patients received the HAGOS by mail.The HAGOS  was deveAll statistical analyses were performed using IBM SPSS Statistics for Windows . Paired samples T-tests were used to analyze differences in scores on the HAGOS, measured pre-operatively and six weeks after surgery. To evaluate possible differences between patients who did or did not fill in the HAGOS at six weeks following surgery, a non-response analysis was performed to assess possible differences in terms of age, gender, procedure type and pre-operative scores on the HAGOS.Bootstrap procedures were used for estimating bias and obtaining confidence intervals . BootstrBetween 2013 and 2017, 39 patients with groin pain were considered for inclusion in the study. The flow chart of the inclusion procedure of respondents is presented in The findings of physical examination and imaging are presented in Of the 31 TEP hernia repairs that were performed, 23 were unilateral procedures and 8 bilateral procedures. A true small inguinal hernia was found in 5 patients (16%) and these were all indirect hernias, type 2 according to the Nyhus classification. One lipoma was found near the internal inguinal ring (3%). No other abnormalities were observed during surgery.All wounds healed within two weeks after surgery and no surgical complications occurred. Of the 31 participants, 20 (65%) filled in the HAGOS questionnaire six weeks after surgery. A non-response analysis showed no difference in demographic factors, symptoms and scores of the HAGOS subscales between responders and non-responders.After six weeks a significant improvement  was seen in every subscale of the HAGOS . A signiThe results of this prospective cohort study demonstrate clearly that reinforcing the posterior wall with a lightweight polypropylene mesh through endoscopic totally extraperitoneal (TEP) hernia repair is an effective treatment for athletes with inguinal disruption who are unresponsive to conservative treatment. It offers pain relief, improvement in physical function and a fast return to sports activity in the great majority of patients only six weeks after surgery.Tenderness over the external and internal inguinal ring (81%) was the most common finding during physical examination. These findings are in line with those of van Veen et al. , who desIn the present study imaging modalities  were used to rule out other causes of groin pain. Despite normal ultrasonography, 5 small inguinal hernias were found peroperatively. Miller et al.  showed iOverall, in six (19%) patients abnormalities of the posterior wall were observed per-operatively which consisted of 5 small indirect inguinal hernias and 1 lipoma in the inguinal canal. These results are in line with the per-operative findings reported by authors in the operative management of chronic groin pain in athletes ,30.To our knowledge only one study  used a vA strength of our study is that all patients were assessed using the HAGOS before and after surgical treatment. A total of 20 HAGOS questionnaires (65%) were returned. Selection bias may be indicated due to non-responders, making it uncertain if the sample reflects the total study population. However, a non-response analysis showed no differences between responders and non-responders, in terms of age, gender, procedure type and pre-operative scores on the HAGOS.In general, the generalizability of study results depends on the extent to which the sample data is representative of the total study population. A way to increase the generalizability of study results is the use of bootstrapping methods in order to give a more precise estimation of the outcome population parameter. Regarding the present study, the relatively small sample size at 6 weeks after the operation may be regarded as a limitation of the generalizability of our study results. We therefore used bootstrapping methods to calculate (bootstrapped) confidence intervals of the differences in HAGOS subscales before and after surgery. A significant improvement in scores of the HAGOS was seen in both the original (non-bootstrapped) data and the bootstrapped data.The lack of MRI may be considered a limitation of this study. Pelvic MRI is often used as diagnostic imaging to visualize pathology in athletes. However, as MRI is based on structural changes in the groin area, it is limited with regard to determine the lesions responsible for the groin pain. Positive MRI findings are often observed in athletes with and without groin pain and can be caused by degenerative changes as well as changes related to exertion . FurtherThe lack of a control group  might be considered a limitation of this study. However, it is difficult to find an adequate control group for surgery as most patients already have tried conservative and alternative treatments for a long time (at least 10 weeks) without any effect. If conservative measures have failed, surgery is provided as an option. Patients serve as their own controls since they are not responding to various conservative treatments. A sham-designed study could be an alternative. However, to perform a surgical procedure that could cause harm without offering a compensating beneficial effect poses ethical problems .Another possible limitation of our study is that no fully standardized post-operative rehabilitation regimen was used. Patients underwent care as usual for their postoperative rehabilitation, which consisted of rehabilitation under supervision of a physiotherapist, chosen by the patient. In general most athletes are able to return to sport 2–6 weeks after laparoscopic surgery . Use of Athletes who suffer from chronic groin pain that is caused by inguinal disruption, should be offered a surgical TEP repair when conservative treatment does not alleviate the complaints. This study showed that reinforcement of the posterior wall with a lightweight polypropylene mesh shows good clinical results and improvement of functional status and health-related quality of life of athletes with inguinal disruption.S1 Dataset(SAV)Click here for additional data file.