Fibromyalgia (FM) is characterized by chronic pain. Impaired growth hormone responses and reduced serum insulin-like growth factor 1 (IGF-1) are common in FM. The aim was to examine changes in serum IGF-1, cerebrospinal fluid (CSF), neuropeptides, and cytokines during aerobic exercise in FM patients.n = 26) or the supervised low-intensity walking (LIW) program (n = 23). Patients participated in blood tests before and after 15 weeks of aerobic exercise. Changes in serum levels of free IGF-1, pain rating on a 0- to 100-mm scale, pain threshold, and 6-minute walk test (6MWT) were examined. CSF, neuropeptides, matrix metalloproteinase 3 (MMP-3), and inflammatory cytokines were determined. Nonparametric tests were used for group comparisons and correlation analyses.In total, 49 patients  with FM were included in the study. They were randomized to either the moderate- to high-intensity Nordic Walking (NW) program (p = 0.033) when compared with LIW. Pain did not significantly change in any of the groups, but tended to decrease (p = 0.052) over time in the total group. A tendency toward a correlation was noted between baseline IGF-1 and a decrease of pain in response to exercise . When adjusted for age, this tendency disappeared. The change in serum free IGF-1 correlated positively with an alteration in CSF substance P (SP) levels , neuropeptide Y (NPY) , and pain threshold . Differing CSF SP levels correlated positively to a change in pain threshold , whereas the shift in CSF MMP-3 inversely correlated with an altered pain threshold .Serum free IGF-1 levels did not change during 15 weeks of exercise between the two groups, although the 6MWT significantly improved in the NW group (The baseline level of serum free IGF-1 did not change during high or low intensity of aerobic exercise. Changes in IGF-1 correlated positively with a variation in CSF SP, NPY, and pain threshold. These data indicate a beneficial role of IGF-1 during exercise in FM.Trial registration: ClinicalTrials.gov NCT00643006. Fibromyalgia (FM) is characterized by chronic pain, tenderness , and enhApproximately one third of FM patients are estimated to suffer from growth hormone (GH) deficiency, with impaired growth hormone responses leading to reduced insulin-like growth factor 1 (IGF-1), a critical mediator of growth hormone -7. A preNerve growth factor (NGF) is increased in cerebrospinal fluid (CSF) in FM patients . NGF supSP is increased in CSF of FM patients -18. CSF Neuropeptide Y (NPY) serum levels are increased in FM patients but not associated with clinical severity ,20. NPY Interleukin-6 (IL-6) is a proinflammatory cytokine and can induce short-term nociceptor hypersensitivity . CSF IL-The aim of the study was to study the effect of 15-week moderate- to high-intensity aerobic exercise on the level of serum bioactive IGF-1 in women with FM. Low-intensity aerobic exercise was used by a control group. Changes in IGF-1, IGFBP3, pain, and CNS markers of inflammation and neuropeptides were studied to get a better insight into the biologic mechanisms involved in pain in FM.n = 26) or a supervised low-intensity walking (LIW) program (n = 23). The supervised exercise programs were conducted twice a week for 40 to 45 minutes for 15 weeks. They participated in a blood test at baseline, after 15 weeks of exercise, and at 30 weeks of follow-up. The effects of Nordic walking on body function were reported previously [Forty-nine patients with FM formed the study population. Patients were randomized either to a moderate- to high-intensity Nordic Walking (NW) program , measured in kilopascals (kPa) . The paiPain was rated on a visual analog scale (0 to 100) of the Fibromyalgia Impact Questionnaire (FIQ)  and reflThe 6-minute walk test (6MWT) reflects physical restriction related to the pain disorder. The patient was instructed to walk as quickly as possible but not to run. The distance covered was measured in meters .n = 49) at baseline and after 15 weeks in the exercise program and at 30 weeks of follow-up (n = 40). Serum samples were acquired by venipuncture of the cubital vein.Serum was collected at rest  at baseline, and 15 patients also participated after 15 weeks of exercise. CSF was collected through lumbar puncture through the L3/L4 interspace. Collected blood and cerebrospinal fluid samples were centrifuged at 800 Biologic markers were analyzed with enzyme-linked immunosorbent assay (ELISA) by using commercially available kits. Assays specific for IL-8 , MMP-3 , serum free bioactive IGF-1 , and IGFBP3  were purchased from R and D Systems . An assay specific for human IL-6  was purchased from Sanquin Reagents . Assays specific for SP  and NPY  were purchased from Phoenix Pharmaceuticals . The human NGF-specific assay was purchased from Promega . All assays were run according to recommendations of the manufacturers. Ordinary colorimetric ELISA was read with a Spectramax 340 from Molecular Devices , and fluorescent ELISA assays were read with a Mithras LB940 from Berthold Technologies .The study was approved by the ethics committee of Sahlgrenska University Hospital (220-09). Written and verbal information was given to all patients, and written consent was obtained from all patients.NCT00643006.ClinicalTrials.gov U test and Kruskal-Wallis test were used to analyze the differences in continuous variables between the groups. The mean of baseline and posttest values was calculated for each individual, and these means were used in group comparisons. The Wilcoxon signed-rank test was used for comparisons of continuous variables within groups. Relations between the variables were examined with the Spearman correlation coefficient. Partial correlational analyses were performed to adjust for baseline pain and age. To control for possible Type I errors, the upper limit of number of false significances was calculated by the following formula: (number of tests - number of significant tests on the level of α) × α/(1-α). All significant tests were two-tailed, and values of p < 0.05 were considered significant. All statistical evaluation of data was done by using the statistic program SPSS Statistics v. 19.Descriptive data are presented as median, interquartile range, the number, and percentage. The Mann-Whitney P = 0.033) in the NW group  when compared with the LIW . Changes in pain levels and pain threshold did not differ significantly between groups , Table P = 0.040), whereas the decrease of pain was not , Table When calculated for the total group after 15 weeks of exercise, 6MWT was significantly improved . Change in 6MWT (Δ6MWT) was correlated with changes in pain thresholds (ΔPT) after 15 weeks  and after 30 weeks .A significant association was found between 6MWT and the pain threshold at baseline (P = 0.795) or the IGFBP-3 (P = 0.906) occurring during the 15-week low-intensity and high-intensity aerobic exercise, respectively.No significant between-group differences were found for changes in IGF-1 (P = 0.300), but it decreased at 30-week follow-up (P = 0.019). IGFBP-3 did not significantly change during the 15-weeks (p = 0.977) or during the 30 weeks (P = 0.426).In the NW group, IGF-1 did not significantly change during the 15-week exercise (P = 0.148), but it tended to decrease during the 30 weeks (P = 0.109). IGFBP-3 did not signficantly change during the 15 weeks (P = 0.881) or 30 weeks (P = 0.796).In the LIW group, IGF-1 did not significantly change during the 15 weeks . To evaluate the relation of basal IGF to the change in pain, we did a partial correlation between baseline IGF and final pain and adjusted for baseline pain. We found a tendency to positive correlation . However, this positive tendency disappeared when age was accounted for .Basal IGF-1 did not correlate with baseline pain , and the correlation reached a significant level at 30-week follow-up . No significant correlations were found between ΔIGF-1 and change in rating of pain (Δpain) when analyzed for the total group.Change in IGF-1 levels (ΔIGF) was associated with ΔPT at 15 weeks (n = 26). Their median age was 51 (46 to 55) years. At baseline, the number of tender points was 14.5 (12 to 16), pain threshold was 207 (161 to 258) kPa, pain level was 70 (44 to 83), and IGF-1 was 4.5 (2.2 to 9.3) ng/ml, implying that they did not significantly differ from the total sample.A smaller group within the study population agreed to participate in the examination of cerebrospinal fluid at the start of the exercise period  years. At baseline, tender points for these 15 individuals was 15.0 (12 to 18), the pain threshold was 207 (177 to 255) kPa, the pain level was 70 (51 to 82), and IGF-1 was 4.2 (2.2 to 9.2) ng/ml, implying that they did not significantly differ from the total sample.rs = 0.802; P = 0.001). The correlation between IGF-1 and ΔCSF SP tended to be significant , Table Changes in serum IGF-1 levels correlated positively with ΔCSF NPY , and inversely with ΔCSF MMP-3 , Table Changes in pain threshold (ΔPT) were associated with ΔCSF SP  and CSF MMP3 . Furthermore, baseline CSF IL-6 was inversely correlated with CSF NGF  and CSF NPY .Baseline CSF IL-6 was positively correlated with CSF SP  and an active control group engaging in low-intensity walking (LIW). Lack of changes in IGF-1 levels is in line with a previous study reporting failure to show increase in IGF-1 in patients with FM . In an eA tendency to correlation was noted between baseline IGF-1 and the decrease of pain in response to exercise. However, this positive tendency disappeared when age was accounted for, and population studies show that IGF-1 levels correlate inversely with age . It mighThe pain threshold was found to decrease in our study population during the 15 weeks of exercise. This implies that the patients exercised at a level that activated their peripheral pain receptors , both inPrevious studies have shown that SP is increased in cerebrospinal fluid (CSF) of patients with FM -18. CSF We studied MMP3 in CSF for its potential role in structural reorganization and inflammation and found that change in CSF MMP-3 correlated negatively with change in pain threshold, which supports the notion that MMP3 is modulated during exercise ,51. The Levels of free IGF-1 and IGFB3 in serum did not change during 15 weeks of aerobic exercise in patients with FM. Baseline IGF-1 was associated with a decrease of pain in response to exercise, but the tendency disappeared when adjusted for age.Changes in levels of IGF-1 correlated positively with changes in SP and NPY in CSF and with changes in pain threshold. It appears that higher level of IGF-1 indicates less pain during exercise in FM, which must be further studied.CSF: cerebrospinal fluid; FIQ: Fibromyalgia Impact Questionnaire; FM: fibromyalgia syndrome; IGF-1: insulin-like growth factor-1; IGFBP3: insulin-like growth factor-binding protein-3; IL-6: interleukin-6; IL-8: interleukin-8; MMP-3: matrix metalloproteinase 3; NGF: nerve growth factor; NPY: neuropeptide Y; PT: pain threshold; 6MWT: Six-minute Walk Test; SP: substance P.The authors declare that they have no competing interests.JB participated in study design, acquisition, analysis, and interpretation of data; MD, in acquisition, analysis, and interpretation of data; ME, in acquisition, analysis, and interpretation of data; MBo, in acquisition, analysis. and interpretation of data. KM worked with study conception, study design, acquisition, analysis, and interpretation of data. All the authors were involved in the drafting of the article and revising it critically for important intellectual content. All the authors approved the final version of the article.


One hundred and twenty-eight gastric cancer patients scheduled to undergo radical gastrectomy under general anesthesia were enrolled in the study. Post-operative, patient-controlled intravenous analgesia of fentanyl was provided for satisfactory analgesia until 48 h after surgery. OPRM1 A118G was screened by DNA sequence analysis of polymerase chain reaction (PCR)-amplified DNA. Differences in fentanyl consumption and adverse effects were compared among the different genotypes at 24 and 48 h after surgery. The ranges of fentanyl dose in the 128 patients at 24 and 48 h after surgery were 5.4–17.3 μg/kg and 12.4–29.9 μg/kg, respectively. Among these patients, there were 54 wild-type homozygotes (AA), 53 heterozygotes (AG) and 21 mutant homozygotes (GG). The frequency of the G allele was 0.371 in the OPRM1 polymorphism. There were no significant differences in fentanyl dose or adverse effects, including nausea, vomiting and dizziness, for the OPRM1 A118G polymorphism (P>0.05). The OPRM1 A118G polymorphism does not play a significant role in post-operative fentanyl analgesic dose or post-operative nausea, vomiting and dizziness in patients undergoing radical gastrectomy.The aim of this study was to investigate the effect of the  Opioids, including morphine and fentanyl, have been widely used in clinical anesthesia and pain treatment for a number of years. However, the analgesic efficacy of opioids varies widely among individuals . Althougμ-opioid receptor protein, which is the main target of the analgesic, fentanyl. Numerous single nucleotide polymorphisms (SNPs) have been identified in the OPRM1 gene [http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=4988]. The OPRM1 A118G mutation is the most common functional variation at position 118 in exon 1. This mutation leads to the conversion of the amino acid asparagine to aspartate at position 40 (N40D) on the extracellular N-terminal domain, which affects a putative glycosylation site of the receptor (The human mu-opioid receptor gene (OPRM1) encodes the receptor . Resultsreceptor –10.Fentanyl is one of the most commonly used opioid analgesics in acute and chronic pain therapy; however, there are few relevant published studies on its use. Several authors identified that subjects with the G allele of the OPRM1 A118G SNP were less sensitive to fentanyl or the fentanyl dose was greater compared to subjects with the AA allele, with regard to post-operative pain management or labor analgesia . HoweverPatients with acute post-operative pain following standardized surgical procedures may be optimal subjects for investigating such associations . DerivinThis study was approved by the Institutional Ethics Committee of the Third Xiangya Hospital of Central South University, China. Signed, informed consent was obtained from all patients. From May 2008 to March 2010, patients classified as American Society of Anesthesiologists (ASA) physical status I-III, aged 20–75 years and undergoing radical gastrectomy were recruited into this study. Liver and renal functions of all patients were normal. Patients had no history of chronic pain, no long-term application of analgesics or cortisol-type drugs, no history of alcohol or drug abuse and no history of allergy to fentanyl. Exclusion criteria were a history of significant cardiovascular disease, diabetes mellitus or psychiatric disorders.Each patient received an evaluation by two psychiatrists of pre-operative anxiety and depression, as measured by the State-Trait Anxiety Inventory (STAI) and self-rating depression scale (SDS) on the night before surgery. STAI is a 40-item self-report measure of enduring (trait) and transient (state) anxiety symptoms . SDS is μg/kg fentanyl and 0.12 mg/kg vecuronium. Following intubation of the trachea, the patients’ lungs were mechanically ventilated to maintain the end-tidal carbon dioxide partial pressure at 35–45 mmHg. Propofol and remifentanil were infused through micropumps and sevoflurane was inhaled for maintenance of anesthesia. Drug doses were adjusted according to changes in the auditory evoked potential and hemodynamics. An intermittent dose of vecuronium (0.03–0.06 mg/kg) was administered to maintain adequate surgical muscle relaxation. During surgery, the fentanyl infusion was discontinued once the surgeons had opened the abdominal cavity and the total dose of fentanyl was maintained at <12 μg/kg to avoid residual effects of post-operative fentanyl dose. Electrocardiogram, noninvasive measurement of blood pressure, pulse oximetry and arterial blood gas measurements were monitored.No pre-medication was used. All patients received general anesthesia, which was induced with 0.05 mg/kg midazolam, 0.2 mg/kg etomidate, 5 μg bolus of fentanyl until a visual analog score  <30 was attained. If they felt no pain, patient-controlled intravenous (i.v.) analgesia (PCIA) commenced if the patients perceived slight pain . Patients were excluded if they received an opioid receptor antagonist. The electronic PCIA pump was filled with 30 μg/kg fentanyl in 0.9% normal saline diluted to 240 ml. It was programmed to administer 1.5 ml/h background infusion with a 20 μg bolus of fentanyl solution, with a 5 min lockout time. PCIA was continued for 48 h after surgery. Post-operative pain was controlled so that VAS was <30 at rest. When patients felt VAS >30 despite being on the PCIA pump, patients were able to increase the dose of fentanyl by pushing the bolus button. No rescue drugs other than i.v. fentanyl were used within the 48 h post-operative period. The total number of fentanyl boluses required during the PCIA coverage was also recorded. Due to the high incidence of nausea and vomiting, all patients received 8 mg ondansetron intravenously to prevent nausea and/or vomiting following surgery. Post-operative blood pressure, heart rate, pulse oxygen saturation and VAS were documented at 2, 6, 12, 24 and 48 h after surgery. The total amount of PCIA fentanyl was recorded at 24 and 48 h after surgery. Adverse effects associated with fentanyl administration, including nausea, vomiting and dizziness were assessed as events for the first post-operative 48 h.Following surgery, all patients were sent to the post-anesthesia care unit (PACU). Once the trachea was extubated, the nurses in the PACU assessed pain severity. If the patients felt severe pain, they were intravenously injected with a 20 Peripheral venous blood (2 ml) from each patient was placed in an ethylenediamine tetraacetic acid (EDTA) tube. DNA was extracted from leukocytes using a standard phenol-chloroform procedure and was stored at 4–8°C. OPRM1 A118G genotyping was performed by DNA sequence analysis of polymerase chain reaction (PCR)-amplified DNA. Primers were designed by the primer design software Oligo 6.0 to cover the polymorphic site. OPRM1 A118G was amplified by PCR with the following primers: forward, GAAAAGTCTCGGTGCTCCTG and reverse, GGAGTAGAGGGCCATGATCG. The DNA sequence of the fragment was determined using an automated sequencer .The investigator conducting the clinical study and the laboratory personnel responsible for geno-typing were blinded to the clinical outcomes of the patients. Statistical analysis was performed using the SPSS v.18.0 software package . P<0.05 was considered to indicate a statistically significant difference. Demographic and clinical data were presented as means ± standard deviation (SD), median and interquartile range or counts, as appropriate. The Chi-square test was used to detect Hardy-Weinberg equilibrium. According to the types of data, t-test, Fisher’s exact t-test or Mann-Whitney U test were used to evaluate whether the clinical parameters, including age, gender, body weight, height, duration of surgery and length of incision, exhibited significant differences among the different genotypes. In the present study, postoperative fentanyl doses at 24 and 48 h were not normally distributed. Therefore, nonparametric analyses, including the Mann-Whitney U test and Kruskal Wallis test were used to detect the effect of genotype on PCIA fentanyl consumption. The incidence of any adverse effects was analyzed using the Chi-square or Fisher’s exact t-test.A total of 158 patients were enrolled in this study. Of these patients, 30 were not included in the study due to no available blood sample (n=6), genotype, analgesic pump failure (n=6), changes in condition (n=5), severe dizziness or vomiting (n=3), or withdrawal from the study (n=10). In the end, 128 patients completed the study. All patients were from a Han Chinese population. The clinical data of patients are summarized in Among the 128 patients, there were 54 wild-type homozygotes (AA), 53 heterozygotes (AG) and 21 mutant homozygotes (GG). The frequency of the G allele was 0.371 for the OPRM1 polymorphism. The allele frequency was in Hardy-Weinberg equilibrium P>0.05; .μg/kg and 12.4–29.9 μg/kg at 24 and 48 h after surgery, respectively. There were no clear correlations of fentanyl analgesic dose at 24 and 48 h after surgery among the genotype groups of OPRM1 A118G . This gave all patients a true baseline pain intensity at the start of the observation period and the same endpoint (VAS=10–30). Doses of fentanyl administered post-operatively were also normalized to body weight. As described above, a number of factors affect post-operative fentanyl dose, so our intent was to be as consistent as possible across patients. When we ruled out interference from these confounding factors, we studied the association between the OPRM1 A118G polymorphism and post-operative dose of fentanyl in Han Chinese patients undergoing radical gastrectomy.In this study, the ranges of fentanyl dose among 128 patients were 5.4–17.3 and 12.4–29.9 et al  and 21.1% 27/128), respectively, for all the patients, which were much higher than the previously reported range of 5.6–28.5% ,25,26. Pl , similar to the report by Lin , similarIn the present study, we controlled a number of confounding factors, including biological and psychological variation, and analgesia management had the same start- and endpoint with intravenous fentanyl, which reflects the real gene-dose association. However, our sample size may be inadequate to make comments on negative genetic effects on fentanyl dose and side-effects. Additionally, we studied only one polymorphism of the OPRM1 gene and other genetic variations in OPRM1 and other candidate genes may also play a role in the response to opioids. Moreover, the mixed-gender study population may have increased variability in post-operative fentanyl requirement, although there was no statistical difference in gender between the different genotypes.Multiple, complex biological systems are involved in opioid pharmacology and pain processing. Age, gender, body weight, psychological state, disease conditions, tolerance to side-effects, genetic variation, race and ethnicity cause different opioid requirements for patients. For different drugs, there are various routes of administration, potential interference from drug interactions and different pharmacokinetics and pharmacodynamics. The differences in the nature and intensity of nociceptive stimuli, including labor pain, acute post-operative pain and chronic pain, as well as the modalities used to describe pain perception and analgesic responses, may also contribute to inconsistent findings. In addition, although a number of functional analyses of the A118G SNP have been performed, the results of these studies are also controversial in animal and clinical studies. Therefore, further studies are required to clarify the association between the A118G SNP and treatment efficacy or side-effects of fentanyl with sufficient samples for each effect size in different races and ethnicities.In conclusion, our study suggests that the OPRM1 A118G polymorphism does not play a significant role in either post-operative fentanyl analgesic dose or the incidence of postoperative side-effects in Han Chinese patients undergoing radical gastrectomy.


Neck pain is a common problem that can greatly affect a person's activities of daily living. Functional status questionnaires are important in assessing this effect, and are used to follow up neck pain management programs. The Neck Disability Index (NDI) is the first-created scale for neck pain-related disability and is widely translated and in common used in many countries. Our aim is investigate to clinometric properties of a Turkish version of modified NDI and to give a choice in daily practise of versions to be used.The modified NDI was applied to 30 patients for reliability. 185 patients participated in the validity study. All patients were recruited from the outpatient clinic of our department. The scale was translated by the forward and backward translation procedure according to the COSMIN criteria. The test was repeated at 48 hours interval for reliability study. SPSS-10.0, software was used for statistical analyses. The Intraclass correlation coefficient was used for the test- retest reliability of the modified NDI. Cronbach α was used for internal consistency. Factor analysis was used for construct validity. The validity of the modified NDI with respect to the SF-36, HAD, VAS pain, VAS disability was assessed using Spearman correlations.The Intraclass correlation coefficient between first and second (within 48 hours) evaluation of test (rs) was 0.92. Questions 1,4,6,8,10 were shown to have excellent reliability. (rs > 0.9). Question 10 was the most frequently challenged question because "recreational and social activities" do not have not the same meanings in Turkey than in western countries. This required that detailed explanations be provided by the investigators. Cronbach's alpha for the total index was 0.88. A single factor accounting for 80.2% of the variance was obtained. Validity studies demonstrated good and moderate correlations (rs) among NDI, HAD, VAS, physical function subtitle of SF 36 .The modified NDI-Turkish version is a reliable and valid test and is suitable for daily practise. Neck pain is a common condition -8. It beVarious scales have been developed for the evaluation self-rated disability in neck pain patients. The Neck Disability Index (NDI)  is the fThe aim of the present study was to investigate the clinimetric properties of a Turkish translation of a modified NDI in order to evaluate self-rated disability in patients with neck pain.The study was planned in three stages. The first stage consisted of the translation and cultural adaptation, including modification, of the original NDI. The second stage consisted of determining the reliability and internal consistency; in the third stage, the concurrent validity of the Turkish modified NDI was studied. This study was conducted without any knowledge of the work of Aslan et al.  which maBefore starting the study, permission for translation of the test into Turkish was obtained from Dr. Howard Vernon on October 01, 2004. The translation of NDI was performed using back-forward method  and confThe instrument was first translated into Turkish by two native Turkish speaker translators who were blinded to each other. The translation was examined by the study team (three professors whose main field of interest was lower back and neck pain). The instrument was then translated into Turkish again by a native English- speaking translator. The equivalence between Turkish translations and the original English version of the text was then reviewed by the study team. Problems in practice were determined in a small sample of 10 persons. Modifications were then made according to the findings of this group .The NDI validity and reliability studies were performed between August 2005-July 2007 on patients with neck pain consecutively presenting in the Physical Medicine and Rehabilitation Clinic of the Istanbul University, Istanbul Faculty of Medicine. The inclusion criteria included:, males and females who were between 18-65 years old, suffering from neck pain alone or from neck pain radiating to arm, with the duration of pain of over 3 weeks, able to read and sign Turkish. Standard clinical, radiological and laboratory tests were applied for diagnosis. Exclusion criteria comprised the inflammatory conditions, malignancy, neck pain due to myopathy, trauma on the neck, prior neck surgery, serious psychiatric disorder and congenital anomalies.SPSS 10.0 package software was used for statistical analysis. Demographic data  of all patients were recorded (Table t-test. Intra-class correlation coefficient (ICC) was evaluated using one-sided random effects model . Test-Retest: in ICC evaluation, values < 0.4 are considered poor, 0.4-0.75 moderate, 0.75-0.9 good and > 0.9 excellent [Thirty (30) patients of the total sample described below, who presented with neck pain in Physical Medicine and Rehabilitation Clinic of the Istanbul Faculty of Medicine Hospital between August 2005 - July 2007 and who met study criteria, were selected according to random numbers obtained using Quick Calc-(GraphPad Software) . The finxcellent . Cronbacxcellent .Factor analysis was performed on the results from all subjects with use of principal component analysis to extract factors. The retained factors in each scale had eigenvalues > 1. Independent factors were obtained by use of the Varimax rotation method .In 185 patients who met the inclusion criteria, VAS-pain  VAS-disaNeck Disability Index (NDI), has a total of 10 sections. Each section has six possible answers. Each item is scored from 0 (no disability) to 5 (complete disability). The total score ranges from 0 (no disability) to 50 , or, in percentage terms, between 0 and 100. Disability increases with increasing score. Items of the scale are: 'intensity of pain', 'personal care', 'lifting', 'reading', 'headaches', 'concentration', 'work', 'driving', 'sleeping' and 'recreation' ,17.This scale was used to evaluate subjective pain intensity. Studies have shown that VAS is a reliable and valuable method. The most important limitation of this method is its focusing to a greater extent on the pain severity, and remaining inadequate in evaluating the affective aspect of pain .Hospital Anxiety and Depression Scale (HAD) is a self-evaluating scale used to determine a patient's risk with respect to anxiety and depression, and to assess the level and change in its severity. It contains total of 14 questions, and seven of these assess anxiety while the other seven measure depression ,38.Short Form-36 (SF-36) is a scale for quality of life with generic measurement qualities that provides a comprehensive assessment. The scale is comprised of 36 items which provide measurement of 8 domains: Physical functioning (10 items), social functioning (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), mental health (5 items), energy/vitality (4 items), pain (2 items), general perception of health (5 items). Subscales assess health according to scores ranging from 0-100.0 indicates the worst health status; 100 defines the best health status ,40.We predicted that the test-re-test and internal consistency coefficients would exceed 0.80. We predicted that there would be a 1-factor structure to the Turkish NDI. We predicted that the correlations between the Turkish-NDI and the pain VAS, HAD and SF-36 mental and physical scales would be moderately large (above 0.50).The study was approved by the Ethics Committee of the Istanbul University of Istanbul Medical Faculty (numbered 270/04).In the translation-pilot study, in the first item on "pain intensity" a modification was made as to "your neck pain". In the third item, 'lifting', a statement of "having weight equal to that you lift when you don't have neck pain" was added for the purpose of providing clarification regarding lifting heavy loads. In item seven, 'work', a statement of "Please check the option G if you are not employed," was added to make it clear that it was the work-life that was evaluated.In the pilot study, the most frequently asked question by participants was associated with item 10. Since "recreation" was better understood as "leisure time activities", it was modified in this way. In the pilot study, there were 9 persons who were non-drivers, and problems arose in answering item 8. Furthermore, to a lesser extent, since there were participants who were non-workers and who did not perform leisure time activities, the option of "never done" was added to sections 7, 8 and 10. The Turkish version of the modified NDI was also used in validity study and, 120 participants (64%) scored item 8 as "never done".In general, patient comments were that the questions were clear. The time for completing the Turkish version of modified NDI was 5.5 minutes. When there were questions that were not understood, explanation was provided by the observer.t test (p > 0.05).Table There were no missing data in NDI. There were very few missing data but no more than 1 item was left unscored in HAD. Percentage of missing data for item 9 in HAD was 1.5%. Percentage of missing item was 0.1% for HAD. That was not remarkable.t test (p > 0.05). Internal consistency was found as Cronbach's α: 0.88. Questions 1,4,6,8,10 were shown to have excellent reliability (r's > 0.9). Question 10 was the most frequently challenged question because "recreational and social activities" do not have not the same meanings in Turkey than in western countries. This required that detailed explanations be provided by the investigators.ICC ranged between 0.87-1.0 for all domains Table . The TurOne factor was extracted in exploratory factor analyses, which accounted for 80.2% of the total variance.A total of 185 patients participated in this study. Except for 'physical role' sub-scoreof the SF 36, significant correlations were found between the Turkish version of the modified NDI and VAS pain (r = 0.6), VAS disability (r = 0.76), HAD depression (r = 0.62), and HAD anxiety (r = 0.58). For the SF-36, there were weak correlations with emotional role and pain, while the strongest correlation (r = 0.68) was with SF-36 physical domain.  approach  was not An additional limitation was the lack of assessment of measurement error and responsiveness. We intend to pursue this is a separate study involving a treatment phase.The modified NDI-Turkish version has been found to be a reliable and valid test and is suitable for daily practise for characterizing concurrent disability. Its use in determining clinical response has not yet been determined.The authors declare that they have no competing interests.All authors read and appoved the final manuscript. NK participated in study design, pretesting, carried out data entry and interpretation of data and wrote the final draft of the manuscript.EO participated design of the study and translation process. HV provided appraisal and made suggestions during all stages of translation process and participated desingn of study and revised the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/25/prepubAppendix S1. Turkish version of modified Neck Disability Index.Click here for file


Chronic localized pain syndromes, especially chronic low back pain (CLBP), are common reasons for consultation in general practice. In some cases chronic localized pain syndromes can appear in combination with chronic widespread pain (CWP). Numerous studies have shown a strong association between CWP and several physical and psychological factors. These studies are population-based cross-sectional and do not allow for assessing chronology. There are very few prospective studies that explore the predictors for the onset of CWP, where the main focus is identifying risk factors for the CWP incidence. Until now there have been no studies focusing on preventive factors keeping patients from developing CWP.Our aim is to perform a cross sectional study on the epidemiology of CLBP and CWP in general practice and to look for distinctive features regarding resources like resilience, self-efficacy and coping strategies. A subsequent cohort study is designed to identify the risk and protective factors of pain generalization (development of CWP) in primary care for CLBP patients.Fifty-nine general practitioners recruit consecutively, during a 5 month period, all patients who are consulting their family doctor because of chronic low back pain (where the pain is lasted for 3 months). Patients are asked to fill out a questionnaire on pain anamnesis, pain-perception, co-morbidities, therapy course, medication, socio demographic data and psychosomatic symptoms. We assess resilience, coping resources, stress management and self-efficacy as potential protective factors for pain generalization. Furthermore, we raise risk factors for pain generalization like anxiety, depression, trauma and critical life events. During a twelve months follow up period a cohort of CLBP patients without CWP will be screened on a regular basis (3 monthly) for pain generalization (outcome: incident CWP).This cohort study will be the largest study which prospectively analyzes predictors for transition from CLBP to CWP in primary care setting. In contrast to the typically researched risk factors, which increase the probability of pain generalization, this study also focus intensively on protective factors, which decrease the probability of pain generalization.German Clinical Trial Register DRKS00003123 Chronic localized pain syndromes, especially chronic low back pain (CLBP), are common reasons for consultation in general practice. CLBP is usually defined as pain, on most days of a three months period, in the back area from underneath the costal margin to the gluteal fold . In someThe association of CWP and several physical and psychological factors are well-documented. Studies show high prevalence of comorbidities  . Our aiGeneral practitioners (GP) are often the main coordinators of CLBP and CWP patients’ management. They provide longitudinal continuity of care and play a major role with respect to appropriate care and health service utilisation . TherefoThe aim of our study is to provide prevalence data on CLBP and CWP for the primary care setting. The differences between both pain localizations, with respect to pain characterisation and comorbidities, will be determined. In addition, we search for risk factors and protective factors of pain generalization in primary care CLBP patients.A 12 month cohort study is performed with baseline data collection (T0) and four follow ups .This project is part of the research Consortium LOGIN “Localized and Generalized Muskuloskeletal Pain: Psychobiological Mechanisms and Implications for Treatment“ funded by the German Federal Ministry of Education and Research.For a multi centre data collection, general practitioners in the State of Hessen, Germany are approached. Due to logistical reasons, recruitment is conducted in four waves. Participating practices (doctors and assistant personnel) are asked to recruit all eligible patients who consult for CLBP during a 5 months period, including patients consulting in home visits and emergency calls. Detailed inclusion and exclusion criteria are shown in Table The number of patients, who deny participation is documented along with the reasons (in an anonymized way), and these patients are accounted for our prevalence analyzes.A pen and paper questionnaire is used for data collection. After written consent is obtained, patients are asked to fill in the first questionnaire. In addition, general practitioners complete a case report form for every participant. CLBP patients, having no CWP at baseline, are included in the cohort study with a 12 months follow up. They receive mailed follow up questionnaires every three months (T1-T4), and if necessary, followed by two telephone reminders. In cases where participants are unreachable, we do ten calling attempts, during different day times before aborting the reminding process. Participants, who do not return questionnaire and do not explicitly refuse future participation, will be sent the next questionnaire as scheduled.For investigating distinctive features (e.g. pain characteristics) between CLBP patients and CWP patients as well as potential risk and protective factors, the following physical and psychological parameters are collected at baseline Table :body pain drawing model from Pfau et al. [For pain localisations and consequently for definition of CLBP and CWP we chose the u et al. , where wu et al. . To allou et al.  and Harku et al. .“German Pain Questionnaire” to determine the characteristics and history of the pain [German Association for the Study of Pain. The questions cover the following aspects: socio demographic data, subjective pain description and perception, factors of pain alleviation and exacerbation, disturbance as a result of pain, subjective pain model, screening for depression and anxiety disorders, health care utilization, as well as medical and psychological comorbidities. Nagel et al. tested the feasibility and content validity in a sample of 3000 patients [We used the the pain . It is tpatients . Comparipatients . For thiWest Haven-Yale Multidimensional Pain Inventory” [To assess the partner’s reaction in response to patient’s pain, we use the social support subscale (3 items) of the “ventory” ,26. It iThe reliability test of the German version (MPI-D) from Flor et al. showed moderate to high internal consistency of the different subscales (α = 0.63-0.90) . For valGraded Chronic Pain” questionnaire (GCP) according to von Korff [To classify subjective severity of chronic pain we use the “on Korff . The selon Korff . This ison Korff , the Geron Korff . There ion Korff .Self Administered Comorbidity Questionnaire” (SACQ) [Comorbidities are assessed by the “” (SACQ) ,30. Part” (SACQ) . Regardi” (SACQ) .Symptom Check-List-90-R” (SCL-90-R) [To identify psychosomatic symptoms, we use the somatization subscale of the “CL-90-R) . It is aCL-90-R) .Hospital Anxiety and Depression Scale” (HADS) [The “” (HADS) ,34 screeFragebogen zu Bewältigungsressourcen bei Rückenschmerzen” from Tamcam et al. to assess coping resources for back pain [We use the FBR-questionnaire “ack pain . It was ack pain . Items aResilience as a potential protective factor towards pain generalisation is estimated using the resilience scale RS-11, a shortened and validated German form of the Wagnild & Young questionnaire [ionnaire ,37. It mCLBP patients, having CWP at baseline, get supplementary concluding measurement instruments , like the cohort group gets during follow ups. Taking into account the length of the questionnaires they are assessed after 3 months. An extensive description of the measurement instruments and our motivation for using it is described in the next chapter.body pain drawing model (T0-T4).To identify incidental CWP (primary outcome), we collected data every three months to screen for pain generalization using the In addition the following physical and psychological parameters are collected at follow up Table :Schmerzempfindungsskala” (SES) during the first follow up [We assess pain perception with the “ollow up . The queollow up .health care utilization and medication during the preceding half year are assessed after the 6th and 12th month (T2 and T4).Just like at baseline, During the 12 months follow up the following data will be collected:Brief COPE from Carver et al. [To assess stress management competence (coping), we use the r et al. ,40). It r et al. . Regressr et al. .general self-efficacy-questionnaire” (GSE) to assess self-efficacy [We use the “efficacy ,43. It aWe use Part 1 of the “Posttraumatic Diagnostic Scale” (PTDS)  to assescritical life events questionnaire from the work of Leist et al. are used [The are used . ParticiWest Haven-Yale Multidimensional Pain Inventory” [Finally, during the fourth follow up measurement point (T4) participants are asked to complete the “ventory” ,26. Thisventory” .GPs are asked to comment on the individual presence of red flags with every patient included in the study. Red flags are frequently used risk factors for identifying serious disorders causing low back pain . In addiBased on the results of the cohort study a qualitative sub-study will be performed, after completed follow up, regarding patients’ and physicians’ perspectives of a resource based treatment approach for prevention and therapy of CLBP and CWP.t-test is applied for comparing means. Effect sizes will be expressed in terms of odds ratios for categorical dependent variables and, for quantitative dependent variables, in terms of group differences or differences per unit change of a quantitative predictor variable.Group comparisons of CWP and CLBP patients will be performed. For this we use measures of central tendency  as well as chi-square tests for categorical data. The For identification of predictors logistic regression analysis will be performed using incidental CWP as dependent variable. We use baseline risk and protective factors as independent variables or predictors. All analyses are supervised and advised by a senior statistician of the Institute of Genetic Epidemiology (IGE), University of Munich and Helmholtz Zentrum München.Focus groups: The results of the focus groups are analyzed according to predefined main topics. Answers of patients and physicians are contrasted.Based on results from previous studies we presumed a CWP prevalence of 10%  leading Assumptions: Prevalence of generalized chronic back pain of 10%. A change of an independent variable by one standard deviation in the population implies an odds ratio of 1.65. Calculated power: 0.83 for alpha = 0.005, which means after adjustment of multiple testing of 9–10 variables an overall probability of the type one error of 0.05 will not be exceeded. The power has been calculated by performing simulations using the software R (R Development Core Team 2010).The study was approved by the local ethics commission of Philipps-University Marburg  and is in accordance with the Declaration of Helsinki.This cohort study will be the largest study which prospectively analyzes predictors for transition from CLBP to CWP in primary care setting. In contrast to the typically researched risk factors, which increase the probability of pain generalization, this study also focus intensively on protective factors, which decrease the probability of pain generalization. The identified risk and protective factors might aloud GPs to identify patients at risk for development of CWP. Furthermore, the acquired knowledge about protective factors will help us to develop an individualized treatment approach for GPs.Selection bias is often the major limitation of a cohort study. The amount of psychological constructs measured in this study can be rather demanding in terms of endurance and intellectual abilities compared to usual studies in primary care setting. For our primary care study population, which includes a high proportion of older people and persons with lower educational background, it may be a problem to deal with the questionnaires. These patients might be more likely to deny participation or abort follow up.It might be possible, that GPs are more likely to remember study recruitment, in special cases  or during times with a lower workload. An incomplete recruitment brings forth the risk of selection bias and lowers external validity.Results of the baseline analysis are expected in the course of this year (2012). Follow up data will be completed, next year (2013).CLBP: Chronic low back pain; CWP: Chronic widespread pain; GP: General practitioner; MPI: West Haven-Yale Multidimensional Pain Inventory; MPI-D: German version of the West Haven-Yale Multidimensional Pain Inventory; GCP: Graded Chronic Pain; SACQ: Self Administered Comorbidity Questionnaire; SCL-90-R: Symptom Check-List-90-R; HADS: Hospital Anxiety and Depression Scale; FBR: Fragebogen zu Bewältigungsressourcen bei Rückenschmerzen (questionnaire for assessing coping resources for back pain); RS: Resilience; SES: Pain perception scale; COPE: Measurement instrument for coping; GSE: General self-efficacy-questionnaire; PTDS: Posttraumatic Diagnostic Scale.Annika Viniol does not state any financial or non-financial conflicts of interest.Nikita Jegan does not state any financial or non-financial conflicts of interest.Konstantin Strauch does not state any financial or non-financial conflicts of interest.Markus Brugger does not state any financial or non-financial conflicts of interest.Jürgen Barth does not state any financial or non-financial conflicts of interest.Erika Baum does not state any financial or non-financial conflicts of interest.Corinna Leonhardt does not state any financial or non-financial conflicts of interest.Annette Becker was a consultant for Grünenthal GmbH, from whom she has also received a speaker’s fee.Annika Viniol collected and analyzed data and wrote the manuscript. Nikita Jegan collected and analyzed data. Konstantin Strauch and Markus Brugger gave statistical support and planned the study. Jürgen Barth and Erika Baum planned and revised study design. Corinna Leonhardt and Annette Becker planned the study, discussed the results and revised the manuscript critically. All authors edited the drafted version of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/77/prepub


Pain is the predominant symptom of knee osteoarthritis (OA) and the main reason of disability. Ultrasound is now one of the new imaging modality in Musculoskeletal medicine and its role in assessing the pain severity in the knee osteoarthritis is evaluated in this study.(1) To study the correlation between ultrasonographic (US) findings and pain score and (2) whether ultrasonographic findings show a better association of pain level than conventional X-rays in patients suffering from primary knee osteoarthritis.In this multi-center study, 193 patients with primary knee OA were asked to score their average knee pain using the Western Ontario and McMaster Universities Arthritis (WOMAC) questionnaire;patients would then go for a radiological and an US evaluation of their painful knee. Findings from both imaging modalities will be studied with the associated pain score.Ultrasound showed that knee effusion has positive correlation with pain score upon walking (r = 0.217) and stair climbing (r = 0.194). Presence of suprapatellar synovitis had higher pain score on sitting (Spearman's Rank correlation  = 0.355). The medial(r = 0.170) and lateral meniscus protrusion (r = 0.201) were associated with pain score upon stair climbing.Our study found that both imaging modalities shown some significant association with the aspect of pain; neither one is clearly better but rather complementary to each other. A trend is found in both modalities: walking pain is related to pathologies of the either the lateral or medial tibiofemoral joint(TFJ)while stair climbing pain is related to both tibiofemoral joint pathologies and also to the patellofemoral joint (PFJ) pathology. This suggested that biomechanical derangement is an important aspect in OA knee pain. Osteoarthritis (OA) is one of the most common medical conditions in elderly people.Pain is the predominant symptom of OA knee and is the main reason for medical consultation; besides, it the main reason of disability especially during painful episodes.Conventional X-rays were used traditionally in diagnosing OA knee by demonstrating the presence of osteophytes, bone deformities and joint space narrowing. However, studies on OA knee had demonstrated that there was not much correlation between the X-rays findings and the severity of OA knee pain.Ultrasound (US) imaging is a non-invasive, widely available and relatively inexpensive technique that can be used to image soft tissues. With the advancement of technology, the newer US machine models can be equipped with high frequency probes that are very useful for musculoskeletal imaging to study the periarticular and intraarticular structures.This study looks at the intraarticular and peri-articular soft tissue changes found among OA knee patients using real-time musculoskeletal US imaging. We aim to investigate (1) the probable correlation between ultrasonographic findings and pain score and (2) whether ultrasonographic findings show a better association of pain level than conventional X-rays in patients suffering from primary knee osteoarthritis. The pain score under the section of Western Ontario and McMaster Universities Arthritis (WOMAC) Index will be used in this study.The study is a multicenter study undertaken in Hong Kong at the primary health care level in three different clinical settings: two private general practice clinics, two public primary care outpatient clinics and one primary care clinic of a private hospital. These three settings cover most of the primary health care consultations in Hong Kong.Convenient sampling was used in this study. Adult patients over 40 years of age attending one of the five primary health care clinics were asked for presence of knee pain in one or both knees for the more than one month. Those patients with a positive answer were screened for presence of OA knee using the ACR clinical criteria of OA knee.Ethics approval had been sought and endorsed from the Kowloon West Cluster, Clinical Research Ethics Committee (KWC-CRE), Hong Kong. Written consent was obtained from patients who agreed to participate in the study; the content of the consent form was approved by the ethics committee.Patients were asked to score their average knee pain during the past month as a baseline on a 10 cm visual analogue scale (VAS) from 0 to 100 mm. If both knees were painful, the most symptomatic knee was used for study. Demographic data obtained from patient included age, sex, height and weight, and body mass index. Patients would then self-complete the pain subscale section of the Chinese version of the WOMAC questionnaire.  A nurse All patients would have X-rays of their more painful knee. A standing weight bearing anterior-posterior (AP)All patients then underwent an US examination on the same knee using a standardized protocol with Esoate (MyLab 25 model) with a linear probe (model LA435 12–18 Mhz) and a centre frequency 13 MHz.  Gray-scaStatistical analyses were performed using the statistical package PASW Statistics 18. Pearson's correlation and Spearman's Rank correlation were used to examine the association among pain scores, ultrasound and X-ray findings where appropriate. Difference of pain scores in X-ray grading as well as trend were examined by Analysis of variance (ANOVA). Two tailed p-values at level of 0.05 or less were considered to be of statistical significance.A total of 193 patients were recruited in this study. In our study, the higher the KL grading was associated with more pain in general. The finding is in line with a recent systematic review that higher grade of osteoarthritis (K/L 3 or above) is a stronger predictor of pain than lower grades (K/L 2 or less).Our study showed that the presence of suprapatellar synovitis had a moderate strong correlation with higher pain score on sitting whereas such correlation was not found upon walking and standing. This could be explained by a previous study conducted by the author that there exist two types of pain among OA knee patients: a mechanical pain and an inflammatory pain. The former, being biomechanical in nature, is associated with joint movements such as walking and stair claiming whereas the latter is caused by flares of joint inflammation.This study showed that knee effusion has positive correlation with pain score upon walking and climbing, but not with sitting. Similar findings are found in other overseas studies.The knee joint is a complex joint consisting of a patellofemoral joint (PFJ) articulating the patella with the femoral condyle and two tibiofemoral joints, one medial and one lateral , articulating the medial and lateral tibial plateau with the corresponding femoral condyles.Although X-rays measure mainly bony pathologies and ultrasound on soft tissue pathologies, both the X-ray and ultrasound findings in our study showed two trends in common(1) walking pain is related to pathologies of the either the lateral or medial TFJ;(2) stair climbing pain is related to both TFJ pathologies and also to the PFJ pathology.Meniscus subluxation was highly associated with painful OA knee.o to 20o of flexion of the femoral condyle during which the lower part of the patella facet is in opposition with the upper part of the femoral condyle,o to 60o of flexion which is beyond the US measurements.Pain with stair climbing, especially on descending stairs is a well known feature with OA knee involving the PFJs.Some limitations of our study should be mentioned. Although all the ultrasounds were performed by musculoskeletal physicians who are Registrants in Musculoskeletal Ultrasound (RMSK) of the American Registry for Diagnostic Medical Sonography and that all of them had undergone a standardization workshop prior to the study, the US inter-observer reliability was not studied. Recent studies had revealed that there still can be high inter-observer reliability.Although X-rays and musculoskeletal ultrasound measure different structural tissues of the osteoarthritic knee, our study found that both imaging modalities shown some significant association with the aspect of pain. However, neither one is clearly better, but they rather complementary to each other. Walking pain is related to pathologies of the either the lateral or medial TFJ. Stair climbing pain is related to both TFJ pathologies and also to the PFJ pathology. This suggests that biomechanical derangement is an important aspect that is often overlooked, but needed to be addressed by physicians in the management of OA knee pain. Future research concerning the prognostic value of the different findings from both modalities in planning treatment or intervention can be conducted in order to improve clinical outcomes of patients suffering chronic OA knee.Appendix S1(DOC)Click here for additional data file.Appendix S2(DOC)Click here for additional data file.Appendix S3(PDF)Click here for additional data file.Appendix S4(DOC)Click here for additional data file.Appendix S5(DOC)Click here for additional data file.


Pain is a cardinal symptom of osteoarthritis (OA) of the hip and important for deciding when to operate. This study assessed the internal consistency reliability, validity and responsiveness of the Brief Pain Inventory (BPI) among patients with OA undergoing total hip replacement (THR).We prospectively included 250 of 356 patients who were accepted to the waiting list for primary THR surgery. All participants responded to the BPI, WOMAC and SF-36 at baseline and 1 year after surgery.Internal consistency reliability (Cronbach's α) was >0.80 for the BPI, the WOMAC and five of the eight SF-36 scales The pattern of associations of the two BPI scales with corresponding and non-corresponding scales of the WOMAC and SF-36 largely supported the construct validity of the BPI. The responsiveness indices for change from baseline to 1 year after THR ranged from 1.52 to 2.05 for the BPI scales, from 1.69 to 2.84 for the WOMAC scales, and from 0.25  to 2.77 (bodily pain) for the SF-36 scales.The BPI showed acceptable reliability, construct validity and responsiveness in patients with OA undergoing THR. BPI is short and therefore is easy to use and score, though the instrument offers few advantages over and duplicates scales of more comprehensive instruments, such as the WOMAC and SF-36. Primary total hip joint replacement (THR) is an effective intervention for severe osteoarthritis (OA) of the hip that relieves the patients' pain, increases physical functioning, and improves health related quality of life (HRQoL). Previously, evaluation of surgery for OA of the hip has typically been done with functional scoring systems, such as the Harris Hip score -3.During the last decade patient-reported outcomes, such as HRQoL, have gained importance in the assessment of outcome after surgery for OA of the hip -7. The tPain is a cardinal symptom of OA of the hip and is probably the most important variable for deciding whether to operate or not. Therefore, questionnaires specifically developed for the assessment of pain can potentially complement the WOMAC and the SF-36 among patients with OA, or possibly be more sensitive to change. The Brief Pain Inventory (BPI) is a self-administered questionnaire developed to assess pain and the impact of pain . It was The reliability, validity and responsiveness of the BPI, or a shortened version of it, after drug interventions, have recently been reported in unspecified patients with OA ,16, but The study was a prospective multi-center study in six hospitals in three Norwegian counties. We included consecutive patients >18 years old, who were accepted to the waiting list for primary THR surgery and had satisfactory proficiency of the Norwegian language to respond to questionnaires. Between June 2003 and June 2004, 356 patients were invited, and 250 (70%) accepted to participate and responded at baseline  acceptance to the waiting list for surgery (baseline), and (ii) 1 year after surgery. At baseline, we mailed the questionnaire to the subjects shortly after an ambulatory visit.Among the 250 baseline respondents, we excluded those that had new joint replacement surgery (n = 4), were not scheduled for surgery (n = 3), had severe complication after surgery (n = 2), had another dominating disease (n = 2), had died (n = 2) or chose another hospital for surgery (n = 1). The remaining 236 baseline respondents received questionnaires 1 year after surgery, of whom 203 responded to the questionnaire . In the planning and establishing of this study sample size was calculated. The study was powered detect a change in HRQoL of 0.5 SD, with power 0.9, and 5% significance level. In paired analysis, this would require a sample size of at least 43 patients for analysis. To account for possible loss to follow-up and comparisons of changes in subgroups, we chose to include about 250 patients.The Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services approved the study.At baseline, patients completed a questionnaire that comprised data on gender, age, marital status, cohabitation, education level, employment status, type of surgery, duration of pain in the joint, and number of years with ambulation problems. In addition, patients completed the Brief Pain Inventory (BPI) , the WOMThe BPI is a short, self-administered questionnaire with 11 items, which was designed to evaluate the intensity of, and the impairment caused by, pain. Originally, the BPI was developed to evaluate cancer pain, but it has been shown to be a valid and reliable instrument for chronic non-cancer pain ,14,17. AThe items are aggregated into two dimensions, (1) Pain severity index, using the sum of the four items on pain intensity, and (2) Function interference index, using the sum of the seven pain interference items ,24,25. MThe WOMAC is a validated and sensitive instrument that can detect clinically important changes following a variety of interventions for OA . It is aFor this study, patients were asked to respond to each item in relationship to the hip joint that was to be replaced and to respond in relationship to the past 48 hours. We used the Norwegian Likert scale version 3.1 ,29.The SF-36 questionnaire consists of 36 items that evaluate eight conceptual domains of HRQoL: general health (GH), physical functioning (PF), mental health (MH), role limitations - physical (RP), role limitations- emotional (RE), vitality (VT), bodily pain (BP), and social functioning (SF) . The SF-Descriptive statistics are presented using the mean (SD) or numbers (percentages). Groups were compared using the chi-square test, independent samples t-test, or Mann-Whitney U test, where applicable. Internal consistency reliability for the BPI, WOMAC and SF-36 scales at baseline was assessed using Cronbach's coefficient alpha . A commoConstruct validity of the BPI was assessed by Pearson's product-moment correlation coefficient between the BPI scale scores and scores on the WOMAC and SF-36 scales, using the baseline data in this study. Before this analysis, based on assessment of the content of the items on the scales, we hypothesized that (1) the Bodily pain (BP) scale of the SF-36 and the Pain scale of the WOMAC would represent similar constructs as the Pain severity index of the BPI, and (2) the SF-36 BP, PF and RP scales, and all three WOMAC scales would correspond with the Function interference index of the BPI. A finding of higher intercorrelations (r > 0.4) between subscales assessing similar constructs, compared with subscales assessing dissimilar constructs, would support the construct validity of the BPI.Responsiveness was evaluated by longitudinal assessment of patients undergoing THR, investigating if the instruments were sensitive to change following the intervention. Responsiveness was further investigated in categories of respondents, stratified according to the response on an item on change in overall health during the past year. We used item two on the SF-36 questionnaire as the rating of overall change: "Compared to 1 year ago, how would you rate your health in general now? ". The respondents were categorized as having a better (1 to 2), unchanged (3) or worse (4 to 5) health status . In asseTo assess the magnitude of the responsiveness, we calculated the effect size (ES), standardized response mean (SRM), and Responsiveness Index (RI). ES= (mean 1 year after - mean at baseline)/SD baseline, SRM= (mean 1 year after - mean at baseline)/SD difference, and RI= (mean 1 year after - mean at baseline)/SD of change scores in patients with unchanged health status -38.Data were analyzed using SPSS for Windows version 13.0 . We chose a 5% significance level using two-sided tests.In total, 203 patients completed the study 1 year after THR, 143 (70%) were female. The patients completing the study had a mean age of 69 years (SD 10), 67% were married/cohabiting, and 61% were retired. The respondents and non-respondents did not differ in baseline characteristics, though the non-respondents tended to be slightly older and more of them were retired than the respondents  Table .None of the BPI indices had marked floor or ceiling effects at baseline, however, at 1 year after THR the BPI pain severity index and function interference index showed a floor effect, but none had signs of a ceiling effect. On the WOMAC subscales at baseline, floor and ceiling effects were minor. One year after THR, the floor effect was larger on all three WOMAC subscales, but most marked on the pain and stiffness subscales. At baseline, floor and ceiling effects on the SF-36 subscales were most marked on the RP and RE scales, and 1 year after THR there was marked ceiling effects on the SF and RE scales Table .In total, 161 of the 203 patients had valid dimension scores on all three questionnaires at baseline and 1 year after THR. The correlations between the two BPI scales and scales of the WOMAC and SF-36 partially supported our hypotheses  for change from baseline to 1 year after THR for the total sample were large, with minimum values of 1.57 for the pain severity and 1.52 for the function interference index Table . Also onOn the eight SF-36 scales the responsiveness indices showed more variation. For the PF, RP and BP scales the responsiveness indices were all above 0.94, for VT and SF scales they ranged from 0.77 to 0.85, except for the RI which was 1.10 for the VT. The remaining SF-36 scales, GH, RE and MH were less responsive, with responsiveness indices from 0.24 to 0.52.In analysis of responsiveness in groups stratified according to the rating of overall health change: 133 reported better, 28 unchanged or worsened overall health than 1 year before. Those that reported an improvement in the rating of overall health change over 1 year had large values on all responsiveness indices on the pain severity index and function interference index of the BPI and all the subscales of the WOMAC and the SF-36, except GH, RE and MH, with values >0.80. All responsiveness indices for this group were larger than for the groups with unchanged or worsened overall health Table .For those with unchanged or worsened overall health the responsiveness indices indicated an improvement in pain and HRQoL, with large responses on the BPI pain severity and function interference indices, the three WOMAC subscales, and for some of the SF-36 scales most related to physical health . For the other SF-36 scales the effects were moderate (VT and SF), small (RE) or unchanged (MH). For the GH scale, the responsiveness indices changed in the opposite direction, suggesting a slight deterioration.In the present study we have documented the psychometric properties of the BPI in patients with OA of the hip, using standard methodology for assessing internal consistency reliability, validity and responsiveness. The BPI showed satisfactory internal consistency reliability with Cronbach's alpha >0.80 in assessment of pain and the impact of pain . The patThe internal consistency reliability for the BPI pain severity and function interference indices was in line with previous reports in patients with chronic non-malignant pain , OA 16]16], or uThe pattern of associations between the two BPI scales and corresponding and non-corresponding scales of the WOMAC and SF-36 largely supported the construct validity of the BPI. Our hypothesis was fairly crude and based on the judgment of items and scales, which cannot be expected to exactly capture all associations. At the same time it suggests that there is some overlap between the instruments, and that the BPI scales to some extent duplicate the BP scale of the SF-36 and the WOMAC pain subscale.A previous study stated that 15% is a critical value for floor and ceiling effects . In the The responsiveness of a measure is commonly appraised by comparing an observed change to another independent criterion, such as patient-perceived transition of health change . In the The results in the unchanged/worsened group seemed to be in the opposite direction of what would be expected, i.e. they suggested some improvement, but less than in the improved group. This may be caused by the crudeness of the rating of overall health change, in an intervention that for the majority of patients was very effective. Alternatively, it may be caused by recall bias, or other changes in health that were unrelated to OA or THR in this sample of elderly people with considerable comorbidity. Hence, the improvement with the disease-specific questionnaires may capture positive changes despite the patients' perspective of unchanged or worsened change in overall health.The responsiveness of the BPI has previously not been reported among patients with OA undergoing THR. However, responsiveness of the BPI has been assessed in two previous studies: in patients undergoing cardiac surgery and patients with OA in a clinical trial of controlled-release oxycodone ,18. BothCompared with the WOMAC and SF-36 the BPI is short, easy to use and score. In the present study there was little difference in missing change scores on the scales of the different instruments. Previous studies have shown that BPI is a feasible instrument for use among patients with pain. Pain is a cardinal symptom among patients with OA of the hip and an important indication for undergoing THR, Therefore, a systematic evaluation of self-reported pain and the impact of pain using the BPI could be a complement to assessment by the physician . FurtherSome limitations of our study should be mentioned. We assessed construct validity by investigating the pattern of associations between the different scales. However, other forms of validity could have been assessed, such as known groups validity or criterion validity, but we thought we had no feasible variables for such analysis. We also did not assess the factor structure of the BPI, which could have been done with confirmatory factor analysis. A two-factor structure of the BPI has been reported in several previous studies ,18,25,42The BPI showed acceptable internal consistency reliability, construct validity and responsiveness in assessment of pain and impact of pain among patients with OA undergoing THR. We conclude that the BPI is a short instrument that can be used as an alternative or complement to more established instruments in this patient group, though the instrument offers few advantages over, and duplicates scales of, more comprehensive instruments, such as the WOMAC and SF-36.None of the authors have any personal or financial interest or relationship with other people or organizations that could inappropriately influence the work.All authors participated in planning and design of the study.HK organised and supervised the data collection. HK and KS did the data analysis, drafted and revised the manuscript. BR reviewed and commented on the manuscript. All authors read and approved the final manuscript.


Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A  was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G  with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia  and transient receptor potential vanilloid 1 1103C>G  to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients. Neuropathic pain arises after lesions or diseases of the somatosensory nervous system and involves multiple somatosensory phenomena. In addition to spontaneous pain, these include negative and positive symptoms and signs such as hypaesthesia, hypoalgesia, thermal and mechanical hyperalgesia and allodynia The understanding of the molecular basis of neuropathic pain has been expanded by the cloning and characterization of the transient receptor potential (TRP) family of voltage-gated ion channels. Among these the TRP vanilloid 1 (TRPV1), TRP melastin 8 (TRPM8) and TRP ankyrin 1 (TRPA1) subfamilies have been found to play important roles in transduction and sensitisation in primary afferent somatosensory neurons Beside these physiological functions, TRPs are thought to play an important role in the generation of neuropathic pain, as demonstrated by in vitro and in vivo animal studies and neurophysiological and psychophysical studies in human experimental pain models and pain patients However, the contribution of a genetic variability in TRP channels on pain perception and pain generation in neuropathic pain patients is unknown. In this study we describe the results of an association analysis of polymorphisms in TRPV1, TRPM8 and TRPA1 genes with somatosensory signs of neuropathic pain patients. The aims were (1) to determine the frequencies of TRP variants in a large group of neuropathic pain patients of different aetiology and a cohort of healthy volunteers and (2) to determine the relationship of TRP gene variants and somatosensory function in neuropathic pain patients. Within this study we could demonstrate significant associations between the somatosensory function and TRP gene variants in neuropathic pain patients but no differences in the TRP frequencies compared with healthy volunteers.All subjects gave their written informed consent and the study was approved by the ethics committee of the Medical Faculty of the Christian-Albrechts-University Kiel and subsequently the Ethic Committees of the other participating DFNS centers and performed according to the Declaration of Helsinki.www.neuro.med.tu-muenchen.de/dfns/) were included in the study . The patients suffered from complex regional pain syndrome, postherpetic neuralgia, peripheral nerve injury, trigeminal neuropathy, polyneuropathy, central pain and neuropathies that did not fulfill diagnostic criteria of the above mentioned syndromes as diagnosed by expert physicians. Patient characteristics are listed in A total of 371 patients with chronic neuropathic pain syndromes, all Caucasians, who participated in the German Research Network on Neuropathic Pain  established by the DFNS to determinate somatosensory function and signs of pain Whole genomic DNA was extracted from venous blood samples obtained from patients and volunteers using the Qiagen Gentra Puregene Blood Kit . The final concentration of gDNA was determined spectrophotometrically. Two SNPs in TRPV1, six in TRPM8 and three in TRPA1 genes were identified by literature review in the context of neuropathic pain and selected for detailed association analysis . Except Before statistical analysis the QST values that did not show normal distribution  were transformed logarithmically In order to identify major subpopulations of patients who are characterized by a typical combination of signs, a cluster analysis was performed in those patients only from whom complete QST results were available  and for bi-allelic polymorphisms each subtest and genotype were calculated using analysis of variance (ANOVA). For dominant and recessive models the t-test was used, if applicable. To correct for multiple testing each test was performed using 100,000 permutations.The frequency distribution of all polymorphisms investigated was in Hardy-Weinberg equilibrium. Moreover, after correcting for multiple comparisons, the frequency of all SNPs did not differ significantly between neuropathic pain patients, healthy controls and data from the HapMap project .First, within the group of patients who suffered from paradoxical heat sensation (PHS) heterozygous and homozygous carriers of the TRPA1 710G>A variant were significantly under-represented as compared to neuropathic pain patients without PHS  . Second,Hierarchical cluster analysis detected two main clusters . ClusterZ-scores of all QST tests were stratified to all TRP variants investigated in the entire sample and in both clusters. After correcting for multiple comparisons, two TRPV1 polymorphisms, 1911A>G and 1103C>G, were identified that had a significant relationship with the somatosensory function in cluster 1 .The TRPV1 1911A>G polymorphism was significantly associated with altered heat pain thresholds (HPT). Neuropathic pain patients being heterozygote or with wild type TRPV1 1911G genotype (AA or AG) tended to show heat hyperalgesia whereas TRPV1 1911G homozygotes exhibited significantly higher, i.e. normal heat pain thresholds . Homozygous variant carriers (GG) exhibited cold hypaesthesia compared with heterozygous or wild type carriers Click here for additional data file.


N-acetyl aspartate (NAA). The purpose of this study was to analyze whether brain MRS could assess pain due to lumbar spine diseases.There is a considerable difference in pain perception among individuals. In patients with chronic pain, recent studies using fMRI, PET and SPECT have shown that functional changes mainly occurred in the anterior cingulate cortex (ACC), prefrontal cortex (PFC) and thalamus. Brain magnetic resonance spectroscopy (MRS) can evaluate brain chemistry by measuring metabolites such as NAA levels were determined relative to the concentration of creatine/phosphocreatine complex (Cr) and choline (Cho), which is commonly used as an internal standard. The NAA/Cr and NAA/Cho ratios in the ACC, PFC and thalamus were compared between six patients with unilateral pain (left side) and six control patients without pain.p < 0.05). Also, in the right thalamus, the NAA/Cho in pain patients was significantly lower compared with controls (p < 0.01). When considering just the right thalamus, there were statistically significant correlations between the numerical rating scale for pain (NRS) and NAA values.In the right thalamus , the NAA/Cr in the patients with pain was statistically significantly lower compared with the control patients (Lumbar pain can be assessed indirectly by analyzing the decrease in NAA concentration in the thalamus. Pain is one of the most frequent symptoms in lumbar spine diseases, as evaluated using a numerical rating scale (NRS), visual analog scale (VAS) and/or faces pain scale , 2. HoweN-acetyl aspartate (NAA) and glucose were observed in the prefrontal cortex (PFC). Recently, Sharma and colleagues . Th. Th30]. The current study has several limitations. The number of patients was very small. Strict age matching and gender matching were not performed. The symptom duration was short. The MRI instrument had no linear combination model (LC model) software that could measure the absolute concentration of NAA , 34. We


To compare the efficacy and safety of frovatriptan and almotriptan in women with menstrually related migraine (IHS Classification of Headache disorders) enrolled in a multicenter, randomized, double blind, cross-over study.Patients received frovatriptan 2.5 mg or almotriptan 12.5 mg in a randomized sequence: after treating 3 episodes of migraine in no more than 3 months with the first treatment, the patient switched to the other treatment.67 of the 96 female patients of the intention-to-treat population of the main study had regular menstrual cycles and were thus included in this subgroup analysis. 77 migraine attacks classified as related to menses were treated with frovatriptan and 78 with almotriptan. Rate of pain relief at 2- and 4-hrs was 36% and 53% for frovatriptan and 41% and 50% for almotriptan (p=NS between treatments). Rate of pain free at 2- and 4-hrs was 19% and 47% with frovatriptan and 29% and 54% for almotriptan (p=NS). At 24-hrs, 62% of frovatriptan- and 67% of almotriptan-treated patients had pain relief, while 60% vs. 67% were pain free (p=NS). Recurrence at 24-hrs was significantly (p<0.05) lower with frovatriptan . This was the case also at 48-hrs .Frovatriptan was as effective as almotriptan in the immediate treatment of menstrually related migraine attacks. However, it showed a more favorable sustained effect, as shown by a lower rate of migraine recurrence.


Studies have shown that N-methyl-D-aspartate receptor (NMIDA) plays an essential role in postoperative pain. It seems that use of NMDA receptor antagonists such as Dextromethorphan intensifies the analgesic effects of opioids.In this study, we evaluated the effect of preoperative administration of Dextromethorphan on postoperative pain reduction.This double blind randomized clinical trial was conducted on arthroscopic surgery candidates. Participants were randomly allocated to interventions and assigned to two groups of Dextromethorphan and placebo. In Dextromethorphan group, the patients received 1 mg/kg Dextromethorphan orally the night before the operation. Pain severity based on the visual analog scale (VAS) up to 16 hours postoperation, use of opioids, and the first request for analgesics were recorded postoperatively.A total of 112 patients in the Dextromethorphan (n = 54) and placebo groups (n = 58) were evaluated. No significant difference was detected between the two groups for age, sex or ASA. The mean amount of opioid consumption was significantly lower in patients who received Dextromethorphan (10.7 ± 5.6 mg) compared to the placebo group (13.1 ± 5.6 mg), (P = 0.03). The mean time until the first opioid request in patients who received Dextromethorphan was longer than that in the placebo group (P = 0.01).The study results demonstrated that preemptive use of Dextromethorphan reduced postoperative pain and opioid consumption. Postoperative pain management is an important part of postoperative care and plays an important role in postsurgical ambulation and general status of patients -4. Also,At present, there is a possibility that preemptive analgesia with NMDA receptor antagonists decreases postoperative pain of patients. Dextromethorphan, ketamine, amantadine, and magnesium sulfate are among the well-known NMDA receptor antagonists. Dextromethorphan and its metabolites are considered as noncompetitive low affinity NMDA receptor antagonists . ConsideSeveral researchers have evaluated the analgesic effects of Dextromethorphan and its impact on peri-and postoperative need for analgesics . In one Considering the effects of Dextromethorphan on decreasing the need for opioids and subsequent reduction in their side effects, causing preemptive analgesia and less need for administration of perioperative analgesics to prevent central sensitization and reducing the incidence of chronic pain, the present study aimed to compare the effect of Dextromethorphan and placebo on reducing the need for administration of opioids and subsequent reduction in their potential side effects.In this randomized double blind controlled clinical trial, candidates for arthroscopic knee surgery admitted to the Orthopedic Department of Rasoul-e-Akram Hospital during 2008-2009 were recruited using convenience sampling. The inclusion criteria were as follows:- Being a candidate for arthroscopic knee surgery - Spinal anesthesia - Older than 18 years - ASA classes I and IIThe exclusion criteria were:- Obese patients- Not consenting to spinal anesthesia- Conversion of arthroscopic knee surgery to open knee surgery- History of opioid consumption- Use of sedatives or analgesics peri operativelyAfter patient selection based on the inclusion and exclusion criteria, they were assigned to the Dextromethorphan and placebo groups alternately. All patients were visited the night before the operation and signed a written informed consent. Instructions were given on how to use the VAS ruler to measure subjective complaints of pain, and the whole procedure was thoroughly explained to the subjects. In the Dextromethorphan group, patients consumed oral Dextromethorphan syrup 1 mg/kg 2-3 hours before the operation . The placebo group consumed normal saline. Also, all patients took a 10 mg Diazepam tablet. In the operating room, an IV line was taken and 500 cc of IV fluid was administered. Patients were placed in a seated position while being monitored, and Marcaine 0.5% was injected as the analgesic agent  into the epidural space at L4/L5 with a 25 gauge needle. Patient’s position was then quickly changed to supine and blood pressure was monitored. After completion of the operation, patients were transferred to the recovery room and then to the ward. The time of the first opioid request after the operation, and the intensity of pain at different time points were recorded.Demographic characteristics of patients including age, sex, surgical indication, and etc. were extracted from their medical files or asked directly and recorded in data collection sheets. Severity of pain in patients was measured 4, 8, 12, 16 and 24 hours postoperatively using the visual analog scale. The patients were received analgesic drug (Morphine) every four hours or PRN when needed. The time of first opioid request after the operation was also recorded as an indicator of postoperative pain severity from the moment of entering the recovery room to patient’s first complaint of pain in minutes. Eventually, the total amount of Morphine administered within 24 hours was evaluated as an indicator of pain intensity.The obtained data were statistically analyzed using SPSS version 13 software. Quantitative data were represented as mean and standard deviation, and qualitative data as frequency. To compare the qualitative and quantitative data between the two groups, in case of normal distribution of data, chi square test and t-test were used, respectively. If data were not normally distributed, nonparametric statistical tests were used. Also repeated measurements ANOVA was used to evaluate the effect of time and its correlation with drug . A total of 112 patients in the two groups of Dextromethorphan (n = 54) and placebo (n = 58) were evaluated. No side effects about Dextromethorphan administration in these patients were reported. Administration of opioids as analgesics during the first 24 hours postoperation is demonstrated in This study showed that preemptive oral Dextromethorphan can reduce the need for administration of opioids after arthroscopic knee surgery compared to the placebo. Also, it was demonstrated that the need for first analgesic was significantly later in the test group compared to the placebo group. As mentioned earlier, postoperative pain is a serious problem in surgical wards and plays a critical role in patient’s postoperative general status and their discharge time from the hospital , 2. In cAlthough reduced consumption of opioids leads to a reduction in their potential side effects like nausea, vomiting and itching, and also in the present study, incidence of these complications was somehow lower in the test group, this difference was not statistically meaningful. In general, it appears that Dextromethorphan can be effective to reduce postoperative pain as a safe drug available over the counter (OTC) if administered preemptively. However, to generalize the results to other surgical procedures, further investigations are required. The present study results revealed that administration of Dextromethorphan can reduce consumption of opioid analgesics compared to the placebo after arthroscopic knee surgery. However, this study failed to significantly reduce the incidence of opioid side effects by preoperative consumption of Dextromethorphan in comparison to the placebo.