This study comprises a test-retest design separated by 7 to 14 days, and evaluates the intra and interrater reliability of regional frontal and horizontal spinal motion in 219 chronic LBP patients using the CA6000 Spine Motion Analyzer. In addition, it compares these results on the frontal and horizontal plane with previously published results on the sagittal plane. 219 individuals with chronic mechanical LBP, classified as either Quebec Task Force group 1, 2, 3 or 4 were included, and kinematics of the lumbar spine were sampled during standardized spinal lateral flexion and rotation motion using a 6-df instrumented spatial linkage system. Test-retest reliability and measurement error were evaluated using intraclass correlation coefficients ICC coefficients varying between 0.68 and 0.73 for the frontal plane and 0.33 and 0.49 for the horizontal plane. Relatively wide LOAs were observed for all parameters. Reliability measures in patient subgroups ICC ranged between 0.55 and 0.81 for the frontal plane and 0.28 and 0.69 for the horizontal plane. Greater ICC coefficients and smaller LOA were observed when patients were examined by the same examiner, had a stable pain level between tests, and were male. ROM measurements were more reliable in patients with a BMI higher than 30, and measurements on patients with LBP and leg pain showed higher reliability and smaller measurement error in all parameters except for the jerk index.The reliability analysis based on the whole study sample showed ICCFrontal plane measurements obtained using the CA6000 Spine Motion Analyzer are sufficiently reliable to be used for group comparisons but not individual comparisons. Measurements in the horizontal plane can be used for neither group nor individual comparisons. It is widely assumed that Low Back Pain (LBP) with mechanical pain behavior is significantly influenced by biomechanical factors –4. ThereIn order for measurements to be clinically useful, data on psychometric conditions such as reliability should be available in the population for which the measurements are intended to be used. , 8. Most) ranging from 0.34 to 0.77 [ coefficients and smaller limits of agreement (LOA) when patients were examined by the same examiner, had a BMI below 30, had a stable pain level between test one and two, were men and could be classified in the Quebec Task Force classifications Group 1.We recently presented values and estimates for reliability and measurement error of sagittal plane spinal motion using a 3D lumbar spinal motion instrument called the CA6000 Spine Motion Analyzer in chronic and care seeking LBP patients and further stratified the sample into subgroups based on body mass index (BMI), gender, differences in pain level, and Quebec Task Force classification . We foun to 0.77 , and a nPrevious studies using the same type of 3D regional lumbar instruments have found measures of flexion/extension and lateral bending movements to be more reliable than axial rotation –16 possiThe overall aim of the present study is to evaluate the reliability of regional frontal and horizontal spinal motion in 219 chronic LBP patients using the CA6000 Spine Motion Analyzer. In addition, we aim to discuss potential differences between frontal and horizontal plane motion, and compare results on the frontal and horizontal plane with previously published results on the sagittal plane .We hypothesize that frontal plane movements show better reliability and have smaller measurement error when compared to similar measures in the horizontal plane. In addition, that reliability and measurement errors in the subgroups  will follow the same pattern as in the sagittal plane motion .During a period of 3 years from 2001 to 2004, 219 subjects were recruited for inclusion in a randomized clinical trial at the Wolfe Harris Center for Clinical Studies at Northwestern Health Science University, Minneapolis, MN, USA . RecruitMechanical LBP was defined as pain with no specific identifiable etiology but reproducible by back movements or provocations tests. Exclusion criteria were previous lumbar spine fusion surgery, progressive neurological deficits, aortic or peripheral vascular disease, pain scores of less than 3 points , ongoing treatment for back pain by other healthcare providers, or participation in pending or current litigation.The study was approved by the institutional review boards of the Northwestern Health Sciences University, the Minneapolis Medical Research Foundation, and the University of Minnesota. Written informed consent was obtained from all the study participants.The test-retest design was conducted as part of the baseline examination for a randomized clinical trial  and inclSubjects who qualified for the clinical trial and agreed to participate were scheduled for a second baseline visit in the clinic 7 to 14 days later, at which time the 3D motion measurements were repeated.Kinematics of the lumbar spine movements in the frontal and horizontal plane were sampled following a standardized test protocol using a 6-df instrumented spatial linkage system with a sampling rate of 100 Hz .Each participant wore a loose T-shirt and pants. We have previously described the attachment of the measuring device . After tWhen the left and right turning had been performed the participant was asked to stand straight and was then given the following instructions both verbally and visually “Ok, this time find your neutral position with your palms on the side of your thighs. Slide your hand down your leg as you lean to the left, then to the right, and then back to neutral. Be sure to go as far as you can go in both directions at your own pace without pausing”. The patient was allowed to practice the movement once, and the equipment was checked before recording started.The procedure was repeated until two valid measurements had been recorded . The outcomes of the two trials were averaged and used for the analysis.A comprehensive description of data processing procedure including MATLAB programming, computerized trial selection algorithm has been published elsewhere . This MAROM lateral flexion defined as the total angular range of spine motion in the frontal plane expressed in degrees from maximum left to right.Mean velocity lateral flexion (°/s) defined as the central limit theorem as the average angular speed from maximum left to right.2/s) defined as the area composed by the phase-plot of lateral flexion left to right angular motion versus velocity. Phase-plot area was calculated based on cross-product calculations between vectors drawn from neutral position to each coordinate point.Phase-plot area lateral flexion  defined as the central limit theorem as the average angular speed from maximum left to right2/s) defined as the area composed by the phase-plot of rotation left to right angular motion versus velocity. Phase-plot area was calculated based on cross-product calculations between vectors drawn from neutral position to each coordinate point.Phase-plot area rotation  version 13 on a personal computer. Taxonomy, terminology, and definitions related to reliability and measurement error are based on Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) .1,1) were calculated to assess reliability [) [Based on the study design each target was rated by a different set of the nine examiners (considered to be randomly selected from a larger population of examiners) and because we aim to generalize to individual ratings the Intraclass Correlation Coefficients )  and Blan [)  with a 9We used Bland-Altman plots  and corrWe stratified into subgroups based on pain distribution, (back and leg pain versus back pain only) by collapsing Quebec diagnostic groups 2, 3, and 4 versus Quebec diagnostic group 1 . The BMIN = 6) and a database storing error (N = 53)). Reasons for dropout were recorded as follows: refused to participate (N = 9), personal conflict (N = 3), increase in musculoskeletal pain (N = 3), insufficient time (N = 2), unknown reasons (N = 2), competing co-morbidity (N = 1) and change of address (N = 1)), leaving 220 complete datasets of which one was excluded because the participant had performed the side-bending movements in reverse order and thus a total of 219 datasets were available for analysis. The clinical characteristics of the study population are showed in . The individuals not available for analysis were however slightly younger (median age of 43 versus 47 years).p = 0.009), Rotation mean velocity , Phase-plot area . For lateral flexion, a statistical difference between the two sessions was found in 2 out of the 4 motion parameters: Lateral flexion mean velocity  and phase plot area   coefficients varying between 0.68 and 0.73 for the frontal plane and 0.33 and 0.49 for the horizontal plane. Furthermore relatively wide LOA values  were found for all motion parameters in both frontal and horizontal plane movements  ranged from 0.28 to 0.69 for horizontal plane and 0.55 to 0.81 for frontal plane movements. For all parameters frontal plane movements showed higher reliability scores than movements in the horizontal plane  values and lower LOA scores between the two sessions in all parameters except the jerk index. Participants examined by the same examiner showed higher ICC coefficients and smaller LOA values between the two sessions in all motion parameters except the Jerk index which showed identical ICC coefficients in the inter and intra examiner analysis.Participants with higher BMI (BMI > 30) had higher ICC coefficients and higher LOA scores between the sessions for the frontal plane movements, whereas the horizontal plane movements showed mixed results – with ICC coefficients being slightly lower for ROM, mean velocity and jerk index and higher for Phase-plot area.Participants with unstable pain showed a trend towards lower ICC coefficient for the Jerk index when compared to participants with LBP only.Finally, participants with LBP and leg pain had less variation in ROM, mean velocity and Phase-plot area between the sessions, but a lower ICC We found systematic differences between the test and retest session for three of the four motion parameters in the horizontal plane and in two of the four motion parameters in the frontal plane with one further parameter showing borderline significant differences between the two sessions. These differences most likely indicate the presence of a learning effect caused by patients’ habituation to the instrument and the testing situation. coefficients on all measured parameters and across all subgroups when compared to the horizontal plane. Frontal plane motions, exhibit moderate to good reliability with ICC values, ranging between 0.55 and 0.8 [ values for horizontal motion parameters range from poor to moderate[ value above 0.69. Finally, LOA where found to be relatively wide. Although frontal plane motion parameters have slightly smaller LOA, we deem the LOA of both planes to be too wide for the CA6000 Spine Motion Analyzer to be used in clinical practice. Therefore, we cannot recommend the use of horizontal movement parameters obtained with this device for neither group nor individual comparisons, and subgroup patterns for horizontal motion should be interpreted with extra care [ values obtained in the horizontal plane using the CA6000 Spine Motion Analyzer may be caused by slipping of the mounting plates across the skin during rotation of the trunk. It should be noted that other types of kinematic devices have been recommended for all planes of trunk movement except extension by other authors [Our hypotheses were confirmed as we found that frontal plane movements yield higher ICC and 0.8 . Therefo moderate, and no tra care , 27. We tra care , that th authors , 29. coefficients and smaller LOA would be found when patients were examined by the same examiner, had a BMI below 30, had a stable pain level, were men and could be classified in the Quebec Task Force classifications Group 1. We found that some of the patterns were as we had hypothesized in that patients, who were examined by the same examiners, had a stable pain level, and were men showed less variation between the two test sessions and had in general smaller LOA. This pattern is consistent across all three planes of motion, and it is therefore a general finding that intraexaminer measurements and measurements made on men and pain stable patients are more reliable than interexaminer measurements, and measurements made on women and patients who have unstable pain.We further hypothesized that in general greater ICCAmong patients with a BMI above 30 and patients with both LBP and leg pain, we unexpectedly found less variation, and smaller LOA between the sessions compared to findings from patients with a BMI below 30, and among patients who had LBP without leg pain. We therefore rejected our second hypothesis as a whole because only some of the subgroup comparisons showed the expected patterns. coefficients, and smaller LOA in ROM for all three planes of motion among patients with a BMI above 30. We speculate that this may be because the larger body mass generally limits motion and thus these measurements likely reflect body size rather than spine function. A secondary comparative analysis on mean ROM in the frontal plane comparing patients with a BMI above 30 to patients with a BMI below 30 did indeed show that patients with higher BMI had lower ROM 44.5(9.5) (mean (SD)) versus 50.4(8.0), p < 0.0001 (paired t-test)). Another secondary analysis showed that patients who reported different pain scores between session 1 and 2, also had more changes in ROM between the two sessions if their BMI was below 30  value 0.43), whereas patients with unstable pain and a high BMI had more similar ROM values between the two sessions  value 0.84).We observed greater ICCOn average people with LBP have reduced lumbar ROM . Our sec coefficients were between 0.05 to 0.28 higher than those found for patients with LBP only. A possible explanation for this phenomenon could be that patients with leg pain represent a more homogeneous population with regard to what is causing their pain.Unexpectedly, we found less intersession variation among patients with both low back and leg pain. For these patients ICC values for the sagittal and frontal plane ROM, mean velocity and the phase-plot, when looking at patients with LBP only. However, the same comparison made among patients with LBP and leg pain revealed ICC values to differ substantially more between the two planes of motion, but always with the frontal plane having the highest ICC values. Together these findings indicate that when measuring patients using the CA6000 Spine Motion Analyzer, results will be equally reliable for the frontal and sagittal plane if the patients suffer from back pain without leg pain, but if the patients suffer from LBP and leg pain, the results will be more reliable for the frontal plane.A further comparison with our previous findings  revealed coefficients the jerk index appears to be almost unaffected by interexaminer bias. This is a consistent finding across all three motion planes [ values in the horizontal plane ranged from poor to low-end moderate, values in the frontal plane ranged from high-end moderate to good. Furthermore all of the ICC values in the frontal plane were also notably higher than the previously published results from the sagittal plane [The jerk index is a particularly noteworthy parameter because it captures the quality and smoothness of the movements and not only the range. Among several observations, we have chosen three to be of particular interest. Firstly, with identical or very similar intra and interexaminer ICCn planes . Secondlal plane  – with tal plane  may contPrevious research has shown the jerk index to change significantly and differently depending on whether patients receive spinal manipulation or exercise . PossiblThe CA6000 Spine Motion Analyzer has previously been described in detail and verified for precision and accuracy , 33–37. To reduce complexity and data abundance, the recorded 3D spinal motion data were reduced into a number of separate motion parameters. The selected parameters could be considered as reductionist models to achieve descriptive measures of complex spinal movement patterns in patients with LBP at the functional level. Obviously, selecting some parameters and certain ways to analyze means that other types of important kinematic information may remain uncovered in the data set.This study has focused on single-plane analysis of the lumbar spine; a combined plane movement analysis may yield different results, which could be of clinical relevance .Use of over the counter pain medication and changes in physical activity may have changed between the two sessions, but were not considered.This study reports inter-session reliability, with the two sessions 7–14 days apart. Intra session reliability was not considered.In addition, these results cannot be extrapolated to other technologies.Using the CA6000 Spine Motion Analyzer, frontal plane measurements are sufficiently reliable to be used for group comparisons but not individual comparisons. Measurements in the horizontal plane can be used neither for group nor individual comparisons. coefficients and smaller LOA were observed when patients were examined by the same examiner, had a stable pain level between tests, and were male.Greater ICCWe found that ROM measurements were more reliable in patients with a BMI higher than 30, and measurements on patients with LBP and leg pain showed higher reliability and smaller measurement error in all parameters except for the jerk index.The jerk index appears to be almost unaffected by interexaminer bias regardless of the examined motion plane, and it is more reliable when it is measured in the frontal plane. The jerk index is the only motion parameter to have a consistent subgroup pattern across all three planes of motion.


Background: About 75% of the symptomatic patients who involved with endometriosis have pelvic pain and dysmenorrhea. Pentoxifyllin is one of the drugs that according to its mechanism could be effective for pain relief of endometriosis which has been used for endometriosis treatment recently.Objective: We conducted a comparative study for detecting the effect of pentoxifylin (as an immonomodelator) in preventing recurrence endometriotic pain with pentoxifylin plus a combined contraceptive pill with low dose estrogen (LD) and also the LD pill alone.Materials and Methods: This was a comparative clinical trial on 83 patients with the chief complaint (CC) of pain  and with the end diagnosis of endometriosis, in an operative laparoscopy. Patients, dividing to 3 groups, were treated with pentoxifylin, pentoxifylin+LD and LD alone for 10 months. The severity of pain (dismenorhea and/or pelvic pain) was detected by visual analogue scale (VAS) before and after the treatment. The severity of endometriosis in the patients was: I in class I and II in class II and III in class III. The groups were matched for the pain. The number of the patients in group 1, 2 and 3 were 28, 28 and 27 respectively.Results: The pain was reduced in the groups of pentoxifylin+LD (p<0.001) and LD alone (p=0.00). The pain relief was not significant in the group of pentoxifylin alone (p=0.136). After treatment, the severity of pain was not significantly different between the LD group and the LD+penthoxyfillin group, but there was difference between these two groups and the group of penthoxyfillin alone.Conclusion: This study showed that penthoxyfillin actually could not have any effect on the pain relief of endometriosis. It also made it clear that penthoxyfillin could not increase the efficacy of LD when used with this medication. Endometriosis is the presence of the endometrial tissue (stroma and the glands) somewhere outside of the endometrial cavity. It can have debilitating symptoms like dysmenorrheal and pelvic pain or can be symptom less and discovered accidentally at laparoscopy . About 7The management of endometriosis is dependent to the managing physician and is chosen by the different factors like: the severity of symptoms, localization of the lesions, desire for pregnancy, age, and manifestation of the medications, surgical complications and finally the expense. Although most of the studies confirm the positive effect of the OCP in reducing the prevalence of endometriosis, but some studies express that it has no effect or even may cause increasing the rate of the disorder -5. In a controlled clinical trial, the effect of the OCP was compared with GNRH agonist. Both had good effects on recovering the pain of endometriosis, while the GNRH agonist showed better effects on treating the dyspareunia -15. One Pentoxifyllin is a methylgesantins suppressor of phosphodiesterase and possibly acts as an anti-inflammatory for the treatment of endometriosis. In addition to dysmenorrhea and pelvic pain, we can think of infertility as an important complication of endometriosis. Different studies have different results about the effect of this medication on infertility. So our study was conducted to compare the rule of pentoxifilin with OCP (LD) as a proved drug for the prevention of recurrence of endometriosis.This was an open-label comparative clinical trial on 83 patients with the chief complaint of dysmenorrhea and or pelvic pain that underwent laparoscopic treatment of endometriosis in a private clinic and its aim was to compare the recurrence rate of the endometrioid symptoms. After obtaining informed consent, patients were randomly allocated to three groups based on the patients file number. Groups 1 and 2 were consisted of 28 patients, and group 3 had 27 patients. The patients were divided into three groups selecting by the simple randomization and after signing the consent form of each group. The number of the patients in groups 1, 2 and 3 were 28, 28 and 27 respectively. Inclusion criteria were mainly the diagnosis of pelvic endometriosis with the clinical symptoms and a full treatment procedure of cystectomy of possible endometrioma was done and/or fulguration of the endometriotic lesions by a bipolar coagulator . The exclusion criteria were refusing the patient of entry to the protocol or the presence of the specific drug manifestation. Each protocol was described clearly for each patient and finally the three groups were constructed as below:- Group 1: 800 mgs of pentoxifyllin in two divided doses (capsules of 400 mgs) daily.- Group 2: Pentoxifyllin capsules with the same dose plus OCP (LD) one tablet per night, from the 3rd day of the menstrual cycle.- Group 3: OCP (LD) one tablet per night. Each treatment duration was about 6 months and no patient knew anything about the other group’s regimen.Statistical analysisWe used the visual analog scale (VAS) method for detecting the severity of the possible pain existence before and after the treatment period (the recurrence). We also used the one way ANOVA and "post Hoc" statistical analysis test for comparing the results of the study and also for comparing the demographic data of the patient’s. P<0.05 was considered "significant" and SPSS 11.5 was used for the data analysis.The mean age of the patients in group one was 27.5±5.5 yr, in group two was 25.27±6.7 yr and in group three was 27.01±4.68 yr. The average mean age was 26.59±4.70 yr with no significant difference between 3 groups (p=0.73). Pain severity comparing before starting the treatment regimen in 3 groups showed no statistically difference (p=0.47). But this comparison before and after the treatment in group one showed a significant difference; 7.67±1.41 vs. 3.64±2.81 respectively (p<0.001) . This was also seen in group two; before (7.70±1.61) and after (3.67±2.70) (p<0.001). In group 3, there was not any significant difference between before and after the treatment; 7.44±1.55 vs. 7.00±1.96 (p=0.136). At the end of the treatment regimen, pain severity comparison shared no significant difference between group one and two, while having significant difference between group three, and one and two (p<0.001).Pain is the most common symptom of endometriosis and about 75% of the symptomatic patients experience dysmenorrhea and pelvic pain. Medical treatment with different regimens has been suggested after the surgery (laparoscopy), to eradicate the possible remnant endometriotic tissue, and to reduce the recurrence of pain . BetweenThe results of our study showed that from these 3 regimens, pentoxifyllin+OCP (LD) and OCP (LD) alone were effective for pain release, and the pain severity scale before and after the treatment were statistically significant; but these two regimens were not significantly different for the pain release. Endometriosis related pain release by pentoxifyllin alone before and after the treatment was nadir and not statistically significant. So, by the above mentioned results, we can say that our study showed satisfactory effects of pain release of endometriosis by OCP (LD), but unsatisfactory effects by pentoxifyllin. And also, the combination of pentoxifyllin with OCP (LD), could not increase the positive results of the pill. et al found no therapeutic effect for pentoxifyllin in treating the infertility induce endometriosis (Crosignani and his colleagues proved the positive immonumedulatory effects of pentoxifyllin for infertility caused by endometriosis, at their own study, but they also concluded that their results were just a beginning to this field and more studies were needed . Balash etriosis . Alborzietriosis .But a prospective randomized study on the patients with moderate to severe dysmenorrheal caused by endometriosis showed that the OCP could reduce the pain of these patients completely better than the placebo for 4 cycle treatment . Most of


The treatment of migraine headache is challenging given the lack of a standardized approach to care, unsatisfactory response rates, and medication overuse. Neuromodulation therapy has gained interest as an alternative to pharmacologic therapy for primary headache disorders. This study investigated the effects of non-invasive vagus nerve stimulation (nVNS) in patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM).pain relief, defined as a ≥50 % reduction in visual analog scale (VAS) score, was 56.3 % at 1 h and 64.6 % at 2 h. Of these patients, 35.4 % and 39.6 % achieved pain-free status (VAS = 0) at 1 and 2 h, respectively. When all attacks (N = 131) were considered, the pain-relief rate was 38.2 % at 1 h and 51.1 % at 2 h, whereas the pain-free rate was 17.6 % at 1 h and 22.9 % at 2 h. Treatment with nVNS was safe and well tolerated.In this open-label, single-arm, multicenter study, patients with HFEM or CM self-treated up to 3 consecutive mild or moderate migraine attacks that occurred during a 2-week period by delivering two 120-s doses of nVNS at 3-min intervals to the right cervical branch of the vagus nerve. Of the 50 migraineurs enrolled (CM/HFEM: 36/14), 48 treated 131 attacks. The proportion of patients reporting Non-invasive vagus nerve stimulation may be effective as acute treatment for HFEM or CM and may help to reduce medication overuse and medication-associated adverse events. Migraine, a highly disabling neurological disorder, is characterized by recurrent moderate to severe attacks associated with vegetative symptoms . PatientA non-invasive VNS device  has been developed and is CE-marked for acute and prophylactic treatment of primary headache disorders including migraine and cluster headache . In a reSan Raffaele Pisana institutional review board (10/2013), and all patients who were enrolled in the study provided written informed consent. The study population excluded patients with a history of cerebrovascular, cardiovascular, or atherosclerotic disease  or any significant neurological or systemic disorder and patients with an implanted electrical device.In this open-label, single-arm, multicenter study, 50 patients aged 18 to 65 years who were experiencing HFEM or CM  were conAt monthly educational meetings involving groups of 3 to 6 patients as well as neurologists and counselors, patients were instructed on how to use the nVNS device and were invited to describe their experiences with migraine and how they usually managed migraine attacks. Patients received basic information on vagus nerve physiology and vagal neurostimulation and watched a video demonstrating how nVNS is believed to work. Prior to study initiation, patients were actively encouraged to use nVNS and received training on the proper use of the device from a physician and via an instructional video.Patients were instructed to use nVNS to self-treat up to three consecutive migraine attacks that occurred over a 2-week period. For each migraine attack, patients delivered two 120-s doses of electrical stimulation at 3-min intervals to the right cervical branch of the vagus nerve within 20 min of the onset of mild or moderate pain.no pain; 1-3 cm, mild; 4-6 cm, moderate; 7-10 cm, severe) at baseline, 1 h, and 2 h. Patients recorded pain severity in a headache diary, along with symptoms of nausea, photophobia, phonophobia, and functional disability (at baseline and 2 h); the use of rescue medications and adverse events were also recorded.Patients were allowed to take a rescue medication if they perceived no reduction in pain 2 h after nVNS treatment. Pain severity was rated using a 0- to 10-cm visual analog scale (VAS) score  with treatment, their willingness to use the device in the future, and their perceptions regarding the safety of nVNS. Descriptive statistics  were used to describe categorical data; no other statistical analyses were performed.n = 36) and HFEM (n = 14)  were pain free. Thirty-one patients (64.6 %) reported pain relief at 2 h, of which 39.6 % (n = 19) were pain free  of attacks at 1 h and for 51.1 % (67 of 131) at 2 h; pain-free status was reported for 17.6 % (23 of 131) of attacks at 1 h and for 22.9 % (30 of 131) of attacks at 2 h  of patients treating 3 attacks and 41.7 % (5 of 12) of patients treating 2 attacks (5 of 12).We enrolled 50 patients  affected by CM  and at 2 h ; achievement ofpain-free statuswas also greater in HFEM at 1 h  and at 2 h  . A similar trend was seen for all 131 attacks. A greater proportion of HFEM attacks achievedpain reliefat 1 h  and 2 h ; more attacks achievedpain-free statusat 1 h  and at 2 h  .The proportion of patients who responded to nVNS in ≥ 50 % of the migraine attacks at 2 h was 62.5 % for pain relief  and 33.3 % for pain free .At 2 h, freedom from nausea was reported in 66.4 % (87 of 131) of attacks; freedom from photophobia and phonophobia was reported in 76.3 % (100 of 131) and 77.1 % (101 of 131) of attacks, respectively. Complete recovery from functional disability at 2 h was reported in 35.1 % of attacks. Rescue medications were taken in 53.4 % (70 of 131) of the attacks.satisfied or very satisfied) with treatment and were willing to use the device in the future. All patients considered nVNS treatment to be safe.No major adverse events were reported. Mild tingling or pricking sensations at the stimulation site, reported by 67 % (32 of 48) of patients, was the only adverse event associated with nVNS. Nearly half of the patients  reported satisfaction  appeared to achieve a better response than those with a higher frequency of attacks . This finding represents an early treatment paradigm in which nVNS was administered when migraine pain was mild or moderate rather than severe. Although this paradigm may increase the placebo effect, it was selected because headaches in CM are typically reported to be mild or moderate compared with more severe headaches in episodic migraine [Moreover, larger studies are required. However, studies of nVNS in migraine [Results from the present study validate prior evidence that shows nVNS is effective for the acute treatment of migraine attacks in patients with HFEM or CM . With enmigraine . Other lmigraine  and clusmigraine  have alsmigraine  and chromigraine  have furWe investigated the benefit of nVNS in a real-world clinical setting; findings from this study will expand the body of clinical evidence on nVNS to the HFEM/CM population whose pain is difficult to manage. Furthermore, we implemented intensive educational training to ensure treatment adherence, assessed headache response at a short interval , and evaluated treatment satisfaction. Our data confirm that nVNS is well tolerated and safe and is associated with treatment satisfaction and therapeutic adherence. From a risk-benefit perspective, nVNS therapy achieved pain relief without serious side effects, which may decrease patients’ reliance on migraine medications and, in turn, lower the risk of medication overuse.


Depression in chronic pain is highly prevalent (60.8%) and is a significant predictor of poorer functioning, pain interference, reduced work status, and increased health care costs. This cross-sectional study aimed to determine the prevalence and impact of depression on health care costs in patients with complex chronic pain. The sample included 1204 patients attending a tertiary pain management service for people with chronic disabling pain, unresponsive to medical treatment. As part of routine care, patients completed a web-based questionnaire assessing mental and physical health, functioning, and service use in the preceding 3 months. Depression was assessed using the 9-item Patient Health Questionnaire. Self-report health care utilisation was measured across 4 domains: general practitioner contacts, contacts with secondary/tertiary care doctors, accident and emergency department visits, and days hospitalised. The participation rate was 89%. Seven hundred and thirty-two patients  met criteria for probable depression, and 407 (33.8%) met the threshold for severe depression. Patients with depression were more likely to be unable to work because of ill health and reported greater work absence, greater pain-related interference with functioning, lower pain acceptance, and more generalised pain. Mean total health care costs per 3-month period were £731 (95% CI £646-£817) for patients with depression, compared with £448 (95% CI £366-£530) for patients without depression. A positive association between severe depression and total health care costs persisted after controlling for key demographic, functional, and clinical covariates using multiple linear regression models. These findings reveal the extent, severity, and impact of depression in patients with chronic pain and make evident a need for action. Effective treatment of depression may improve patient health and functioning and reduce the burden of chronic pain on health care services. Estimates ranged from 4.7% to 22% in population-based studies and from 5.9% to 46% in primary care studies. Variability in estimates was particularly striking in studies of specialist pain populations (1.5%-100%). Most of these studies, however, were conducted in the 1980s and included fewer than 100 participants. More recent studies of depression in specialist pain settings have yielded prevalence estimates ranging from 12.1% to 72%, but sample sizes remain small.33Chronic pain and depression are each prevalent and often co-occur.21 Given the magnitude of these costs, surprisingly, few studies have examined the factors associated with health care utilisation in people with chronic pain. Blyth et al.8 found that a high level of pain-related interference was associated with a greater number of general practitioner (GP) and emergency department visits and more frequent hospitalisation, in the general population. Azevedo et al.4 identified depressed mood and pain-related disability as the main drivers of increased medical consultations, and Andersson et al.1 found that people with chronic pain and depressive symptoms made more physician visits than those with pain alone. These population-based studies indicate that pain interference and depression may predict health care use, but there remains a dearth of data from more complex, multiproblem, specialist pain populations.Chronic pain poses an enormous economic burden on society both in terms of medical care and lost productivity. A National Institutes of Health report in 2011 estimated the total annual incremental cost of health care due to pain in the United States at $261-$300 billion. The total cost to society, including indirect costs of pain due to lower economic productivity, was estimated at $560-$635 billion—greater than the cost of heart disease, cancer, or diabetes.If depression modifies the relationship between chronic pain and health care utilisation, there may be opportunities to reduce the burden of chronic pain on both the individual and society, through improved detection and treatment of the disorder in this context. Up to date evidence on the prevalence and impact of depression in specialist pain services is therefore necessary to determine the need for increased investment in mental health resources for this population. The aims of this study were (1) to determine the prevalence of depression in a specialist pain population and (2) to describe the impact of depression on health care utilisation and costs.The study sampling frame was all patients attending an initial assessment consultation at the INPUT pain unit at Guy's and St Thomas' NHS Foundation Trust in central London, United Kingdom, between February 2013 and June 2015. The INPUT pain unit is a specialty interdisciplinary pain management service that provides residential, outpatient, and individual treatment for patients with chronic pain. Generally, the referral population for the service includes people with chronic pain , and disability, who have sought previous primary care and hospital care, such as pain clinic, orthopedics, or rheumatology services, for their pain without satisfactory resolution. Most referrals are from the south east of England. The INPUT pain unit is a typical U.K. tertiary care service.29 IMPARTS is a multifaceted service development package designed to improve integration of mental and physical health care. It does this through (1) routine measurement of mental and physical patient-reported outcomes, with real-time feedback and decision support through the electronic patient record; (2) development of mental health referral pathways for individuals with identified mental health needs; (3) training staff in core mental health skills; and (4) development of self-help materials specific to the condition in question. Further information about IMPARTS has been reported elsewhere.29 The INPUT pain unit implemented IMPARTS in February 2013 to facilitate systematic assessment of depression alongside other outcomes pertinent to the chronic pain population. Patients were approached to participate in screening at their first visit to INPUT, which is an assessment consultation to determine their suitability for the treatments provided. Consecutive patients attending the assessment clinic were invited by reception staff to complete a questionnaire on a touchscreen e-tablet in the waiting room, before their consultation. IMPARTS establishes routine outcome measurement as a service development rather than as a research project. Therefore, formal consent was not required, but patients were informed and given information sheet explaining that completion of the questionnaire was voluntary and that responses would be confidential and only used for audit or research if fully anonymised. On completion of the questionnaire, patients' screening results immediately populated their electronic patient record, ready for the clinical team to review.Data were collected as part of routine care using the IMPARTS  web-based screening interface.IMPARTS has research ethics approval from the National Research Ethics Service Research Database Committee , which permits the use of de-identified data collected through IMPARTS for research purposes, with the added safeguard that each project was approved by a patient-led research oversight committee.Measures were selected for inclusion in the IMPARTS questionnaire in collaboration with the INPUT clinical team, based on appraisal of the existing scientific literature. The questionnaire was necessarily brief so that it could be completed in the course of routine care, with minimal impact on staff and patients' time.35 which has been validated in patients with a broad range of physical health problems, including chronic pain.9 A meta-analysis of 113 studies examining the diagnostic accuracy of depression case-finding tools in chronic illness showed that the PHQ-9 had high sensitivity  and specificity  compared with other commonly used screening tools such as the Hospital Anxiety and Depression Scale and the General Health Questionnaire 12.25 Choi et al.9 found that the PHQ-9 was among the best-performing tools  in their comparison of case-finding instruments for depression in patients with chronic spinal pain.Depression was assessed using the 9-item Patient Health Questionnaire (PHQ-9),24 The CPAQ-8 measures the extent to which the patient is able to experience pain without struggling to control or avoid it. It has a 2-factor structure: pain willingness (disengagement from efforts to control or avoid pain) and activity engagement . Level of pain acceptance is measured on a 0 to 6 rating scale. Pain willingness, activity engagement, and total pain acceptance scores are calculated by summing the responses in each domain. Psychometric evaluations of the short-form CPAQ-8 have shown the same factor structure as the original 20-item version, with good reliability and validity.31 Low pain acceptance has been found to be strongly associated with depression, independent of pain intensity.38Criteria for probable major depressive disorder (MDD) were met if the patient reported low mood or loss of interest and at least 5 of 9 symptoms in total, for more than half the days in the last 2 weeks. Item 9  counted towards the diagnosis of MDD if present at all. Severe depression was defined as MDD caseness with PHQ-9 score 20 to 27, moderate depression was defined as MDD caseness with PHQ-9 score 15 to 19, and mild depression was defined as MDD caseness with PHQ-9 score <15. Suicidal ideation was assessed by item 9 of the PHQ-9 and defined as having “thoughts that you would be better off dead or of hurting yourself in some way” for more than half the days in the previous 2 weeks. Pain acceptance was measured using the 8-item version of the Chronic Pain Acceptance Questionnaire (CPAQ).Self-report resource use data were collected as part of the IMPARTS questionnaire. Four domains of health care service use for pain in the preceding 3 months were measured: 1) GP contacts, (2) contacts with other doctors , (3) accident and emergency department (A&E) visits, and (4) days hospitalised. For example, patients were asked “How many times have you seen your GP in the past 3 months for your pain?” To monetarily value patient-reported health care utilisation, each service was assigned a unit cost. Health care costs were calculated by multiplying each resource use item by the unit cost. All unit costs, in British Pound Sterling, were from the financial year 2013 to 2014 and were obtained from sources detailed in Table  GP conta5 We assessed pain interference using the Brief Pain Inventory (BPI).13 The pain interference dimension of the BPI comprises 7 items measuring the degree to which pain interferes with functioning in the following domains: general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life. Level of interference is measured using a rating scale from 0 (no interference) to 10 (complete interference), and the mean score denotes the total level of pain interference. The BPI has been widely used and validated as a measure of pain interference in daily functioning.37 Research indicates that pain interference is a powerful independent predictor of depression12 and may also be a driver of higher health service costs.8Pain interference is associated with depression and has been shown to predict health care utilisation in population-based studies.13 Additionally, patients were asked about the duration, location, and extent of their pain and whether they experienced generalised pain (yes/no). Smoking status and occupational functioning were also assessed.Pain relief provided from treatments or medications was also measured by the BPI. Question 7 asks the patient to select the percentage that best indicates the extent of relief, on a 10-point scale from 0% to 100%.2 test for categorical data and the Mann–Whitney U test for continuous data that were not normally distributed. For ordinal data, test for trend was calculated using logistic regression, with P values derived from the Wald test. Mean costs were compared using the Student t-test. Inferences about average cost differences should always be based on a comparison of the arithmetic mean, even though cost data are often skewed.6Prevalence and severity of probable depression were expressed as the percentage of cases determined by the PHQ-9, with 95% CI. The sociodemographic and clinical characteristics of patients with and without depression were compared using the χ18 Given that there is uncertainty in the literature regarding the causal network linking depression, health care costs, and potential confounders such as pain severity, we computed 4 models with varying levels of adjustment, to examine how selection of adjustment variables impacted the relationship between depression and health care costs: model 1, unadjusted; model 2, adjusted for age and sex; model 3, additionally adjusted for occupational status; model 4, additionally adjusted for pain interference, pain acceptance, and generalised pain. Health care costs were skewed to the right; therefore, nonparametric bootstrapping (1000 replications) was used to estimate bias-corrected and accelerated confidence intervals around cost differences. All statistical analyses were performed using Stata 11 software.Multivariate analysis of the impact of depression on health care costs was conducted using multiple linear regression models (ordinary least squares). We expected health care costs to vary by depression severity; therefore, for the regression analysis, we categorised depression into 4 categories (none/mild/moderate/severe). The purpose of the regression analysis was not to find the best model to explain variability in health care costs but rather to test the hypothesis that depression is predictive of cost whilst controlling for potential confounders. Potential adjustment variables were selected based on established associations identified in the literature and statistical relationships with outcome and exposure variables detected in the data. Automated selection procedures and model fitting based solely on significance testing may result in inappropriate inclusions and exclusions. Although there is no agreed optimal strategy for modelling, confounder identification should be based on a priori knowledge about associations and causal pathways (research evidence and expert judgement) in addition to statistical information.During the study period (February 2013 to June 2015), 1352 patients attended an assessment consultation at the INPUT pain unit, and of these, 1204 (89%) completed the IMPARTS questionnaire. Data on the reasons for nonparticipation were not recorded, but clinic staff reported that the most common reasons were patients arriving late and an inadequate number of e-tablets being available.Two-thirds of the sample were women, and the median age was 47 . Just over half of the sample 52.8%) reported being unable to work for health reasons, whereas 22% was currently employed. The median duration of pain was 7 years. Lower back pain was the most frequent primary complaint, and 88% of the sample reported experiencing generalised pain  met criteria for probable MDD. Sixty-nine patients (5.7%) met the threshold for mild MDD, 256 (21.3%) met the threshold for moderate MDD, and 407 (33.8%) met the threshold for severe MDD. One hundred eighty-three of 1204 patients (15.2%) reported suicidal thoughts.Table P = 0.001).Table P < 0.001), with moderate and severe depression increasing 3-month costs by £48 (CI £21-£78) and £43 (CI £20-£66), respectively. Severe depression also increased costs for A&E attendance, hospital admission, and other doctor contacts, although these effects were not statistically significant.Table This study documents a high prevalence of depression in people with chronic pain, 60.8%, based on a standard self-report measure in a large specialty care sample. The symptoms of depression reported in this group reflected a high severity, with 55.6% of those meeting criteria reporting a severe level of symptoms or 33.8% of the total sample. Overall, patients who met criteria for depression were more likely not to work because of ill health and reported greater work absence, more generalized pain, greater pain-related interference with functioning, lower pain acceptance, and greater health care use and costs, relative to those who did not meet these criteria. These patients were also more likely to smoke.Depression was linked to greater health care use in each of the services assessed, including GP visits, other doctor visits, A&E visits, and hospital admissions. The greater use of A&E and hospital admission was particularly notable, proportionally 31% and 44% greater, respectively. In multivariate analyses, which included key covariates, the association between depression and higher health service costs persisted for patients with more severe symptomatology. In the fully adjusted model, we found significantly higher total health care costs for patients with severe depression. General practitioner costs also remained significantly higher for patients with moderate-to-severe depression. The persistence of the effect indicates that the association between depression and health care costs is independent of pain severity.33 Methodological differences—most notably the use of different case-finding tools—may have led to the apparent variation or there may be another explanation, such as a local factor relating to the region or service where this study was conducted. For example, the INPUT pain unit is a tertiary care service. Patients referred here have previously sought primary and secondary care for their pain without satisfactory resolution and thus may be at increased risk of depression. Preferential referral of patients presenting with psychological distress may also partially account for the high prevalence of depression in this patient group. Our single centre design limits the extent to which we can make general statements regarding the study findings. Health care utilisation and depression might be higher in this sample than in other pain populations because both may predict entry to the INPUT unit. Even those classified as nondepressed may have had relatively high depressive symptomatology, resulting in a smaller association between depression and health care costs than would be observed in populations with greater variability. Further study is needed to test the reliability of our results and their applicability to different settings.The range of available prevalence estimates suggests that depression is a substantial problem among patients with chronic pain. This study updates and underscores this finding. The prevalence of depression observed here is somewhat higher than the average for other recent studies of this same type of population, those seeking specialty treatment for chronic pain.25 It nonetheless lacks the depth and diagnostic validity of the gold standard clinical interview and will both miss cases and identify cases erroneously. The PHQ-9 uses the 9 core DSM-V criteria for depression but does not take account of exclusionary criteria that should preclude diagnosis—ie, that symptoms should not be caused by substance misuse or a general medical condition nor be better accounted for by bereavement. Furthermore, several symptoms assessed by the PHQ-9, such as difficulty concentrating and sleep disturbance,3 may be attributable to depression or pain. It is therefore possible that some study participants reporting these symptoms were misclassified as depressed, resulting in an inflated estimate of depression prevalence and dilution of the true strength of the association between depression and health care costs. Additionally, it should be noted that temporally, health care utilisation preceded measurement of the PHQ-9. In assessing depression subsequent to health care spending, our analysis assumes that depression is a relatively stable behaviour pattern that also preceded the health care. Yet, it is possible that some patients who screened positive for depression on the PHQ-9 were not depressed in the previous 3 months, and some who screened negative may have only recently remitted. Nevertheless, the impact of depression instability on our results is likely to be small,26 and we believe it is plausible that depressed patients with high health care costs in the preceding 3 months would continue to have high costs in subsequent months.A notable limitation of this study is the potential for misclassification of exposure. The PHQ-9 is a self-report screening tool that has been shown to have high sensitivity and specificity compared with other case-finding tools.34 These attributes make self-report particularly suitable for studies with large samples and those assessing several domains of health service use. Studies in general medical and mental health populations have shown good levels of reliability and high congruency rates between self-report and medical records for recall periods of up to 12 months.17 Nevertheless, the most accurate measure of service use is obtained by using multiple sources, and our reliance on a single method of data collection is a limitation that we acknowledge. Furthermore, Rozario et al.32 found that depression was a marginally significant factor in predicting lower congruence between self-report and medical record data, and there is some evidence that severely depressed patients may overreport health care utilisation.30 It is therefore possible that recall bias may have inflated the association between severe depression and health care costs observed in this study.The possibility of inaccurate recall of health care utilisation is another limitation. In this analysis, health care utilisation, and therefore health care costs, relied on information collected from patients. Self-report is an efficient, widely used method of assessing service use, recognised for its simplicity and cost efficiency compared with retrieval of medical records.10 and health care utilisation, with illness worry, a long timeline perspective, and belief in serious consequences, predicting high service use.16 Differences in underlying comorbidity and ongoing treatment of depression are also possible confounders. Patients with chronic conditions requiring regular medical intervention and those being treated for depression are likely to see their GP more frequently. Although patients were asked to report specifically on health service use for pain, some may have found it difficult to disentangle the primary reason for their consultation, and this may have led to an overestimation of the association between depression and GP visits in our sample. It would also have been helpful to include sociodemographic information such as ethnicity and social deprivation in the analysis. However, a high level of data errors and omissions from clinical records meant that these data were not consistently accurate or available.A limited number of variables were assessed in this study, necessarily so, as the routine assessment process needed to be short. Potentially, there are other confounding variables that, if available, could have led to differing conclusions about associated factors, impacts, service use, and costs. For example, illness perceptions have been shown to be associated with both depressionWe adopted a narrow costing approach, focusing on the impact of comorbid depression on health care service costs. Exploration of indirect costs due to reduced economic productivity would be needed to estimate the cost impact from a societal perspective. Finally, we have not approached the question of mechanism here. Although depression is associated with greater impacts of pain, essentially poorer health and functioning, and greater health care costs, we can only speculate about the processes that underlie these links. Our study was cross-sectional so cannot identify the order of events or causal relations between variables.23 that combines core behavioural, cognitive, and emotional processes that likely underlie both common health problems, such as pain and depression, and ostensibly varied therapeutic approaches. Perhaps, this kind of approach, which sees pain and depression as rooted in the same psychological and biological processes, rather than as separate disorders that co-occur, could help untangle the problems examined here. Such processes might include general psychological avoidance or what is known as “experiential avoidance” and failures in goal-directed engagement, both components of what is referred to as psychological inflexibility.23 A clue to the relevance of this model is here in the data showing an association between depression and acceptance of pain, the opposite process to experiential avoidance.Elsewhere, we have proposed the application of an integrated theoretical model39 in addition to improving physical functioning. Such treatment could be further developed and made more available. Of course, the other option is to develop treatment specifically targeted on depression in this population. It is not clear which, a depression-specific approach or a broader psychological approach focused on shared processes underlying both problems, will produce the more effective and cost-effective result.The findings of this study indicate a need for action. Further research is required to fill gaps in our understanding of the links between chronic pain and depression and the ways in which they combine to impact health and health care use. Such research may in turn contribute to treatment and health service developments. There is evidence that psychological treatments for chronic pain can reduce depression,The authors have no conflicts of interest to declare.


OnabotulinumtoxinA injection according to PREEMPT protocol is a second-line therapy for chronic migraine (CM). While iWe enrolled 25 patients who underwent botulin injections from April 2014 to June 2015. We evaluated patients at baseline  and every three months, along with a new injection session. Evaluation consisted in a multiparametric self-assessment questionnaire: pain intensity through 11 point Box Scale (BS-11) and Present Pain Intensity (PPI), changes in functioning through 6-point Behavioral Rating Scale (BRS-6), quality of pain through Short-form McGill Pain Assessment Questionnaire (SF-MPQ) and disability through Migraine Disability Assessment (MIDAS) questionnaire and HIT-6.At the present time, we have follow-up data for 57% of patients at three months (T1) and for 38% of patients at six months (T2).We found a global reduction in the intensity of perceived pain and in restriction of activities due to headache: Wilcoxon signed-rank test showed significant reduction in median values of BS-11 at T1 (p 0.026) and T3 (p 0.017), of PPI at T1 (p 0.02) and T3 (p 0.046), of BRS-6 at T1 (p 0.008) and T3 (0.026). Analysis of SF-MPQ showed a significant reduction in median values of the descriptors “throbbing” at T1 (p 0.041), “splitting” at T1 (p 0.041) and “tiring-exhausting” at T1 (p 0.011). We did not find significant difference in MIDAS score at T1 and T3 and in frequency of headache in the past three months.Our preliminary results show that the OnabotulinumtoxinA usefulness is primarily in improving the quality of life more than in reducing the frequency of headache.Written informed consent to publication was obtained from the patient(s).


Chronic non-specific low back pain is a major socioeconomic public health issue worldwide and, despite the volume of research in the area, it is still a difficult-to-treat condition. The conservative analgesic therapy usually comprises a variety of pharmacological and non-pharmacological strategies, such as transcutaneous electrical nerve stimulation. The neuromatrix pain model and the new findings on the process of chronicity of pain point to a higher effectiveness of treatments that address central rather than peripheral structures. The transcranial direct current stimulation is a noninvasive technique of neuromodulation that has made recent advances in the treatment of chronic pain. The simultaneous combination of these two electrostimulation techniques  can provide an analgesic effect superior to isolated interventions. However, all the evidence on the analgesic efficacy of these techniques, alone or combined, is still fragmented. This is a protocol for a randomized clinical trial to investigate whether cerebral electrical stimulation combined with peripheral electrical stimulation is more effective in relieving pain than the isolated application of electrical stimulations in patients with chronic nonspecific low back pain.Ninety-two patients will be randomized into four groups to receive transcranial direct current stimulation  + transcutaneous electrical nerve stimulation  for 12 sessions over a period of four weeks. The primary clinical outcome (pain intensity) and the secondary ones  will be recorded before treatment, after four weeks, in Month 3 and in Month 6 after randomization. Confounding factors such as anxiety and depression, the patient’s satisfaction with treatment and adverse effects will also be listed. Data will be collected by an examiner unaware of (blind to) the treatment allocation.The results of this study may assist in clinical decision-making about the combined use of cerebral and peripheral electrical stimulation for pain relief in patients with chronic low back pain.NCT01896453 Low back pain is one of the main musculoskeletal complaints in clinics and hospitals and is still one of the six most often found health conditions in developed countries . In BrazMany efforts have been made to find effective treatments; however, back pain remains difficult to treat . ConservNew concepts like neuromatrix of Melzack  propose Accordingly, treatments specifically addressing the cerebral cortex can complement the action of peripheral interventions and result in a more effective tool for the relief of chronic pain. The transcranial direct current stimulation (tDCS), despite not being a new modality, has presented recent advances in the treatment of chronic pain -30, estaAccording to our literature review, there are only three studies involving the tDCS technique in chronic nonspecific low back pain: (1) a protocol study without prior results , (2) an The identification of effective non-invasive and non-pharmacological treatments can trigger a substantial gain in pain relief and physical capacity, resulting in decreased morbidity and lower costs associated with low back pain. By simultaneously combining the two electrical stimulation techniques , the analgesic effect could be enhanced by the reorganization of cortical neuron activity and by the segmental inhibition of nociceptive stimulus. The aim of this experiment is to investigate whether cerebral and peripheral electrical stimulation combined are more effective in relieving pain than the isolated application of electrical stimulations in patients with chronic nonspecific low back pain.The primary objective of this study is to investigate the analgesic efficacy of transcranial  direct current stimulation combined with transcutaneous  electrical nerve stimulation in patients with chronic nonspecific low back pain compared with cerebral and peripheral electrical stimulations applied alone. The analgesic efficacy will be analyzed through the decrease of pain intensity four weeks after randomization.The secondary objectives are:To analyze the difference between cerebral, peripheral and combined stimulations in pain intensity in patients with chronic nonspecific low back pain assessed in Month 3 and in Month 6 after randomization.To analyze the difference between cerebral, peripheral and combined stimulations in the sensory and affective aspects of pain in patients with chronic nonspecific low back pain assessed after four weeks, in Month 3 and in Month 6 after randomization.To analyze the difference between cerebral, peripheral and combined stimulations in the functional capacity of patients with chronic nonspecific low back pain assessed after four weeks, in Month 3 and in Month 6 after randomization.To analyze the difference between cerebral, peripheral and combined stimulations in the perception of the overall effect of patients with chronic nonspecific low back pain assessed after four weeks, in Month 3 and in Month 6 after randomization.To analyze the patients’ satisfaction with the treatment.Our hypothesis is that tDCS and TENS simultaneously combined are more effective in reducing the intensity and sensory aspect of pain, presenting less disability and having a better effect on global perception when compared to patients receiving the treatments alone.A controlled factorial (2 × 2) clinical trial will be conducted to evaluate the analgesic efficacy of cerebral and peripheral stimulation in chronic low back pain Figure .Figure 1This project was approved by the Ethics Committee of the School of Medicine, University of São Paulo (USP) (protocol 308/13). The study will be conducted at the Clinical School of Physiotherapy, School of Medicine, USP, and at the Rehabilitation Center of the Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil.Patients with complaints of low back pain who seek treatment at the physiotherapy clinic of the School of Medicine, USP, and at the physiotherapy clinic of the Irmandade da Santa Casa de Misericórdia de São Paulo, will be initially evaluated by the medical staff of the institutions. After the diagnosis of chronic nonspecific low back pain and referral to the physiotherapy services, the patients will be thoroughly informed about the present study. The physiotherapist responsible for the evaluations will clarify the objectives of the study, possible treatments, eligibility criteria and potential risks resulting from the application of cerebral and peripheral stimulations. Patients who agree to the conditions and sign the consent form may participate. Participants who meet the eligibility criteria will be included in the study.This study will involve 92 participants (both genders) who seek treatment at one of our rehabilitation centers through medical referral complaining of nonspecific low back pain for more than three months.Participants who meet the following criteria will be eligible: (1) age between 18 and 65 years, (2) medical diagnosis of nonspecific low back pain present for at least three months, (3) spontaneous search for treatment and (4) signature of informed consent.Participants will be excluded from the survey under the following conditions: (1) low back pain assessed <4 by Numeric Rating Scale (NRS) during one-week daily monitoring (patient registration); (2) previous spine surgery less than six months ago; (3) previous treatment with TENS less than six months ago; (4) previous tDCS treatment; (5) disk herniation with nerve compression with neurological compromise; (6) neurological, psychiatric and rheumatologic diseases; (7) use of pacemakers or other implanted devices; (8) pregnancy; (9) drug use and (10) abuse of medicines and alcoholic beverages.The regular use of prescribed medications will not be an exclusion criterion, but the dose and type of medication will be recorded and documented. Patients with moderate psychiatric comorbidities such as anxiety and depression that are under medical supervision will not be excluded.Before starting treatment, a randomized generating program will place patients in one of the four groups: (1) real transcranial direct current stimulation (tDCS-r) + real transcutaneous electrical nerve stimulation (TENS-r), (2) real transcranial direct current stimulation (tDCS-r) + sham transcutaneous electrical nerve stimulation (TENS-s), (3) sham transcranial direct current stimulation (tDCS-s) + real transcutaneous electrical nerve stimulation (TENS-r) and (4) sham transcranial direct current stimulation (tDCS-s) + sham transcutaneous electrical nerve stimulation (TENS-s). The randomization and allocation concealment will be carried out by a collaborator not participating in the research, who should organize the patients’ records and their previously allocated treatments in individual opaque envelopes. The schedule of treatment will be revealed to the physiotherapist responsible for the treatments at the moment of electrical stimulation application. The “blinding” of evaluator and patients will be kept until the end of the research and data processing.After the fulfillment of eligibility and subsequent adherence and signature of the consent term, information on participants will be collected through a structured interview. Data will include personal data, clinical history and radiological findings (if any) and anthropometric characteristics. Subsequently, a clinical psycho-functional evaluation will be conducted according to the recommendations of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) for clinical trials of effectiveness of treatment for chronic pain . The maiPain intensity will be assessed on a numerical scale of 11 points (0–10), 0 accounting for no pain and 10 for the worst pain possible. The patient will be asked to describe the pain of the past seven days . Pain inThe short version of the McGill Questionnaire (SF-MPQ) contains 15 descriptors of pain sensation (11 sensory and four affective), each descriptor rated on a 4-point scale where 0 = none, 15 = mild, 25 = moderate, and 35 = severe . Three mThe Roland Morris disability questionnaire assesses the overall functional capacity of the patient through the physical limitations resulting from low back pain. The questionnaire consists of 24 questions related to the normal activities of daily life, each affirmative answer corresponding to one point. The final score is determined by the sum of the scores. Values close to zero mean the best results, i.e. lower limitation, and values close to 24, the worst results, i.e. greater limitation. The highest number of responses is related to greater disability due to low back pain ,41,42.The effect felt as a result of treatment will be assessed by the scale of global perceived effect that assesses the perceived level of the patient’s recovery from the treatment, comparing the initial symptoms with those of the last days. The resource is a numerical 11-point scale ranging from −5 to +5, with −5 = extremely ill, zero = no change, and +5 = completely recovered, with the highest score representing the fullest recovery .Depression and anxiety may be important confounding factors that influence the improvement of the patient’s pain. Thus, symptoms of depression and general anxiety will be assessed at the beginning and the end of treatment by the Brazilian version of the Beck Depression Inventory (BDI)  and VisuThe record of symptoms and adverse events resulting from the use of tDCS and TENS is passively collected by the patient’s spontaneous reports. Active collection uses a questionnaire with records of the duration and intensity of adverse symptoms reported by the patient. Then the patients will be asked to rank the certainty of their claims according to a Likert scale  .The approval of patients receiving treatment will be evaluated by the Medrisk questionnaire, which measures the satisfaction of patients undergoing physical therapy care. This questionnaire consists of 20 items, 10 of them related to the therapist-patient interaction, eight not related to it and two items considered overall items. The patient chooses his or her level of satisfaction with each item by selecting a Likert-like scale ranging from 1 (“strongly disagree”) to 5 (“strongly agree”) or by choosing option “not applicable,” where high scores represent high satisfaction .The evaluation of the blind condition of patients and the evaluator-therapist will be conducted at the end of four weeks of treatment. Both will be asked to guess which intervention was used for tDCS and TENS, whether real or sham. Then patient and evaluator will be required to rank the certainty of their claims according to a Likert-like scale . To ensure that the evaluator is not induced to correctly guess the participants’ allocation, the latter will be instructed not to reveal which sensation was felt during the sessions.The treatment will be carried out for four weeks, with three sessions per week, totaling 12 sessions of electrical stimulation. The sessions will take place individually in schedules of alternate days from Monday to Saturday. The program of schedules will allow a 20-minute interval between sessions so as to avoid possible contact between patients.After the enrollment and initial assessment (pre-treatment) and before randomization, the participants will be informed about the possible sensations arising from cerebral and peripheral stimulations. They will be informed that the unit of electrical stimulation may cause a slight tingling, itching or burning sensation the entire time or only at the beginning of application. The difference in sensations occurs according to the sensitivity of each individual. Participants will also be informed about the possibility of no perceptible sensation during the procedure. Regardless of the stimulus felt, all participants will be instructed not to reveal the sensation experienced.2; 5 × 7 cm)  covered by a sponge damped with physiologic saline  and fixed to the head with elastic bands.The transcranial stimulation is applied by a DC generator powered by a 9-volt battery . The current will be applied using two electrodes  will be treated with electrical current intensity of 2 mA, density of 0.057 mA/cm minutes . The gro minutes . This fe minutes ,48 becauThe peripheral stimulation will be applied through a rectangular asymmetric two-phase electrical current apparatus . Both units of stimulation  will be applied, using four self-adhesive electrodes (VALUTRODE 5 × 9 cm). The electrodes will be placed in a paralleled and bilateral position of the lumbar segment on the painful area.The groups that will receive the real TENS (TENS-r) will be treated with current intensity (amplitude) according to their sensory threshold, characterized as an intense, yet comfortable, pulse frequency of 100 Hz, pulse duration of 200 μs and application time of 40 minutes . During Although some studies report no differences between high (100 Hz) and low (4 Hz) frequency for the treatment of chronic low back pain , prolonga priori estimated by the analysis of power [The sample size was of power  to detecof power . The effAll statistical procedures will be performed according to the principles of intention to treat. Linear mixed models will be used to identify intra- and inter-group differences at the end of treatment and in Month 3 and Month 6 of follow-up. All data will be analyzed using software SPSS v.20 for Windows. The level of significance is 0.05.According to our review, this is the first randomized double-blind clinical trial to investigate the analgesic efficacy of transcranial direct current stimulation (tDCS) combined with transcutaneous electrical nerve stimulation (TENS) in patients with chronic nonspecific low back pain. The factorial design used in this study will allow three interventions to be evaluated simultaneously: cerebral stimulation, peripheral stimulation and combined stimulation. Furthermore, the use of sham tDCS and sham TENS represents a more robust experimental design to control the placebo effects. The results of this study will provide important information for clinical practice and conservative management of chronic low back pain. The possibility of synergistic and additive effect of these noninvasive, nonpharmacological, well-tolerated techniques presenting minimal adverse effects can turn them into a promising therapeutic tool for health professionals, improving the health status of the population and reducing the socioeconomic consequences of chronic low back pain.


Cornea confocal microscopy (CCM) is a novel non-invasive method to detect small nerve fiber pathology. CCM generally correlates with outcomes of skin biopsies in patients with small fiber pathology. The aim of this study was to quantify the morphology of small nerve fibers of the cornea of patients with fibromyalgia in terms of density, length and branching and further phenotype these patients using standardized quantitative sensory testing (QST). Small fiber pathology was detected in the cornea of 51% of patients: nerve fiber length was significantly decreased in 44% of patients compared to age- and sex-matched reference values; nerve fiber density and branching were significantly decreased in 10% and 28% of patients. The combination of the CCM parameters and sensory tests for central sensitization, , yielded four phenotypes of fibromyalgia patients in a subgroup analysis: one group with normal cornea morphology without and with signs of central sensitization, and a group with abnormal cornea morphology parameters without and with signs of central sensitization. In conclusion, half of the tested fibromyalgia population demonstrates signs of small fiber pathology as measured by CCM. The four distinct phenotypes suggest possible differences in disease mechanisms and may require different treatment approaches. Evidence for this hypothesis comes from observations of increased neuronal activity during non-noxious stimulation in brain regions involved in pain processing, and indications of dysfunctional endogenous pain modulatory systems2356789et al.12Fibromyalgia is characterized by chronic widespread pain accompanied by a range of symptoms including headache, fatigue, cognitive dysfunction, depression and sleep disturbances1The diagnosis of small fiber pathology is usually based on assessment of neuropathic symptoms, quantitative sensory testing, electromyography and/or skin biopsies, with skin biopsies considered the gold standard for diagnosis. In addition to the invasive nature, intra-observer and intra-patient variability contributes to difficulties when using skin biopsies to diagnose peripheral neuropathy151617To our knowledge, a comprehensive study in fibromyalgia patients including corneal nerve quantification, sensory testing, and questionnaires, is lacking. Combinatory testing aids in the construction of patient phenotypes, identifying possible differences in disease mechanisms that could steer clinical decision-making. The main aim of the current study was to quantify the heterogeneity of the fibromyalgia patient population and assess whether multiple subgroups with distinct phenotypes may be detected based on the morphological state of small fibers and standardized quantitative sensory testing and neuropathic pain questionnaires . We hypothesized that small fiber pathology, as detected by CCM, is present in a subset of patients with fibromyalgia and that abnormalities in cornea small fiber morphology overlap with abnormalities in QST and questionnaires.Patient characteristics of 39 patients that completed the study are given in th percentile of their age and sex reference group. As reference values are given per age group, individual scores are presented per age categories in th percentile of controls in 10% and 28%, respectively. Abnormalities in cornea morphology were correlated. For example, CNFL values correlated with CNBD (Pearson’s r = 0.81) and CNFD (Pearson’s r = 0.90) (p < 0.01).Cornea nerve quantification of the left and right eye in each patient was similar (data not shown). Data were therefore averaged per patient. Average values  for CNFD, CNFL and CNBD are given in The average PainDetect score was 19 (range 8–30) points . Twenty-QST analysis showed that a large number of patients displayed abnormalities with signs of allodynia and hyperalgesia in one or more tested regions . Most imvs. PainDetect: r = −0.11; p = 0.52; CNFL vs. SFNSL: r = −0.12; p = 0.47; CNFL vs. CDThand: r = 0.21; p = 0.19; CNFL vs. MDThand: r = −0.24; p = 0.15; CNFL vs. PPThand: r = 0.15; p = 0.37.Pearson’s r showed a strong significant correlation between the SFNSL and PainDetect questionnaires . No significant correlations were observed between cornea morphology scores and PainDetect, SFNSL or QST scores. For example, CNFL Patients with normal and abnormal CNFL values did not differ with respect to QST parameters on face, hand or foot , PainDetect (p = 0.74) and SFNSL (p = 0.51) scores. Similarly, these two populations did not differ in the number of tender points (p = 0.08), WPI (p = 0.21), SSS (p = 0.66), age (p = 0.86), BMI (p = 0.69) or years with fibromyalgia symptoms (p = 0.73).We defined four subgroups of fibromyalgia patients, based on cornea morphology and signs of central sensitization 20et al.The main aim of this study was to assess the involvement of small fiber pathology in patients with fibromyalgia as quantified by CCM and to relate cornea morphology results to patient-reported symptoms and standardized QST. We extended observations by Ramirez CCM is a relatively new, non-invasive method to analyze the quantity and quality of small nerve fibers in the cornea. The technique has been validated in several studies involving patients with peripheral neuropathy from various underlying causes, and most studies demonstrate good correlation with intra-epidermal nerve fiber density results from skin biopsies15172223pathology rather than SFN. This difference in terminology1326In the past 5 years multiple efforts have been made to establish small fiber pathology in patients with fibromyalgia57810To better define our patient population, we performed a subgroup analysis to further phenotype the fibromyalgia syndrome based on cornea fiber abnormalities and the presence of central sensitization as suggested by QST parameters cold pain threshold, mechanical pain threshold and mechanical pain sensitivity, allodynia and wind-up 202129. W2021We cannot exclude that in patients with signs of a peripheral origin of pain, central causes of pain may additionally play a role. One of the criteria in the diagnosis of fibromyalgia is widespread pain: the presence of axial pain, bilateral pain, and upper and lower segment pain32343538In conclusion, in a small cohort of fibromyalgia patients we observed signs of small fiber pathology in 51% of patients as measured by cornea confocal microscopy. Further profiling these patients shows that four distinct phenotypes were present: a group with normal cornea morphology with and without signs of central sensitization, and a group with abnormal cornea morphology parameters with and without signs of central sensitization. These phenotypes indicate possible differences in disease mechanisms and additionally may steer the clinician in his or her choice of treatment of this complex, multi-factorial disorder. Since this and other previous studies were relatively small, larger cohorts of patients with fibromyalgia are needed to come to definite conclusions regarding the existence of subgroups in sensory testing and involvement of small-fiber pathology in the mechanism of disease.The protocol was approved by the Ethics Committee of the Leiden University Medical Center , and all study procedures were conducted according to GCP guidelines and adhered to the tenets of the Declaration of Helsinki. The study is registered in the Netherlands Trial Register (NTR3769).Forty patients with fibromyalgia were recruited for the study. Inclusion criteria were: age between 18 and 75 years, fibromyalgia diagnosed by a rheumatologist according to the 1990 or 2010 American College of Rheumatologists criteria30et al.Bilateral CCM was performed on 39 patients, using the Rostock Cornea Module with the Heidelberg Retina Tomograph III . Images were acquired and quantified as follows: After topical anesthesia of both eyes, the microscope was placed at the surface of the cornea apex. Confocal images were acquired with a field of view of 400 × 400 μm and automatically quantified using ACCmetrics software . Cornea nerve fiber length (CNFL), cornea nerve fiber density (CNFD), and cornea nerve branching density (CNBD) were quantified after manual selection  of 5 to 10 representative, high-quality images per eye. Taken the good correlation between semi-automated (CCmetrics) and automated (ACCmetrics) corneal nerve fiber quantification42To assess neuropathic pain involvement in daily pain, patients filled out the PainDetect questionnaire, a screening tool to detect neuropathic pain symptoms. This questionnaire assesses pain perception over the last 4 weeks and the current pain score, and patients are asked to localize and qualify their pain . A score of 19 or higher indicates that a neuropathic pain component is likely. The validated Dutch version of the PainDetect was used. To screen for small fiber involvement, patients filled out the small fiber neuropathy screening list (SFNSL) which assesses complaints consistent with small fiber involvement such as indigestion, dry eyes, allodynia, tingling sensations, chest pain and others. The Dutch version validated for sarcoidosis patients was usedz-scores, according to published reference valuesQST was performed on the face , hand and foot  according to the protocol of the German Research Network on Neuropathic Pain using 13 tests per anatomic locationvs. normal CNFL) were compared with the Fisher’s exact test for normal vs. abnormal results of: the PainDetect and the SFNSL questionnaire; and all QST parameters. Other comparisons between subgroups were evaluated with the Mann Whitney U test. P values < 0.05 were considered significant. Data are presented as average ±95% confidence interval or (range), unless otherwise indicated.Statistical testing was performed using GraphPad Prism 6  and SPSS statistics 20 . For correlation analysis Pearson’s correlation coefficient or Spearman’s rho were used. Subgroups of patients .