Mirizzi syndrome is a rare complication of long standing cholelithiasis. The purpose of this study is to retrospectively estimate the diagnostic and treatment methods applied in patients with Mirizzi syndrome.Our experience with 27 cases with Mirizzi syndrome is presented. They were diagnosed either by imaging techniques, or during surgical operation. All of the patients were managed surgically.8 patients were diagnosed preoperatively and the rest intraoperatively. Morbidity rate after surgery was 18,5%, and mortality rate was zero. The patients presented free of symptoms three months after surgery during the follow-up.Mirizzi syndrome is rarely diagnosed preoperatively and US proved inadequate for this purpose. Surgery is the only therapy and usually provides additionally definitive diagnosis. Mirizzi syndrome is an unusual complication of gallstone disease and occurs in approximately 1% of all patients with cholelithiasis . The majThus a constant vigilance during intraoperative dissection of Calot's triangle is required in order to avoid injury of the bile duct.nd Department of Propaedeutic Surgery, Medical School, University of Athens. A total of 2,978 cholecystectomies were performed during this period. Among the 27 patients with Mirizzi syndrome, 21 patients  had type I disease, 5 patients  had type II disease and one patient  had type II/III disease. The records of these 27 patients were reviewed for clinical symptoms, diagnostic methods, surgical procedures, complications and follow-up. The Csendes classification was followed to categorize the patients. For types II, III or IV when cholecystobiliary fistula existed, the classification was made intraoperatively. All patients were seen in the surgical department within 3 months from their discharge from the hospital and every 6 months thereafter for a mean period of five years (range: 3–13 years). Four patients were lost from follow-up 1–2 years after surgery. All were symptom free with normal liver function tests through the last follow-up visit. None of the patients with Mirizzi syndrome had previous hepatobiliary surgical intervention prior to diagnosis. Females outnumbered males by sixteen to eleven. The age of patients ranged from 48 years to 86 years. Upper abdominal pain, fever and jaundice were the most frequent symptoms and signs. The diagnosis of Mirizzi syndrome was achieved preoperatively in 8 patients . The other 19 patients  were diagnosed intraoperatively. For preoperative evaluation of the patients the technological advancements of the last three decades were employed.This is a retrospective study of 27 consecutive patients with Mirizzi syndrome in the last 20 years (1986–2005), treated at the 2Despite arguments in the literature about the usefulness of ultrasonography (US) in diagnosis, it proved to be of limited value, as in only 8 patients was US indicative for Mirizzi syndrome. In these 8 cases, the diagnosis was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) in 6 cases, while by magnetic resonance cholangiopancreatography (MRCP) and percutaneus cholangiography (PC) the remaining two cases. The diagnostic value of the employed non-invasive imaging techniques in our series is shown in table Surgical treatment was applied in all patients with Mirizzi syndrome. In 21 patients with type I disease, partial cholecystectomy was performed in 15 cases and complete cholecystectomy in 6 cases. In 4 cases laparoscopic cholecystectomy was attempted but only in one case it was achieved. Among the six patients with cholecystobiliary fistula, in five patients with type II disease T-tube insertion from the fistula or directly to the common bile duct using the gallbladder as a pedicled graft in either case was performed.th postoperative day was necessary. All patients had a tube drain left in the subhepatic space that remained for 2 to 15 days. Furthermore, two patients developed wound infection necessitating open drainage. Overall morbidity was 18,5% (5 cases). The mortality rate in our series was zero. Histology did not reveal concomitant carcinoma of the gallbladder in any of the patients.In the remaining patient with type II or III disease with a particular appearance of the fistula opening after extraction of the gallstone (photo) and considering the risk of postoperative biliary stricture increased, a Roux-en-Y cholecysto-choledochal-jejunostomy was carried out Fig. . No bile2. McSherry in 1982 suggested a subclassification of the Mirizzi syndrome into two types.Mirizzi syndrome (MS) was described in 1948 as obstructive jaundice due to gallstone/s impacted in the cystic duct or Hartmann's pouch, compressing the common hepatic ductType I regards the external compression of the common hepatic by a calculus in the cystic duct or Hartmann's pouch whereas, in type II the stone has eroded partially or completely into the common hepatic bile duct and a cholecystocholedochal fistula has resulted .In 1989 a new classification of patients with Mirizzi syndrome and cholecystobiliary fistula was presented. Type I lesions are those with external compression of the common bile duct; in type II lesions a cholecystobiliary fistula is present with erosion of less than one third of the circumference of the bile duct; in type III lesions, the fistula involves up to two thirds of the duct circumference; and in type IV there is complete destruction of the bile duct .Therefore, Mirizzi syndrome and cholecystobiliary fistula appear to be different, evolving stages of the same pathological condition; thus, it is reasonable that Lubbers proposes that the term Mirizzi syndrome could not be abandoned, as it is only the first stage of a more complete process .2 sections can differentiate a neoplastic mass from an inflammatory one, which U/S or CT scan may not be capable of doing.Nevertheless, gallstone erosion into the common duct is a rare complication of cholelithiasis and is mainly the result of the long-standing gallstone disease. Cholecystocholedochal fistula is an important complication of Mirizzi syndrome but it occurs only in 1% of all biliary operations . ClinicaThe association of Mirizzi syndrome and gallbladder carcinoma is also of interest; in such cases it is obvious that complex surgical procedures should be avoided ,8. HowevIn fact, surgery is the treatment of choice for patients with diagnosis of Mirizzi syndrome. The surgical strategy includes complete removal of the gallbladder or partial cholecystectomy for MS type I, while various surgical approaches have been used for MS type II, where cholecystobiliary fistula is present and requires treatment.The following approach is rather more accepted for type II. After the gallstone has been removed and partial cholecystectomy has been performed, the remaining gallbladder is used for choledochoplasty. A T-tube is introduced into the common hepatic duct above the repair site. Furthermore, in our department, in order to close the hole in the common bile duct, we have used, besides the gallbladder cuff, a pedicled graft of the round ligament of the liver ,12. ReceIn our opinion, an 8–15 mm cuff of the gallbladder or round ligament is sufficient in order to close the defect in the common bile duct.The role of laparoscopic approach in the treatment of Mirizzi syndrome remains controversial. Some authors consider the condition unsuitable for laparoscopic surgery since the inflammatory tissue in the area of Calot's triangle offers a high operative risk in dissection ,14,15. OIn high-risk patients suffering from MS, biliary drainage by endoscopic sphincterotomy and placement of a stent in the choledochal duct has been carried out . MoreoveAlthough the diagnostic imaging techniques have been perfected, preoperative diagnosis of MS is not an easy affair and continues to be a challenge for the surgeon. Therefore, even intraoperative precautious recognition of the condition and application of the appropriate surgical method according to the characteristics of each case will lead to successful treatment. In conclusion, it is important to identify patients with Mirizzi syndrome preoperatively but it seems even more important to consider its diagnosis during surgical dissection.U/S: Ultrasonography; ERCP: Endoscopic retrograde cholangiopancreatography; MRCP: Magnetic resonance cholangiopancreatography; PC: Percutaneous cholangeography; MS: Mirizzi Syndrome; CT: Computed tomographyThe authors declare that they have no competing interests.M.Safi Surgeon who performed the operation and edited a part of the manuscript.MSta who performed the operation and prepared the draft.PS Literature search, revision of bibliography.AS Surgeon who contributed to the performance of the operation.CR Radiologist who made the diagnosis of the laboratory findings.CS Literature search, revision of bibliography.All authors have read and approved the final manuscript.


Approximately 28% of patients with cancer pain die with severe untreated pain despite effective multidisciplinary techniques that should treat these patients effectively. Despite Interventional pain management procedures are most often used in concert with standard analgesic regimens to reduce opioid side effects or gain better analgesic efficacy. The interventional analgesic technique may be used at any time during the course of cancer treatment but is often employed during the more aggressive phases of disease. IntervenBefore jumping into interventional technique, patients should receive appropriate trials of opioid and non-opioid analgesics. A complete pain evaluation with pain history, appropriate physical examination (including a neurologic examination), and a tentative etiology for the pain is necessary prior to any invasive procedures. A neurologic examination identifies any preexisting neurologic deficits as well as areas of minor motor or sensory reduction, Informed consent is a prerequisite, especially with the neurolytic blocks that may result in permanent motor/sensory deficits. A local anesthetic block is usually performed prior to any “permanent” neurolytic procedure to evaluate the likelihood of success and identify neurologic deficits that may be intolerable.Virtually all studies, to date, recommend the proper selection of patients so that less invasive analgesic techniques may be utilized as first-line therapy.The wide variety of interventional pain management techniques available in the present situation should encourage physicians to consider “something further” in almost all cases of cancer pain. The appropriate use of anesthesiologic interventions to help manage cancer pain will improve the quality of life for all patients.There is a need for research to determine clear indication and benefit from interventional pain management techniques in cancer pain patients.


This study assesses the validity and reliability of the Spanish version of DN4 questionnaire as a tool for differential diagnosis of pain syndromes associated to a neuropathic (NP) or somatic component .A study was conducted consisting of two phases: cultural adaptation into the Spanish language by means of conceptual equivalence, including forward and backward translations in duplicate and cognitive debriefing, and testing of psychometric properties in patients with NP  and NNP. The analysis of psychometric properties included reliability  and validity .A sample of 164 subjects , 94 (57.3%) with NP  and 70 with NNP was enrolled. The questionnaire was reliable  and valid for a cut-off value ≥ 4 points, which was the best value to discriminate between NP and NNP subjects.This study, representing the first validation of the DN4 questionnaire into another language different than the original, not only supported its high discriminatory value for identification of neuropathic pain, but also provided supplemental psychometric validation  and showed its validity in mixed pain syndromes. Appropriate therapeutic management of pain requires an accurate diagnosis, distinguishing its cause and origin. According to the International Association for the Study of Pain (IASP), neuropathic pain (NP) is defined as a pain initiated or caused by a primary lesion (or dysfunction) of the nervous system, and comprises a very large group of neurological conditions including diabetic and other sensory polyneuropathies, trigeminal neuralgia, post-herpetic neuralgia, stroke, spinal cord injury, and multiple sclerosis, as well as common conditions such as lumbar or cervical radiculopathies, traumatic or postsurgical nerve injuries, etc -4. VirtuDue to the lack of validated or consensual diagnostic criteria, diagnosis of NP has traditionally been based on identification of the neurological lesion through the medical history, neurological examination, and appropriate electrophysiological or imaging investigations ,12. A seIn order to test this hypothesis, this study analyzed the psychometric properties of the DN4 questionnaire translated into Spanish. The DN4 questionnaire was originally developed and validated in French . It is aThus, the aim of this study was not only the translation and cultural adaptation of the DN4 questionnaire into Spanish, but to provide also a supplemental psychometric validation of the questionnaire. In particular, in addition to the general diagnostic properties of our translated questionnaire (i.e. sensitivity and specificity), its test-retest reliability was verified, and the influence of various factors, such as pain intensity and educational level, on the DN4 results was analyzed. The DN4 was also administered to a group of patients with a combination of neuropathic and non-neuropathic pain to support its validity in mixed pain syndromes.The DN4 questionnaire  consistsThe adaptation into Spanish of the DN4 questionnaire and the subsequent assessment of its psychometric properties  have been performed following the traditional recommendations for adaptation and validity of health questionnaires and diagnostic tests -25. In tPatients of both sexes with chronic pain for more than 3 months aged 18 years or over, with an adequate cultural level to understand health questionnaires administered in Spanish were included in this study. Chronic pain could be of a neuropathic, non-neuropathic, or mixed (i.e. both neuropathic and non-neuropathic components) origin. Pain was classified based on the medical history, physical examination, and any procedures  considered appropriate by the clinicians to establish the diagnosis of the type of pain. All patients gave their written informed consent before entering the study. Tables In addition to the DN4 questionnaire, average daily pain intensity was measured using a 100 mm visual analogue scale (VAS), and the short-form McGill Pain Questionnaire (SF-MPQ)  was usedAll investigators were pain experts. At each participating center, the main investigator collected the sociodemographic and clinical data required for patient characterization and was required to classify patients into two broad diagnostic categories corresponding to NP and NNP, and to further subcategorize NP into peripheral, central or mixed pain. The diagnosis of the principal investigator was considered as the reference (gold standard) diagnosis. Patients were then separately seen within 2 days by two other investigators (raters A and B) blinded to the diagnosis proposed by the principal investigator, who administered the DN4 and SF-McGill questionnaires.This study was conducted according with usual standard of care in each participant centre, and it did not involve any drug or therapeutic management. Nevertheless, the study design was approved by the IRB of the Universidad Autónoma de Madrid and was conducted in compliance with the Helsinki Declaration for research in humans.The internal consistency of the Spanish version of the DN4 questionnaire was separately established for raters A and B by calculating Cronbach's α coefficient that assesses the contribution of each item to the precision of measurements by the instrument. Cronbach's α coefficient was assessed in the complete questionnaire and after removing each item from it to assess the independent contribution of each item to the measurement error in the instrument.Inter-rater reliability was assessed by the agreement of the results obtained by raters A and B for each item and the total score of the DN4 questionnaire. Agreement was determined by calculating the Cohen's kappa coefficient. Inter-rater agreement was also determined by calculating the intra-class correlation coefficient of the total scores assigned by each pair of raters to the same subject, and the answers to each individual item, using a two-factor model and mixed effects.In a subject sub-sample (n = 68), the test-retest reliability of the questionnaire was assessed by a third administration, after at least 48 hours, of the DN4 scale by rater B. Stability of the questionnaire was analyzed by measuring the intra-class correlation coefficient between the scores of clinicians completing test and retest and using Cohen's kappa coefficient of agreement for the total retest sample and in subgroups by type of pain.A ROC (receiver operating characteristic) curve analysis was performed to determine the cut-off value of the questionnaire score providing the best values of sensitivity and specificity for NP diagnosis and determination of Youden's index for the total patient sample included in the study. This was repeated in two sub-samples excluding either patients with mixed pain only or patients with mixed and subjects with central NP . For each cut-off value of the scale score, in addition to sensitivity and specificity and Youden's index, the positive (PPV) and negative predictive value (NPV), the kappa coefficient of agreement with the diagnosis according to the standard criterion or reference diagnosis, and the area under the curve (AUC) calculated by the trapezoid method and its significance level were estimated. The 95% confidence intervals (95% CI) of the estimators of the cut-off point selected as optimum were calculated. Validity indicators  were recalculated individually for the presence of each descriptor symptom of the DN4 questionnaire. The Youden's index was calculated by the equation: sensitivity + specificity - 1 .Descriptive statistics were prepared for the variables tested in this study to assess central positition, dispersion, and distribution of variables tested by the Kolmogorov- Smirnov test. A Student's t test for independent groups or a Mann-Whitney's U test was used in the case of a non-normal distribution to compare continuous or ordinal variables respectively between patients with NP and NNP. All statistical tests were two-tailed, and an α error of < 0.05 was accepted as statistically significant. Data were analyzed using SPSS version 12.0 statistical software.The study was conducted from June to November 2005. Table Table Inter-rater reliability, which is essential for an instrument that contains a semi-structured interview subject to interviewer interpretation, was good to very good. The total scores in each diagnostic group did not show statistically significant differences, and the intra-class correlation coefficient values ranged from 0.84 and 0.93  were removed, and worsening when such patients were included  between both studies. In particular, our analysis of the properties of the questionnaire according to pain intensity revealed significantly lower sensitivity and specificity in patients with mild pain intensity. The influence of pain intensity on the psychometric properties of neuropathic pain screening tools had not been previously tested with the DN4 or with other questionnaires. The data reported here suggest that these tools might be much less discriminant and should therefore be used with caution in patients with reduced pain intensity. However, this would have to be confirmed in further studies with the DN4 or other diagnostic questionnaires, because the subgroup of patients with mild pain intensity was relatively small in this study. By contrast, our results suggest that the discriminant value of the DN4 questionnaire did not depend on the educational level, confirming that these simple symptom-based questionnaires are easily understood and that their administration should not be restricted to highly educated patients. A supplemental validation investigated in this study concerned the stability over time (i.e. test-retest reliability) of the DN4 questionnaire, which was excellent in our patients with or without NP.The results of the DN4 were similar in patients with "pure" neuropathic pain or mixed pain syndromes, (i.e. the combination of neuropathic and non neuropathic pain in the same patient). Thus, the present data suggest that the neuropathic component of the "mixed pain" syndrome has clinical characteristics similar to those of "pure" neuropathic pain. Interestingly, this is consistent with the results recently reported by Freynhagen et al , showingThe results of this study support the transcultural validity of the DN4 questionnaire. More generally, our data tend to confirm the interest of symptom-based diagnostic tools for identification of the neuropathic pain component. These simple clinical tools may be used not only in daily practice, but also in the clinical research setting . Future studies directly comparing the performance of the different available tools are warranted.DN4: Douleur Neuropathique 4 questions;NP: Neuropathic pain;NNP: Non Neuropathic pain;IASP: International Association for Study of Pain;VAS: Visual Analogue Scale;SF-MPQ: Short-form McGill Pain Questionnaire;ROC: Receiver Operating Characteristic;PPV: Positive Predictive Value;NPV: Negative Predictive Value;AUC: Area under the curve;PCP: Primary Care Physicians.Javier Rejas is employed at Pfizer Spain. The author(s) declare that they have no competing interests.CP and JR designed the study and were responsible for the idea of the study. CP, RG, SH and JI participated in patient enrrollment and manuscript elaboration. DB wrotte the manuscript in part and was responsible for consultation and scientific support of the project. SD was responsible for monitoring, logistic and evaluation of data. All authors read and approved the final manuscript.Cuestionario DN4. This appendix includes the Spanish version of DN4 questionnaire.Click here for file


Migraine is highly prevalent along with the high percentage of treatment-refractory cases. ONS may provide pain relief for patients with otherwise refractory primary headache disorders. It is more generally applicable than other invasive methods.We therefore investigated ONS in a series of patients to determine efficacy, complications and outcome.We included a case series of 20 patients who had chronic headaches for a duration of 5.3 y who underwent ONS lead implantation . Prior to surgery patients had received conservative and surgical therapies including antidepressants, occipital nerve blocks, opioids, cervical posterior fusion (one patient), without success. 9 patients suffered from chronic migraine, 1 had a history of thalamic infarction, 1 patient suffered from cluster headache, 4 patients complained tension headache and 5 patients with recurrent cervicozephalgia after spine surgery. Using a midline approach two octrodes were placed subcutaneously and positioned across the level of C1 using fluoroscopy. Leads were placed under general anesthesia and externalized for three days.Device dislocation was found in 3 cases. 16 patients mentioned significant relief of pain, so that they all underwent insertion of the generator , in 3 patients 30% pain reduction was achieved, one patient did not benefit. Decreases in pain led to an improvement in functional capacity during the 3 months follow-up after implantation. The mean VAS score changed from 8.2 ± 1.5 to 3.5 ± 1.3 at the 6 months follow-up. No complicaoccurred.The exact mechanism of neuromodulation in the tratment of different headache syndromes remains unclear. ONS is safe and efficacious in the treatment of medically intractable headaches conditions. Further investigations are required to evaluate predictor for patient selection and sstimulation setting among this crucial pain conditions.SS and JV received consultant fees, GB received a fellowship stipendium from St. Jude Medical.


The anticonvulsants pregabalin and gabapentin are both indicated for the treatment of peripheral neuropathic pain. The decision on which treatment provides the best alternative, should take into account all aspects of costs and outcomes associated with the two therapeutic options. The objective of this study was to examine the cost – effectiveness of the two agents in the management of patients with painful diabetic neuropathy or post – herpetic neuralgia, under the third party payer perspective in Greece.The analysis was based on a dynamic simulation model which estimated and compared the costs and outcomes of pregabalin and gabapentin in a hypothetical cohort of 1,000 patients suffering from painful Diabetic Peripheral Neuropathy (DPN) or Post-Herpetic Neuralgia (PHN). In the model, each patient was randomly allocated an average pretreatment pain score, measured using an eleven-point visual analogue scale (0 – 10) and was “run through” the model, simulating their daily pain intensity and allowing for stochastic calculation of outcomes, taking into account medical interventions and the effectiveness of each treatment.Pregabalin demonstrated a reduction in days with moderate to severe pain when compared to gabapentin. During the 12 weeks the pregabalin arm demonstrated a 0.1178 (SE 0.0002) QALY gain, which proved to be 0.0063 (SE 0.0003) higher than that in the gabapentin arm. The mean medication cost per patient was higher for the pregabalin arm when compared to the gabapentin arm (i.e. €134.40) over the 12 week treatment period. However, this higher cost was partially offset by the reduced direct medical costs . Comparing costs with respective outcomes, the ICERs for pregabalin versus gabapentin were €13 (95%CI: 8 – 18) per additional day with no or mild pain and €19,320  per QALY gained.Neuropathic pain carries a great disease burden for patients and society and, is also, associated with a significant economic burden. The treatment of pain associated with DPN and PHN with pregabalin is a cost-effective intervention for the social security in Greece compared to gabapentin. Thus, these findings need to be taken into consideration in the decision – making process when considering which therapy to use for the treatment of neuropathic pain. Neuropathic pain (NeP) is defined by the International Association for the Study of Pain (IASP) as “Pain caused by a lesion or disease of the somatosensory nervous system”. NeP can be a result of a variety of conditions associated with impairing the functioning of the nervous system, such as diabetes, multiple sclerosis, trauma and herpes zoster infections . It is aThe anticonvulsants pregabalin and gabapentin are indicated for the treatment of neuropathic pain. Treatment with the third generation anticonvulsant - pregabalin can be started at a dose of 150 mg per day given as two to three divided doses. Based on individual patient response and tolerability, the dose may be gradually increased, if needed, to a maximum dose of 600 mg per day. Clinical trials using pregabalin for both peripheral and central NeP, showed a reduction in pain scores within the first week, which was maintained throughout the treatment period ,8. AlterA cohort study by Toth et al.  investigAlong with the previously mentioned high incidence, chronicity, maladaptivity and co-morbidities associated with NeP, comes the significant economic burden to the national health system. In an attempt to estimate the costs associated with NeP, Dworkin et al. (2010) calculated the excess healthcare costs associated with peripheral NeP between $1,600 and $7,000 . In the .Thus, the benefit of treatment for patients with chronic neuropathic pain is dual, including both the effects of reduced morbidity as well as their subsequent contribution in societal and health care costs. However, the decision on which treatment provides the best alternative, should take into account all aspects of treatment costs included. In this decision – making process, pharmacoeconomic tools, such as economic evaluation, are deemed pivotal. In light of the above, the purpose of this study was to examine the cost – effectiveness of pregabalin versus gabapentin in the management of patients with painful diabetic neuropathy or PHN in view of the third party payer in GreeceThe cost – effectiveness analysis was based on a dynamic simulation model ,18 whichIn the model, each patient was randomly allocated an average pretreatment pain score, measured using an eleven-point visual analogue scale, with 0 referring to “no pain” and 10 to “the worst pain imaginable”, which was derived from the actual distribution of pain levels in a randomized, double-blind controlled trial of pregabalin in patients with chronic NeP, defined as subjects with DPN or PHN . FollowiThe time frame of interest in the model was twelve weeks and all NeP-associated direct costs were considered. Several outcomes were derived from the above dynamic simulation model. The number of days with no or mild pain was the primary measure in the model, but also the mean number of days with 30% and 50% reduction in pain score were estimated. Other outcomes of interest included Quality Adjusted Life Years (QALYs) gained and the cost per QALY gained along with costs of medication and NeP-related healthcare services.In the model, the cost effectiveness of pregabalin at a daily dose of 150 – 600 mg . Moreover, for the purposes of the analysis, it was assumed that no cost variations would result from prescribing divided doses of the comparator therapies. The costs per health service and diagnostic tools were derived from the official NHS price lists.To identify healthcare resource utilization data according to pain severity, a survey, was conducted in a group of 100 general practitioners and 20 specialized pain clinics in Greece. General practitioners were requested to provide the percentage of patients that were referred to pain clinics, according to pain score, whereas data on utilization of diagnostic tests and other health services arose from the survey of referable specialized pain clinics  perspective and reported in year 2011 values.To address parameter uncertainty, a series of one-way sensitivity analyses, were performed, by recalculating the results, after a ±20% change in baseline values, for selected parameters. The sensitivity analysis focused on the cost of pregabalin, the weekly probability of physician visiting due to NeP and the health utility values in association with neuropathic pain. Additional scenarios of calculations included alternating daily dosages of gabapentin (1800 mg and 1200 mg) as well as the exclusion of non-medication related health-resource use (i.e. consideration of medication costs only).The clinical outcomes at endpoint (t = 12 weeks) are presented in Table The mean medication cost per patient was higher for the pregabalin arm when compared to the gabapentin arm (i.e. €134.40 higher) over the 12 week treatment period. However, as presented in Table The sensitivity analysis showed that parameters with the greatest impact on results were the daily cost of pregabalin and the utilities associated with pain severity Table . The incThe present study aimed at estimating the cost-effectiveness of pregabalin, versus gabapentin for the treatment of DPN or PHN, taking into account the perspective of a social security organization in Greece. For that purpose, a previously presented and validated health economic model was adapted for the Greek healthcare setting, taking into account direct costs of treatment and follow up for a hypothetical cohort of 1,000 patients that were treated under the two alternatives for a 12 week period, based on the efficacy profile of each intervention as recorded in the results of published clinical trials.The results of the analysis indicate that pregabalin is a more costly but also a more effective treatment option compared to gabapentin. The excess costs of pharmaceutical treatment for pregabalin are partially offset by its improved clinical profile in terms of reductions in resource utilization and its improved outcomes in the patient level, thus leading to incremental cost-effectiveness ratios of €13 per additional day with mild/no pain and €19,320 per QALY gained.In Greece there are currently no established thresholds under which interventions can be classified as cost-effective. In general, the accepted willingness to pay per QALY gained falls within £20,000 – £30,000 in the UK and $50,000 – $100,000 in the US ). A geneThe findings of this study are in accordance to previously published literature ,11 that As with any study of its kind, the present one has some limitations that should be acknowledged. Firstly, the data on efficacy of the treatments under comparison are based on clinical trial data, which considered patients in a different healthcare setting than that in Greece. Thus, the trial cohorts might not be fully representative for patients with painful DPN or PHN in Greece, Nevertheless, the magnitude of this (possible) discrepancy is extremely difficult to quantify and to include in the calculations of the analysis. Moreover, the perspective of the analysis  does not include other costs, such as the indirect expenses due to productivity losses. If the societal perspective had been adopted, there is evidence that the ICERs would probably be more favourable (i.e. lower). For example, a recent cost analysis of adding pregabalin or gabapentin to the management of community – based patients with peripheral NeP, which estimated also the indirect costs, showed that although the pharmaceutical costs of pregabalin were significant, the overall patient cost was lower in the pregabalin group due to reduced sick leave and lower healthcare costs, and thus was compensated the higher treatment acquisition cost of pregabalin . A limitAnother limitation of the analysis that should be considered is the source of data regarding the resource use incorporated in the calculations, i.e., the elicitation of some data via a questionnaire survey. Although an ideal approach would be to review actual patient data, the absence of centralized patient records or databases containing relevant data in the Greek NHS, rendered necessary the use of a questionnaire survey. Inevitably, the above mentioned approach introduces uncertainty in the calculations, whose extent, however, is quite difficult to quantify. Nevertheless, the magnitude of the study sample, the simplicity of the data that were requested and the extensive sensitivity analysis on the baseline values, enhance the robustness of outcomes.Finally, the present study concludes that the intervention under investigation was followed by favourable incremental cost-effectiveness ratios, compared to other treatment strategies on pain management. However, the discussion on the adoption of such a policy by the Social Insurance will be complete, in economic terms, when accompanied by estimations of this intervention to insurance budgets, i.e. a budget impact analysis. This issue certainly constitutes an area of future research.Neuropathic pain carries a great disease burden for patients and society and, also, a significant economic burden. From a third part payer perspective, the treatment of pain associated with painful DPN and PHN with pregabalin is a cost-effective intervention for the social security in Greece compared to gabapentin. Notwithstanding its limitations, the study’s findings need to be taken into consideration in the decision – making process when considering which therapy to use for the treatment of neuropathic pain.DPN: Diabetic peripheral neuropathy; EQ-5D: Euroqol-5D; GBP: Gabapentin; IASP: International association for the study of pain; ICER: Incremental cost effectiveness ratio; NeP: Neuropathic pain; NHS: National health service; PHN: Post herpetic neuralgia; PGB: Pregabalin; QALY: Quality adjusted life years; WHO: World health organization.EV and LL are employees of Pfizer Hellas. KA has received funding in the past from Pfizer with the purpose of data analyses and manuscript revision.The authors declare no other financial or non-financial competing interests.KA and IP performed the calculations and analyses reported in the text. EV and LL reviewed the literature for relevant data and documentation. IP and EK drafted the manuscript which was edited and critically revised by KA and JK. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/56/prepub


Background. Chronic injury-related pain could be influenced by psychological symptoms such as depression, anxiety, and stress that also affect daily life. Methods. Patients with chronic pain caused by an injury (n = 86) aged 18–65 years referred to the Pain Rehabilitation Clinic at the Umeå University Hospital answered a set of questionnaires to assess pain intensity, depression, anxiety, posttraumatic stress, sleep disturbance, and fatigue. Results. A significantly higher proportion of women (47.5%) reported depression ) than men (22.2%). In all patients anxiety (HAD) was reported by 39.5% and moderate/severe posttraumatic stress  by 30.2%. A majority reported sleep disturbance (84.9%) and fatigue (90.7%). Significant relationships were found between posttraumatic stress and depression and anxiety. Conclusion. These findings indicate the importance of assessing and treating psychological symptoms associated with chronic pain as the result of trauma. Chronic pain (more than three-month duration)  is an acThe causes of musculoskeletal chronic pain vary and are in several patients unknown. Some of the most common causes reported are injuries related to traffic accidents, falls, or sports injuries. In western countries, whiplash as the result of traffic injuries has a high annual incidence with 1.0 to 3.2/1000 per year . WhiplasChronic injury-related pain may be influenced by different physical and emotional factors that also affect daily life. During the last decade, attention has been paid to psychological factors such as depressive symptoms, anxiety, and negatively coloured cognitions that could be associated with future impairments , 7.Moreover, posttraumatic stress reactions might play an important role in the persistence of symptoms after injuries and chronic pain after traffic accidents. In patients with traffic injury-related problems, 10–30% of the patients suffer from severe post-traumatic stress symptoms and receive a post-traumatic stress disorder (PTSD) diagnosis . AlthougIt is largely unknown how depression, anxiety, and posttraumatic stress interact in patients with injury-related chronic pain long after injury. A previous pilot indicated relationships between pain and stress, depression, and anxiety in patients with chronic pain . Since mParticipating subjects were 86 patients, 59 women and 27 men, aged 18–65 (41.1 ± 10.3) years, with chronic pain caused by an injury and referred from regional general practitioners to the Pain Rehabilitation Clinic at the Umeå University Hospital  between October the 1st 2007 and September 30th 2008. Written, signed informed consent was obtained from all participants. The participants suffered from pain caused by falls (14.0%), whiplash injuries (44.4%), other traffic injuries  (8.1%), horseback riding (8.1%), sports (1.2%), assaults (5.8%), and other injuries  (18.4%). The time between injury and assessment was more than one year in all patients.Patients answered a set of questionnaires at the assessment in the clinic. Information about each participant's trauma history was collected from hospital records.Pain intensity was rated by the Visual Analogue Scale (VAS). The scale consists of a 100 mm straight line with defined end points (“no pain” and “worst pain imaginable”) on which the patients were asked to mark their experienced pain (results in mm). The VAS is considered to have a high degree of reliability and validity .The Hospital Anxiety and Depression Scale (HAD) is an instrument that measures anxiety and depression which is developed and validated on nonpsychiatric medical patients. The questionnaire comprises of 14 items divided into two parts, for rating of depression and anxiety. Each item has a 4-response category range between 0 and 3. The scale ranges between 0 and 21 for both depression and anxiety. According to Zigmond and Snaith the cutoff level for possible cases of anxiety disorder and depression is a score ≥8 on each subscale .The Impact of Event Scale (IES) is a widely used self-report scale. It is a valid measure of posttraumatic stress reactions and has been suggested as a screening tool for posttraumatic stress disorder (PTSD). The IES comprises 15 statements: seven questions regarding intrusive symptoms and eight address avoidance symptoms. The patients answer the questionnaire regarding their symptoms during the last week. A total score can vary from 0 to 80 . AccordiThe symptoms sleep disturbance and fatigue were rated on the Rivermead Post-Concussion Symptoms Questionnaire . PatientU test. Pearson's correlation coefficient was calculated for the analysis of bivariate correlations. The results of logistic regression analysis are presented as OR (odds ratio), which indicates an increased (OR > 1) or a decreased (OR < 1) likelihood of the event (coded as 1) occurring. The reliability of the OR is expressed as 95% confidence intervals (CI). Statistical significant level was set at 0.05. The study was approved by the ethics committee of Umeå University.All statistical analysis was performed with SPSS, version 19.0. Data are reported as mean values ± standard deviations unless otherwise indicated. Comparisons of populations were made using the Mann-Whitney Pain intensity on the VAS for all patients was 65.8 ± 20.2 mm. No statistical significant difference was found between women (65.5 ± 21.1 mm) and men (66.8 ± 18.2 mm).P = 0.038). A statistically significant correlation was found between depression on the HAD and IES total score . In a logistic regression analysis of HAD depression, patients with possible-probable depression were chosen as a dependent variable . For patients with a possible-probable depression statistically significant association was found for moderate-to-severe posttraumatic stress (IES ≥ 26) .Depression scores on the HAD for all patients were 6.9 ± 4.4 mm . A significantly higher proportion of women (47.5%) reported possible-probable depression (HAD score ≥ 8) in comparison with men (22.2%) . In a logistic regression analysis of HAD anxiety, patients with possible-probable anxiety were chosen as a dependent variable and coded as a binary variable . A possible-probable anxiety was statistically significant associated with moderate-to-severe posttraumatic stress (IES ≥ 26) .Anxiety scores on the HAD for all patients were 6.9 ± 4.2, women 6.9 ± 4.5 and men 7.0 ± 3.9. The frequency of patients with possible-probable anxiety (HAD score ≥ 8) was 39.5%. No statistically significant difference between men (40.7%) and women (39.0%) was found. A statistically significant correlation was found between anxiety on the HAD and IES total score .Total scores of the IES for all patients were 19.3 ± 15.0 and the scores for the subscales Avoidance 9.8 ± 9.1 and Intrusion 9.5 ± 7.3. Subclinical stress response was reported by 32.6%, mild stress by 37.2%, moderate stress by 22.1%, and severe stress was reported by 8.1%. No statistically significant difference between men and women was found with respect to total IES , Avoidance , and Intrusion . In a logistic regression analysis of posttraumatic stress, patients with moderate-to-severe posttraumatic stress were chosen as a dependent variable and coded as a binary variable . A statistically significant association was found between moderate-to-severe posttraumatic stress and age <  40 years  and women .The present study shows that the levels of depression, anxiety, and stress were high in patients with chronic injury-related pain and that a majority reported sleep disturbance and fatigue. The frequency of depression was significantly higher in women than in men.As whiplash is reported as the most common traffic injury,  it was nPain intensity on the VAS was rated high in the present study in comparison with several other chronic pain studies and higher in comparison with previous studies from our clinic , 16. ThiAmong psychological consequences after trauma, depression is frequently reported but the level of depression is seldom classified. In the present study a possible-probable depression was found in nearly 50% of women. These findings are clearly higher in comparison with previous studies that focus on whiplash injuries long after injury. Although there was no difference between men and women on the HAD anxiety, the frequency of anxiety was high in all patients. More than 40% of the patients fulfilled the criteria for possible-probable anxiety. The anxiety scores were in accordance with previous results from our clinic , 16 and Psychological problems may also include posttraumatic stress reactions. Despite the fact that posttraumatic stress decreases with time, the level of moderate-to-severe stress (30.2%) was clearly higher in the present study than previous studies that documented patients both in the acute phase and several years after whiplash injuries , 19. In Patients with chronic pain often report sleep dysfunction, and sleep dysfunction can aggravate pain . In the Some limitations of this study should be noted. In this study general practitioners referred the patients to a pain rehabilitation clinic because of injury-related chronic pain due to an accident that occurred more than one year before the referral. Thus the results represent a selected group of patients with chronic pain with severe consequences after the injury, yet the most severe cases are referred to specialist departments at university hospitals. The results with high scores on the instruments therefore seem reasonable. Although patients reported symptoms that they referred to as the result of a previous injury, there may be symptoms of other origins that occur during the time between the trauma and the assessment. These factors might have influenced the patients' results.This study has implications for clinicians, because the results indicate the importance of assessment of depression, anxiety, stress, and sleep disturbance in patients with chronic pain after trauma in order to optimize treatment.In conclusion, this study shows high frequencies of psychological symptoms and sleep disturbance together with high pain intensity after trauma. These aspects should be taken into consideration in the management of patients with injury-related chronic pain.


Despite the fact that NDPH has been considered one of the most refractory headaches, there are limited data available regarding the clinical characteristics, pharmacological treatment and prognosis of NDPH.To discuss cases which were identified as NDPH by the International Headache Society diagnostic criteria.Our NDPH patients consisted of 8 females and 3 males, with an onset age ranging from 15 to 72 years old. The duration of the headaches, location, intensity and nature of the pain, precipitating factors and treatments were investigated.The duration of the headaches ranged from 9 months to 24 years. Pain was diffuse in 3 patients, occipital-neck area in 4, frontal in 1 and left-sided in 1. Pain intensity was mild in 1 case, mild to moderate in 2, moderate in 7 and moderate to severe in 1. The nature of the pain was more similar to a chronic tension-type headache (73%) than a migraine-type, although 4 cases were found to be throbbing in nature. Headaches were related to stressful life events in 2 patients and exercise in 1 case. While two of the patients had received stellate ganglion blocks, all patients had received several kinds of drugs including analgesics, muscle relaxants, tricyclic antidepressants, selective serotonin reuptake inhibitors, anti-anxiety agents and anti-epileptic drugs. Nine patients were refractory to the pharmacological treatments.Despite the general tendency that the pain of NDPH is dull, patients occasionally suffer from bouts of throbbing pain. NDPH is the refractory headache and requires optimal pharmacological regimens on an individual basis.None


The inguinal hernia is one of the most common diseases in the elderly. Treatment of this type of pathology is exclusively surgical and relies almost always on the use of local anesthesia. While in the past hernia surgery was carried out mainly by general anesthesia, in recent years there has been growing emphasis on the role of local anesthesia.The aim of our study was to compare intra-and postoperative analgesia obtained by the use of levobupivacaine compared with that of bupivacaine. Bupivacaine is one of the main local anesthetics used in the intervention of inguinal hernioplasty. Levobupivacaine is an enantiomer of racemic bupivacaine with less cardiotoxicity and neurotoxicity. The study was conducted from April 2010 to May 2012. We collected data of forty male patients, aged between 73 and 85 years, who underwent inguinal hernioplasty with local anesthesia for the first time.Minimal pain is the same in both groups. Mild pain was more frequent in the group who used bupivacaine, moderate pain was slightly more frequent in the group who used levobupivacaine, and the same for intense pain. It is therefore evident how Bupivacaine is slightly less preferred after four and twenty four hours, while the two drugs seem to have the same effect at a distance of twelve and forty-eight hours. Bupivacaine shows a significantly higher number of complications, as already demonstrated by previous studies. The request for an analgesic was slightly higher in patients receiving levobupivacaine.After considering all these elements, we can conclude that the clinical efficacy of levobupivacaine and racemic bupivacaine are essentially similar, when used under local intervention of inguinal hernioplasty. The inguinal hernia is one of the most common diseases in the elderly. The Italian National Health System is geared to recognize the role of local anesthesia for the surgical treatment of inguinal hernia. Treatment of this type of pathology is exclusively surgical and relies almost always on the contribution of local anesthesia. While in the past, hernia surgery was carried out mainly by general anesthesia, in recent years there has been growing emphasis on the role of local anesthesia. This type of anesthesia has significantly improved the treatment of inguinal hernia, significantly reducing recurrences, complications, recovery time and return to normal working activities.Hernia surgery should be approached according to a technique as simple and safe as possible that is at the same time accepted by the patient and easily realizable by the surgeon . InguinaThe aim of this study was to compare two local anesthetics, levobupivacaine and bupivacaine, commonly used in the surgical treatment of inguinal hernia.From April 2010 to May 2012 we studied forty patients recovered in the department of General Surgery, University of Naples “Federico II”, affected by inguinal hernia for the first time and treated in this period of time. The patients were divided into two groups, corresponding to the two drugs that we have studied. We interviewed patients at the end of the operation using the VAS Scale. During the interview, we have focused on some aspects: the intra-operative pain, post-operative pain, need for analgesia in the postoperative period and the overall satisfaction with anesthesia. We compared the results obtained and we made interesting observations, for a condition which, we are sure, will be increasingly common in the coming years due to progressive aging of the Italian population. We collected data of forty male patients, aged between 65 and 85 years, who underwent inguinal hernioplasty under local anesthesia for the first time. In Table In Table In this study, continuous variables was reported as an average, more or less the standard deviation, and analyzed using ANOVA . It is a parametric test that is used in statistics to compute the variance between two or more different groups. Analysis of variance is a set of statistical techniques that are part of the inferential statistics that allow us to compare two or more groups of data comparing the internal variability of these groups with the variability between groups. Categorical variables were reported as proportions instead and analyzed using chi-square test. Chi-square test is one of the tests used in statistics using the chi-square variable causal to verify if the null hypothesis is probabilistically compatible with the data. The values relating to the intra-operative pain and post-operative pain, as well as those relating to the taking of analgesics during the postoperative course, were always reported and analyzed through chi-square test. A P value less than 0.05 was considered statistically significant. Based on previous studies, the difference in the level of pain between the group of levobupivacaine and bupivacaine was 1.5.International literature shows how local anesthesia is certainly more advantageous in terms of costs for the structure. While there are no particular differences between regional and general anesthesia, local anesthesia results seem to be better. A potential advantage of local anesthesia realized without any monitoring or additional drugs administered intravenously  .Levobupivacaine is a local anesthetic with long duration of action. It works by blocking nerve conduction of sensory and motor nerves, interacting predominantly with the voltage-gated sodium channels in the membrane of the cell, but also blocking potassium channels and calcium. Levobupivacaine also interferes with the transmission of the pulse and the conduction in other tissues where the effects on the central nervous system and cardiovascular system are the most important for the occurrence of clinical adverse reactions. Chirocaine is a compound based levobupivacaine hydrochloride. It is capable of producing a block on both the sympathetic system and on the parasympathetic system demonstrating hemodynamic changes significantly milder than Ropivacaine, which instead has the greatest influence on the sympathetic system with respect to that parasympathetic . The dosEspecially in recent years local anesthesia allows the surgeon to monitor patients and to have simultaneously shorter hospitalization times and lower costs for the structure. Local anesthesia applied during endarterectomy surgery allows the surgeon to assess the levels of cerebral perfusion in an awake patient, giving a better chance of cerebral protection during arterial clamping. All these elements indicate that such interventions performed under local anesthesia with levobupivacaine compounds offer greater chances of success with significantly reduced rates of morbidity and mortality -14.Locally hernioplasty has proved to be the method with the minor impact on the functioning of organs and systems, as it appears to be safe, effective, with a low incidence of side effects, enabling a rapid mobilization of the patient and significantly reducing the time of hospitalization, in less than twenty-four hours .Among rare complications of surgery, hernioplasty under local anesthesia include: cardiovascular instability, nausea, vomiting, urinary retention, scrotal hematoma, edema, infection, orchitis, testicular atrophy and recurrences. Normally this type of surgery shows a lower incidence of complications than the same operation performed with general anesthesia. Compared with other types of anesthesia, post-operative complications of the respiratory and circulatory systems are significantly reduced .The use of local anesthesia also allows the patient to be awake, aware, and thus able to collaborate actively conducting a stress-test by performing the Valsalva maneuver or a cough, which allows the surgeon to evaluate intra-operatively the presence of defects, latent trusses and sealing of the repair of plastic, reducing significantly the proportion of surgical failures ,18.The anesthetic block consists of four phases: The first phase, percutaneous, provides the block troncular selective ilioinguinal nerves and iliohypogastric. The second phase, percutaneous, blocks the genital branch of the genitofemoral nerve, through a puncture performed below the inguinal ligament, lateral to the pubic tubercle. The third phase, percutaneous, provides for the infiltration of the surgical incision using a 22 gauge spinal needle. The anesthetic block is completed in the incisional phase by means of an open infiltration performed in each anatomical floor during the course of surgery . Local aThe purpose of this study was to compare the perception of pain intra and post-operative, found as a result of intervention with the Levobupivacaine, compared to that recorded after the same intervention carried out with the racemic bupivacaine. We used the same dose for both anesthetics. The forty patients we studied, were randomly distributed in two groups, and were classified on the basis of a number of variables: age, weight, sex, type of hernia, ASA Stadium and location of the hernia. The first point on which we focused was intra-operative pain. In the group of patients treated with levobupivacaine, 10 % reported minimal pain, 55% mild pain, 30% moderate pain, 5% severe pain. In the group of patients treated with bupivacaine, 10% identified minimal pain, 65% mild pain, 25% moderate pain and no one intense pain. Therefore, we can say that minimal pain is the same in both groups. Mild pain was more frequent in the bupivacaine group, moderate pain slightly more frequent in the Levobupivacaine group and the same for intense pain. The second point on which we focused was post-operative pain, assessed in three positions within 48 hours. In the first group, 10% of patients reported pain in the supine position, 15% in the sitting position and 10% standing up. In the second group, 10 % reported pain in the supine position, 15% in the sitting position and 15% standing up. Therefore the data show the same results for the first two positions and a slight preference for levobupivacaine in the upright position. With regard to the assessment of pain during the forty-eight hours, we evaluated the impressions of the patient's at four time intervals: four, twelve, twenty-four and forty-eight hours. In the levobupivacaine group, 15% of patients expressed pain relief after four hours, 10% after 24 hours, 5% after 48 hours. In the bupivacaine group, 10% of patients experienced pain after four and twelve hours, 5% after twenty-four and forty-eight hours. It is therefore evident how Bupivacaine is preferred slightly after four and twenty four hours, while the two drugs appear to be equivalent at a distance of twelve and forty-eight hours. The third point we considered werethe postoperative complications and overall patient satisfaction. In the Levobupivacaine group, 20% experienced symptoms such as nausea and / or vomiting, 5% itching, no one with an infection. In the bupivacaine group, 25% noted nausea and / or vomiting, 5% itching, 5% infection. Bupivacaine shows a significantly higher number of complications, as already demonstrated by previous studies. The overall satisfaction towards the intervention was high in 65% of patients receiving levobupivacaine, moderate in 30% and sufficient in 5%. Instead patients who received bupivacaine expressed 65% complete satisfaction and 35% satisfaction moderate. In neither of the two groups were found signs of toxicity by local anesthetic, such as tinnitus, pallor circumorale, cardiovascular or neurological manifestations. Finally, the last point on which we have focused our work has been the application of analgesic in post-operative period. Seventy percent of patients who received levobupivacaine required at least an analgesic (paracetamol) within twenty-four hours surgery and 30% required others analgesics. In the bupivacaine group, 60% took some paracetamol after twenty-four hours, 25% required other analgesics. The request for ananalgesic was slightly higher in patients receiving levobupivacaine.After considering all these factors, we can conclude that the clinical efficacy of levobupivacaine and racemic bupivacaine are essentially similar. When we perform inguinal hernioplasty surgery with local anaesthesia, Levobupivacaine could be preferred because it has a lower cardiac and neurological toxicity compared to bupivacaine, as previously demonstrated by other clinical studies.The authors declare that they have no competing interests.RC, BA: conception and design, interpretation of data, given final approval of the version to be published; GV, GC, MA, GA: acquisition of data, drafting the manuscript, given final approval of the version to be published; AP, CM, FI, DP: critical revision, given final approval of the version to be published.


Patients with depersonalization disorder (DPD) typically complain about emotional detachment. Previous studies found reduced autonomic responsiveness to emotional stimuli for DPD patients as compared to patients with anxiety disorders. We aimed to investigate autonomic responsiveness to emotional auditory stimuli of DPD patients as compared to patient controls. Furthermore, we examined the modulatory effect of mindful breathing on these responses as well as on depersonalization intensity.22 DPD patients and 15 patient controls balanced for severity of depression and anxiety, age, sex and education, were compared regarding 1) electrodermal and heart rate data during a resting period, and 2) autonomic responses and cognitive appraisal of standardized acoustic affective stimuli in two conditions .DPD patients rated the emotional sounds as significantly more neutral as compared to patient controls and standardized norm ratings. At the same time, however, they responded more strongly to acoustic emotional stimuli and their electrodermal response pattern was more modulated by valence and arousal as compared to patient controls. Mindful breathing reduced severity of depersonalization in DPD patients and increased the arousal modulation of electrodermal responses in the whole sample. Finally, DPD patients showed an increased electrodermal lability in the rest period as compared to patient controls.These findings demonstrated that the cognitive evaluation of emotional sounds in DPD patients is disconnected from their autonomic responses to those emotional stimuli. The increased electrodermal lability in DPD may reflect increased introversion and cognitive control of emotional impulses. The findings have important psychotherapeutic implications. Depersonalization disorder (DPD) is characterized by persistent or recurrent depersonalization, i.e. experiences of unreality, detachment, or being an outside observer with respect to one’s thoughts, sensations, actions or feelings and is often accompanied by derealization, i.e. experiences of unreality or detachment with respect to surroundings. During these experiences reality testing remains intact, and these symptoms are not caused by direct physiological effects  or better explained by another mental disorder (e.g. panic disorder). Finally, these symptoms are a source of significant burden or impairment (DSM-V) ,2. The pThe antithesis of depersonalization is mindfulness, i.e. nonjudgmental attention to present-moment experiences ,14. A roWith these findings and considerations in mind we designed the present study to investigate the autonomic responsiveness to emotional stimuli and the cognitive evaluation of those stimuli in DPD patients as compared to patient controls. As most DPD patients are comorbid with depression and anxiety -4,28, weWe hypothesized firstly, that DPD patients as compared to patient controls will show blunted autonomic responses to emotional stimuli, and secondly, that mindful breathing will increase their autonomic responsiveness and reduce depersonalization severity.The study was approved by the Ethics Committee of the Rhineland-Palatinate State Board of Physicians (Germany). All participants provided their written informed consent to participate in this study. The sample consists of n=22 DPD patients and n=15 patient controls . The diaThe Cambridge Depersonalization Scale (CDS) ,33 consiPhysiological responses were recorded with a Biopac MP100 system  and stored at 200 Hz for further offline processing. Skin conductance was measured by a constant voltage system (0.5 V) using a bipolar recording with two Ag/AgCl electrodes (0.8 cm diameter) filled with 0.05 M NaCl electrolyte. The electrodes were placed at the palmar surface of the medial phalanx of the index and second finger of the non-dominant hand. An electrocardiogram (ECG) was measured with pre-gelled electrodes placed at the right arm and left leg.A set of acoustic emotional stimuli from the International Affective Digitized Sounds (IADS)  was usedThe experiment started with a 5 min rest period. Patients were instructed to sit quietly on a comfortable chair with their eyes closed. Electrodermal and heart rate data were acquired continuously during this rest period to allow for analyzing tonic physiological activation in DPD patients as compared to patient controls.Subsequently, participants were informed about the upcoming stimulation period. They were asked to keep their eyes closed and listen to the sound presentation via circumaural earphones. The acoustic stimuli were presented in a random order  while continuously measuring autonomic physiological responses. For presentation we used a Dell Latitude E6500 laptop with an Intel IDT 92HD71B7 HD Audio (ICH9) soundcard and AKG K141 MKII circumaural headphones. The volume was adjusted individually, so that the patients felt comfortable with the volume. Each sound of 6 seconds duration was followed by a jittered pause that lasted between 10 and 20 s . Measurements were obtained in two conditions, whose sequential order was counterbalanced across subjects: a) Listen to the sounds and be attentive to the emotional scenarios b) breathe mindfully while listening to the sounds, i.e. direct your the attention to the bodily sensations while letting yourself sink in the sound scenarios. Participants had no formal training in mindfulness exercises.Subjective ratings of valence and arousal for all sounds were obtained in a separate session by using the Self-Assessment Manikin . The SelIn order to capture subjective changes induced by the mindful breathing manipulation, participants rated the degree of feeling grounded in their body on a self-constructed 21-point-Likert-scale (-10=extremely detached (no-body), 0=normal, +10=grounded very much) and the overall intensity of the sounds . Further, participants rated present depersonalization intensity by the state CDS. The participants rated their degree of feeling grounded in their body and the severity of present depersonalization directly after each condition . The degree of feeling grounded was not rated by two patients from the DPD group and the overall intensity rating and S-CDS was missing from one patient of the DPD group. Thus, corresponding analyses rely on n=20 or n=21 DPD patients, respectively, and n=15 patient controls.2) and normalized units (n.u.). We specifically analyzed HF and time domain measures as indicators for cardiac-vagal tone and additionally calculated LF/HF that can be interpreted as a measure of sympathovagal balance. The quality of the ECG recording of one DPD patient was insufficient for further analyses. Therefore, HR measures were analyzed for n=21 DPD patients and n=15 patient controls.From the electrodermal data that were recorded during the rest period, we calculated the skin conductance level (SCL) as the average low pass filtered skin conductance signal (cutoff frequency 0.05 Hz) as well as the number of nonspecific skin conductance responses with an amplitude of at least 0.02 µS . FurtherTo quantify phasic physiological responses to the emotional sounds, we measured skin conductance response (SCR) amplitudes and heart rate changes. For SCR quantification, we measured the largest increase in skin conductance during a period from 1 to 8 s after stimulus onset as change in μS. These values were log-transformed to reduce the skew of the amplitude distribution . For theT-tests were used to assess differences between DPD patients and patient controls in tonic physiological activity during the 5 min rest period. Ratings of valence, arousal and vividness were compared between patient groups using t-tests  or 2×2×2 analyses of variance (ANOVAs) with patient group as between-subject factor and valence category (positive vs. negative) and arousal category  as within-subject factors, respectively. To assess discrepancies between affective ratings and IADS norm ratings, we calculated differences between each participant’s ratings and gender-specific norm ratings. These differences were compared to 0 as well as between groups using a one-way ANOVA  with patient group as between-subject factor or a 2×2×2 ANOVAs  with the additional within-subject factors valence category (positive vs. negative) and arousal category . Ratings of mindful breathing effects were subjected to a 2×2 ANOVA using patient group as between-subject factor and experimental condition  as within-subject factor. Finally, SCR amplitudes and HR changes that were elicited by the neutral sounds were analyzed using 2×2 ANOVAs with patient group as between-subject factor and experimental condition  as within-subject factor; corresponding responses to the emotional sounds were analyzed using 2×2×2× 2 ANOVAs with the additional within-subject factors valence category (positive vs. negative) and arousal category . Significant interaction effects in the ANOVAs were followed by post-hoc t-tests with Bonferroni correction. Finally, we correlated affective ratings and physiological responses with anxiety (STAI-T/-S) and depression scores (BDI-II) using Pearson’s product-moment correlation coefficient.2 (for main and interaction effects in the ANOVAs) or Cohens’s d (for comparisons of two groups) are reported as effect size estimates.An a priori significance threshold of α=.05 was used for all analyses. Partial ηThere were no differences between both groups for age, sex, years of education, severity of current depression, anxiety, symptoms of dissociative amnesia and childhood traumatic experiences. However, severity of depersonalization and self-rated mindfulness differed strongly between the groups see 1.As shown in 2=.80, indicating that patients of both groups rated positive sounds as pleasant and negative ones as unpleasant. Moreover, as revealed by a significant valence × arousal category interaction, F=20.44, p<.001, η2=.38, this difference was more pronounced for highly arousing, t(34)=17.58, p<.001, d=3.00, as compared to medium arousing sounds, t(34)=5.37, p<.001, d=0.91. Finally, a significant group × valence category interaction was obtained, F=7.13, p<.05, η2=.18. DPD patients rated unpleasant sounds as less unpleasant than patient controls, t(33)=2.36, p<.05, d=0.81, whereas no such difference was observed for positive sounds, t(33)=1.72, p=.19, d=0.59 <1, d=0.07, arousal, t(33)<1, d=0.06, or vividness ratings for neutral sounds, t(33)=1.21, p=.24, d=0.41. With respect to the emotional sounds, the ANOVA on the valence ratings revealed a significant main effect of valence category, F=132.53, p<.001, η2=.19, and valence category, F=67.23, p<.001, η2=.67, indicating that highly arousing as well as negative sounds were rated more arousing. Furthermore, similar to the valence ratings, a significant interaction of valence × arousal category was obtained, F=11.51, p<.01, η2=.26. Thus, arousal ratings differed significantly between medium and highly arousing negative sounds, t(34)=6.10, p<.001, d=1.03, whereas no such difference was obtained for positive sounds, t(34)=1.55, p=.26, d=0.26. Finally, a significant group × valence category interaction, F=8.13, p<.01, η2=.20, indicates that differences in arousal ratings between negative and positive sounds varied between groups. However, corresponding post-hoc tests within each valence category did not reveal significant differences between groups.The ANOVA on the arousal ratings of emotional sounds revealed significant main effects of arousal category, F=7.85, p<.01, η2=.22. Across groups, vividness ratings only differed between medium and highly arousing positive sounds, t(34)=4.62, p<.001, d=0.78, but not for negative sounds, t(34)=1.75, p=.18, d=0.30 =9.44, p<.01, ηWith respect to the comparison to IADS norm ratings of neutral sounds, we did not observe significant effects for the intercept or the patient group, neither for valence, nor for arousal ratings. Thus, affective ratings of neutral sounds were very similar to the norm sample and did not differ between patient groups 2=.29, significant main effects of valence category, F=9.33, p<.01, η2=.22, and arousal category, F=4.81, p<.05, η2=.13, as well as a significant interaction of patient group × valence category, F=7.31, p<.05, η2=.18. As can be seen from With respect to differences in valence ratings of emotional sounds, we obtained a significant intercept, F=13.64, p<.001, η2=.17, as well as significant main effects of valence, F=13.41, p<.001, η2=.29, and arousal category, F=4.25, p<.05, η2=.11. Overall, arousal ratings were lower than in the norm sample =6.95, p<.05, ηm sample . Moreove2=.21. DPD patients felt significantly less grounded than patient controls in both conditions, F=32.14, p<.001, η2=.49 =5.61, p<.01, η2=.14, mindful breathing significantly reduced DP intensity in the DPD group, t(20)=2.99, p<.01, d=0.65, but not in patient controls, t(14)<1, d=0.19 =8.85, p<.01, η=.49 see . State d0.19 see . With re2=.20, and the patient group, F=5.22, p<.05, η2=.13. Thus, SCR amplitudes were higher for DPD patients and decreased under mindful breathing in both groups =14.92, p<.001, η2=.30, and arousal category, F=11.19, p<.01, η2=.24. However, these main effects were qualified by significant interactions of group × valence category, F=6.21, p<.05, η2=.15, group × arousal category, F=4.93, p<.05, η2=.12, and arousal × valence category, F=10.02, p<.01, η2=.22. As shown in The ANOVA on the SCR amplitudes for neutral sounds yielded significant main effects of the mindful breathing manipulation, F=8.82, p<.01, ηoups see  and 4. T2=.20, indicating that highly arousing sounds elicited larger SCR amplitudes than medium arousing sounds in the mindful breathing condition, t(36)=3.22, p<.01, d=0.53, whereas no such global effect was observed under normal listening conditions, t(36)<1, d=0.07 =8.95, p<.01, η0.07 see .2=.12, indicating that highly arousing sounds were more likely to elicit a HR deceleration than medium arousing sounds =4.51, p<.05, ηg sounds .Correlation analyses did not reveal significant associations of anxiety or depression scores with electrodermal or heart rate responses, neither in the whole sample nor in the two groups.The main findings were: DPD patients and patient controls, matched for severity of depression and anxiety, showed similar low levels of traumatic childhood experiences and of dissociative amnesia. However, dispositional mindfulness was much lower for DPD patients (d=0.92). DPD patients showed more non-specific skin conductance responses than patient controls, but had similar skin conductance levels, HR and HRV during the rest period. DPD patients rated unpleasant sounds as less unpleasant  as compared to patient controls (d=0.81) and to IADS norm ratings (d=0.83). Comparable differences were also observed when comparing both patient groups to healthy individuals . Despite their neutralizing ratings, DPD patients showed overall stronger electrodermal responses to emotional sounds than patient controls and their SCR amplitudes depended on emotional valence and arousal whereas no such modulation was observed for the control group. These differences were also evident when comparing the response pattern of both patient groups to healthy individuals . Both patient groups experienced an increase of feeling grounded by mindful breathing, but only DPD patients endorsed a significant reduction of DP intensity (d=0.65). Across both groups, mindful breathing enhanced differential electrodermal responses to highly and medium arousing sounds. Neither anxiety nor depression had an effect on autonomic responses, neither in the whole sample, nor in the two groups.Contrary to our expectations and to previous studies ,18, showDid sample differences contribute to the discrepant findings? The psychometric characteristics of our DPD sample match with severe and chronic cases of DPD ,52. TheyConcerning effects of mindful breathing, we showed for the first time that mindful breathing immediately reduced state depersonalization in DPD patients (d=0.65), increased feelings of being grounded and enhanced differential electrodermal responses to highly and medium arousing sounds. We assume that directing the attention to the physical sensations of breathing while listening to the affective sounds, increased the affective-sensory processing of the emotional sounds as reflected in the improved electrodermal modulation of the emotional stimuli. As a result, DPD patients became more grounded by attending to their breathing instead of losing themselves in ruminative self-observation as reflected in a momentary decrease of depersonalization severity. Cognitive-behavioral and psychodynamic conceptualizations consider ruminative and detached self-observation as a core mechanism contributing to the symptom building and maintenance of depersonalization ,53,54. MBy interpreting the results of our study, the following limitations seem crucial: We cannot preclude, that discrepant findings may be due to the different modality of emotional stimulation . However, it has been shown in normative samples that acoustic cues yield similar affective responses as compared to pictures  Mindfulness exercises, which immediately decrease DP intensity, may be helpful by strengthening the modulation of autonomic responses and thus increasing self-awareness. 2) the DPD patient needs special help to increase his conscious awareness for bodily signals, and to recognize and evaluate his affective reactions properly, or to reword Paul Schilder (1939) “to acknowledge himself as a personality” .This study extends evidence that DPD is associated with a specific impairment of emotion processing and thus constitutes a nosological entity in its own right. Further studies are needed to understand the complex interplay of affect, cognition and attention in DPD.Table S1Current mental disorders other than DPD in both groups.(DOC)Click here for additional data file.Figure S1Valence and arousal ratings for neutral and emotional sounds.The left panel shows mean ratings (center of ellipses) and SEM (radii of ellipses) for the current sample. The right panel depicts average differences to the norm ratings (Bradley & Lang 2007). The dots represent mean norm ratings and the crosses depict average ratings of the current sample. Neut = neutral, neg = negative, and pos = positive sounds; -/+ indicate medium and high arousal, respectively.(TIF)Click here for additional data file.Figure S2Physiological responses elicited by neutral and emotional sounds.Skin conductance response (SCR) amplitudes are depicted in the left panel and phasic heart rate (HR) responses in the right panel. Error bars indicate SEM, neut = neutral, neg = negative, and pos = positive sounds; -/+ indicate medium and high arousal, respectively.(TIF)Click here for additional data file.Figure S3Differences in ratings (A) and electrodermal responses (B) between healthy controls, patients controls, and patients with depersonalization disorder (DPD).Error bars indicate SEM, neut = neutral, neg = negative, and pos = positive sounds.(TIF)Click here for additional data file.Text S1Additional information about the psychometric questionnaires.(DOCX)Click here for additional data file.Text S2Evaluation of the selected emotional sounds.(DOC)Click here for additional data file.Text S3Comparison of patient groups to healthy participants.(DOC)Click here for additional data file.


Low back pain is an important public health problem that is associated with poor quality of life and disability. Among the electrophysical treatments, interferential current (IFC) has not been studied in patients with low back pain in a high-quality randomised controlled trial examining not only pain, but pain mechanisms and function.Primary outcome: Pain intensity. Secondary outcomes: The pressure pain threshold, global impression of recovery, disability, function, conditioned pain modulation and temporal summation of pain, discomfort caused by the current. All outcomes will be measured at 4 weeks and 4 months after randomisation. The between-group differences will be calculated by using linear mixed models and Tukey’s post-hoc tests.A three-arm randomised controlled trial with patient and assessor blinded to the group allocation. One hundred fifty patients with chronic, nonspecific low back pain from outpatient physical therapy clinics in Brazil. The patients will be randomly allocated into 3 groups . The interferential current will be applied three days per week (30 minutes per session) over four weeks. The use of a placebo group and double-blinding assessor and patients strengthen this study. The present study is the first to compare different IFC carrier frequencies in patients with chronic low back pain.http://RBR-8n4hg2Brazilian Registry of Clinical Trials:  Low back pain is an important public health issue that directly affects an individual’s quality of life and activities of daily living (ADLs) . Low bacInefficient endogenous pain control and central sensitivity are important characteristics in patients with low back pain . ProlongThe treatment of chronic low back pain aims to reduce pain and disability . ExercisDespite various adjustments to the amplitude-modulated frequency (AMF) often used in clinical practice to treat different injury or disease stages, studies have indicated that AMF does not influence hypoalgesia in healthy individuals ,14, whicThis is a three-arm randomised controlled trial with patient and assessor blinded to the group allocation. Figure Patients seeking physical therapy treatment at the clinic of the Universidade Cidade de São Paulo - UNICID and the Centro de Especialidades Médicas de Guarulhos - CEMEG through medical referral who present nonspecific low back pain for at least 3 months and with a minimum pain intensity of 3 in the 0–10 pain numeric rating scale (NRS-Brazilian-Portuguese version)  during tParticipants will be assessed by the researcher responsible for the assessments during the study to verify that they fit the inclusion criteria. If eligible, they will be informed of the study objectives. They will then sign an informed consent form to participate in the study. The present study was approved by the Research Ethics Committees of Universidade Cidade de São Paulo and Centro de Especialidades Médicas de Guarulhos.Due to the nature of the intervention, only the therapist responsible for application of IFC will be aware about group allocation; the assessor and the participants will be blinded to the group allocation. To keep the evaluator blind to the study groups, the device will be covered with a dark cloth.Each participant will be randomly allocated to one of 3 groups: Group IFC 1 kHz (n = 50), Group IFC 4 kHz (n = 50) and a Placebo IFC Group (n = 50). All participants will receive 30 minutes of current stimulation (the current amplitude will not be increased for the participants in the placebo group) 3 times per week on alternate days for 4 weeks for a total of 12 sessions.The present study will use the Neurovector equipment that produces a medium-frequency alternating current . This equipment was developed exclusively for the present study and is not commercially available. The technique used will involve a bipolar mode with 2 channels located 5 cm from the L3 and L5 spinous processes. The following parameters will be employed: current carrier frequency according to the patient group (1 or 4 kHz); AMF = 100 Hz; Sweep = 50 Hz; 1:1 swing pattern and 30 minutes of stimulation.The procedures for the placebo group will be similar to those of the other groups; however, the current amplitude will not be increased. The patients will be informed that they may or may not feel any sensation at the application site of the electrodes . For thePain intensity after all treatment sessions and 4 months after randomisation.(1) pressure pain threshold; (2) current discomfort; (3) disability; (4) global impression of recovery; (5) functional performance; (6) conditioned pain modulation and pain temporal summation; and (7) analgesic use measured in all time-points.Pain intensity will be assessed using the pain numerical rating scale (NRS) , which aThe pain will be assessed prior to applying the current, at 30 minutes of treatment with the current still on and 20 minutes after the current is turned off. This variable will be measured in all sessions, after treatment and in the follow-up examination after 4 months.th minute of stimulation and 20 minutes after the session has ended. This assessment will be performed in the first and last sessions.The pressure pain threshold (PPT) will be measured using a Somedic digital pressure algometer . Assessments will be performed prior to application of the current, immediately after the 30Hygienisation with soap and water will be performed at the assessed sites. After cleaning the skin, the areas to which the algometer will be attached will be marked with a tape measure and a pen. Two points will be marked bilaterally: the first located 5 cm lateral to the L3 spinous process  and the The assessor will conduct a preliminary study of intra-observer reliability for measuring the pressure pain threshold at the evaluation points that will be used in the study. Ten participants with chronic low back pain will be recruited and assessed on two occasions that are 48 hours apart. The intra-evaluator reliability for the measurement of the PPT will be estimated by calculating the intraclass correlation coefficients  for the tibialis anterior muscle and the low back muscles.2 area) will be positioned perpendicular to the skin and pressed at approximately 50 kPa/s [During the PPT measurements, the circular probe of the algometer  where the far left end indicate “very comfortable” and the far right end indicate “very uncomfortable” . The disDisability will be assessed by the Roland-Morris disability questionnaire, which is widely used to assess the functional performance associated with low back pain . This inThe global impression of recovery will be assessed through the global perceived effect scale ,27, whicFunctional performance will be assessed through a sit-to-stand test. The patients will be instructed to sit and stand 5 times from a chair with a backrest with their arms crossed in front of them as quickly as they can . The tes2. The evaluator will be trained prior to the data collection. The area selected for TS analysis will be the site indicated as the lower pain threshold in the low back algometry in which three stimuli per second will be applied with a pressure of approximately 2 kg/s to determine the best value for use in the TS test. Next, 10 stimuli will be performed using the algometer on the selected region. Each TS stimulus will be maintained for 1 second before being released, and the stimuli will be spaced at 1-second intervals. A timer will be used to ensure that the intervals are respected and that the stimuli are maintained. Participants will be instructed to report pain using the NRS, which will be posted on the wall in front of them, at the first, fifth and tenth stimulus [Temporal summation (TS) will be induced by an analogue pressure algometer  with a circular metal tip measuring 0.79 cmstimulus . The TS A cold pressor test will be used to assess the activation of the conditioned pain modulation (CPM) . The conTo assess the use of analgesics during the treatment, the assessor will complete a record listing the days of the week from the beginning of the treatment until the date of the last session to note the use of analgesics or anti-inflammatory drugs and their dosage during treatment . With thAfter assessment, the patients will be referred to the therapist responsible for the treatment, who will open the sealed envelope prior to initiating the treatment to determine in which group the patient will be included . The randomisation of groups will be performed using a computer-generated, random-number list compiled by an investigator not involved in the patient recruitment or data collection. The group allocation will be concealed by printing the group allocation onto cards and sealing them in consecutively numbered opaque envelopes. The envelopes will be stored in a secure cabinet accessibly only to the allocation investigator and will be opened immediately prior to the intervention allocation.Following the treatment and the follow-up assessments, the therapist will ask the assessor if she believes that the patient received interferential current or the placebo. Additionally, the study participants will answer the same questions justifying their answers. The answers to these questions will be recorded and used to measure the effectiveness of the study blinding .Data will be double-entered and analysis will be performed by a blinded statistician. All statistical procedures will be conducted following the intention-to-treat principles. Initially, the descriptive statistics will be used for the studied variables. The data normalisation will be analysed through a visual inspection of the histograms. The between-group differences in the measurements of the primary and secondary outcomes will be compared via linear mixed models using the interaction terms “group versus time” with a Tukey’s post-hoc test. For the data analysis, the SPSS  version 19.0 for Windows and Microsoft Excel 2007 will be used. All tests will be performed assuming a significance level of p < 0.05.To obtain the total number of participants in the present study, the sample size was calculated to detect a difference of 1 point in the pain intensity outcome as measured by the numerical rating scale (NRS)  with a standard deviation of 1.47 points . A statiThe results of the present study will provide more accurate estimates of the therapeutic effects and parameters of interferential currents. The last systematic review on the subject  suggestsThe strengths of the present study include a high quality design that supports strong clinical evidence. The use of a placebo group enables an analysis of the therapy’s effectiveness and aids in understanding the placebo effect. The study’s blinding assessment indicates the reliability of the assessor and patient blinding. The present study is the first to compare different IFC carrier frequencies in patients suffering from pain and to assess the long-term effects of the treatment.The study’s limitations include the impossibility of completely blinding the therapist due to the nature of the intervention and the lack of a control group (undergoing no treatment) for comparison with the other groups.ADLs: Activities of daily living; TENS: Transcutaneous electrical nerve stimulation; CNS: Central nervous system; IFC: Interferential current; AMF: Amplitude-modulated frequency; NRS: Numeric rating scale; PPT: Pressure pain threshold; ICC: Intraclass correlation coefficients; VAS: Visual analogue scale; TS: Temporal summation; CPM: Conditioned pain modulation.We certify that no party with a direct interest in the results of the research supporting this article has or will confer benefits on us or on any organisation with which we are associated.JBC, REL, LOPC and KAS were responsible for conceiving and designing the study. REL and LPOC are the study coordinators. JBC and NTBO are responsible for data collection. All authors have contributed for writing and approved this manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/195/prepub