To investigate perceived changes in body perception and psychosocial aspects in chronic neck pain patients after participating in a yoga program.Eighteen patients with chronic non-specific neck pain participated in a 9-week Iyengar yoga-program. Before and after the program, patients were asked to complete a drawing of their neck and shoulder region in a way that reflects their subjective body perception. Semi-standardized interviews were used to retrieve more information on body perception, emotional status, everyday life and coping, and changes in these dimensions after attendance in the program. An interdisciplinary interpretation group analyzed the interviews using the content analysis approach according to Mayring.Patients reported changes on 5 fundamental dimensions of human experience: the physical, cognitive, emotional, behavioral and social dimensions. On the physical dimension patients mainly reported a renewed body awareness and body mindfulness. This was also obvious in the body drawings that were distorted and incomplete before the yoga program and normalized after attendance of the program. Patients further described changes on the cognitive dimension, mainly increased perceived control over their health and cognitive reappraisal of physical activity, and on the emotional dimension, particularly acceptance of their pain and life’s burden. On the behavioral dimension patients reported the enhanced use of active coping strategies, and on the social dimension patients particularly described a renewed participation in active life.Yoga induced changes on a wide range of experiential dimensions. Patients perceived yoga as helpful in coping with their pain, gaining more control over their health and well-being and increasing pain acceptance. Body awareness seems to be a key mechanism of these changes.


In male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anaemia and depression. Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available.To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine , we tested the administration of testosterone via a gel formulation for one year. Hormonal , pain (VAS and other pain questionnaires), andrological  and psychological  parameters were evaluated at baseline (T0) and after 3, 6 and 12 months .The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12. Pain rating indexes (QUID) progressively improved from T3 to T12 while the other pain parameters  remained unchanged. The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time.In conclusion, our results suggest that a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient's quality of life, an important clinical aspect of pain management. Awareness of the need to adequately treat pain, particularly chronic pain, is slowly increasing among patients and pain therapists. Opioids are among the most prescribed analgesic drugs but present several side effects such as nausea, itching, constipation and hypogonadism ,2. For hOpioid-induced hypogonadism in males  is usually ignored by pain physicians and rarely considered for treatment  despite The aim of the present study was to describe the time course/interactions between opioids and testosterone replacement therapy in a clinical sample of male chronic pain patients diagnosed with OPIAD and receiving morphine via the epidural route. This kind of patient was chosen to reduce variables due to the high numbers of opiates available, their dosage and combinations. Moreover, all these patients had been suffering from chronic pain for many years and their pain condition was considered severe and stable. To obtain a broad picture of the effects induced by this treatment, we considered different aspects using a multidisciplinary approach. A team of experts, namely an andrologist, a psychologist, the project co-ordinator and a local pain therapist, met with each patient monthly for one year to check the clinical and laboratory outcomes. Testosterone was replaced via a gel formulation able to restore and maintain testosterone levels  by virtuMale chronic pain patients referred to two Italian pain centres  were asked to take part in this study. To obtain the most homogeneous group of patients possible, only male subjects suffering from non-oncological chronic pain and undergoing epidural morphine were considered; morphine treatment had to have been carried out for at least six months; hypogonadism was diagnosed for testosterone values less than 2-3 ng/mL in at least two determinations in the previous 3-4 months. Other inclusion criteria were the presence of clear symptoms indicative of hypogonadism  and negative urological problems. Experimental procedures were carried out in agreement with the Code of Ethics of the World Medical Association (Helsinki Declaration) and were approved by the Local Ethics Committee.Once included in the study, each subject met with the experimental team once a month for one year during the morphine pump refilling session and underwent clinical, psychological and hormonal evaluations. In particular, the following procedures were performed during the monthly meeting:- Blood collection,- Complete clinical evaluation by the pain therapist, including the administration of specific pain questionnaires for pain assessment ,- Psychological evaluation, including the administration of specific questionnaires for anxiety, depression and quality of life ,- Andrological evaluation, including manual exploration of the prostate and transrectal prostate echography when necessary. The patient was asked to complete a specific andrological questionnaire (AMS). The subject was also examined for any adverse effects that might be related to the gel, including local skin irritation. At each visit, the subject was given a one-month supply of testosterone gel, a hydroalcoholic compound containing 50 mg testosterone in 5 g gel in each sachet. So as not to introduce other variables, the dose of testosterone gel was maintained constant independently of the blood testosterone levels shown by the patient. The patient was asked to apply the gel on the skin of the upper arm/shoulder or abdomen each morning at the same time, alternating the site of application each day and not taking a shower until 5 hours after application. He received verbal instructions to record in a diary any change that may have occurred in his daily activities and physical and mental performances.All procedures took about 2 hours per patient per month.All questionnaires were self-administered, but supported by the presence of the expert clinician.VAS (0-100), was used [A Visual Analogue Scale, was used  to estimQUID [The quality and intensity of the current pain experience was evaluated by the Italian Pain Questionnaire, QUID . The QUIArea%) was measured according the Margolis method [The percentage of body surface area in pain (s method . It consAMS) questionnaire [The impact of treatment on the androgens-related quality of life was measured by the Ageing Males' Symptoms scale . The ticipant  and consticipant .CES-D [Centre for Epidemiological Studies Depression Scale (CES-D). The Italian version of CES-D  was usedCES-D . The CESCES-D .SF-36 [Italian version of the SF-36  questionhttp://www.issam.ch/freetesto.htm, according to Vermeulen's formula [Blood was collected between 8.00 and 10.00 am in one EDTA-added tube (5 ml to obtain plasma) and one empty tube (10 ml to obtain serum). In addition to general laboratory exams performed locally , serum and plasma samples were taken to the Stress and Pain Neurophysiology Laboratory of the University of Siena, where the following hormones were determined at baseline (T0), 3 (T3), 6 (T6) and 12 (T 12) months: total testosterone (TT), free testosterone (fT), dihydrotestosterone (DHT), estradiol (E2), sex hormone-binding globulin (SHBG), cortisol (C). Prostate-specific antigen (PSA) was determined each month. These values were used to calculate bioavailable testosterone (BioT) through the website  formula .Total testosterone (TT) was measured by RIA using a kit from RADIM . The cross reactivity of the antiserum coated in the tubes was 5.6% for DHT, 1.6% for androstenedione and lower than 0.1% for androstenediol, SHBG, estrone, DHEAS, estradiol. The lower limit of quantitation of TT measured by this assay was 0.017 ng/mL. The intra- and inter-assay coefficients were 1.5% and 7.8%, respectively, at the normal adult male range: 3.5-8.5 ng/mL in our laboratory.Free testosterone (fT) was measured by RIA using a kit from Diagnostic Systems Laboratories . The cross reactivity of the antiserum coated in the tubes was 0.35% for 19-nor testosterone, 0.21% for 17 alpha-methyltestosterone, 0.13% for 11-oxo-testosterone and non-detectable reactivity for DHT, DHEA, DHEA-S, progesterone, estradiol, corticosterone and other androgens. The lower limit of quantitation of fT measured by this assay was 0.18 pg/mL. The intra- and inter-assay coefficients were 4.5% and 7.9%, respectively, at the normal adult male range: 14.7-32.7 pg/mL in our laboratory.Sex hormone-binding globulin (SHBG) was measured by IRMA using a kit from Diagnostic Systems Laboratories . Concerning the specificity, no human serum protein is known to cross react with the antibodies employed in the DSL SHBG IRMA system. The lower limit of quantitation of SHBG measured by this assay was 3 nmol/L. The intra- and inter-assay coefficients were 2.7% and 10.2%, respectively, at the normal adult male range: 28-94 nmol/L in our laboratory.Dihydrotestosterone (DHT) was measured by RIA using a kit from Diagnostic Systems Laboratories . The cross reactivity of the antiserum coated in the tubes was 3.3% for androstandiol glucuronide, 0.6% for testosterone, 0.03% for androstandiol and no reactivity for androstenedione, estradiol, androsterone glucuronide, dehydroepiandrosterone, cortisol, deoxycortisol, 17 alpha-OH progesterone, progesterone. The lower limit of quantitation of DHT measured by this assay was 4 pg/mL. The intra- and inter-assay coefficients were 5.5% and 9.5%, respectively, at the normal adult male range: 250-750 pg/mL in our laboratory.Estradiol (E2) was measured by RIA using an ultra-sensitive kit from Diagnostic Systems Laboratories . The cross reactivity of the antiserum coated in the tubes was 2.4% for estrone, 0.21% for 17 alpha-estradiol and 16 keto-estradiol, 0.64% for estriol. The lower limit of quantitation of E2 measured by this assay was 2.2 pg/mL. The intra- and inter-assay coefficients were 6.5% and 9.3%, respectively, at the normal adult male range: 10.0-25.1 pg/mL in our laboratory.Cortisol (C) was measured by RIA using a kit from RADIM . The present method has not shown cross reaction with the following steroids: estradiol, testosterone, prednisone, cortisone, corticosterone, deoxycorticosterone and 11-deoxycortisol. The lower limit of quantitation of serum C measured by this assay was 0.9 microg/L. The intra- and inter-assay coefficients were 4.9% and 7.9%, respectively, at the normal adult male range: 50-250 microg/L in our laboratory.Prostate-specific antigen (PSA) was measured by IRMA using a kit from Diagnostic Systems Laboratories . Ferritin, hCG, prolactin, atropine, flutamide, diethylstilbesterol, acetylsalicylic acid, caffeine, ibuprofen, indomethacin do not interfere with the measurement of PSA in the DSL-9700 ACTIVE® PSA coated-Tube IRMA assay. The lower limit of quantitation of serum PSA measured by this assay was 0.013 ng/mL. The intra- and inter-assay coefficients were 4.6% and 9.8%, respectively, at the normal adult male range: 0.42-2.20 ng/mL in our laboratory.Data are expressed as mean ± SEM. Changes of the data across time were analysed by Friedman analysis of variance (ANOVA) and Kendall concordance. To better define any possible drug effect, we compared the values at each time of observation  with the basal level (T0) using the non-parametric Wilcoxon test. All analyses were performed with Statistica software. A level of P ≤ 0.05 was considered statistically significant.In the six-month period devoted to patient selection, 25 outpatients referred to the pain clinics involved in the study and meeting the inclusion criteria were asked to participate; 17 of them met the enrolment criteria and signed a written informed consent form. The study design was prospective, pre-post analysis. All patients were affected by intractable non-cancer chronic pain treated for many years with different pharmacological regimens until the present when they received morphine . In some instances, as in tetraplegic patients, morphine was associated with an adjuvant .The morphine dose was changed according to patient requirements Figure . The dos2 = 3.98, p = 0.26 and χ 2 = 3.86, p = 0.27, respectively)  were high and not modified by treatment; ANOVA did not show any significant variations   and in the sensory , affective  and evaluative PRIr . The PRIr-sensory and PRIr-evaluative were already lower at T3 (p < 0.018 for both), the miscellaneous at T6 (p < 0.046) and the PRIr-affective at T12 (p < 0.046)  ; in particular, the score increased progressively to become significantly higher at T12 than at T0 (p < 0.04) , while CES-D was always higher than 16 and SF-36 lower than 50. None of the POMS subscale scores or CES-D ratings showed significant changes, while the SF-36 Mental Index displayed a significant improvement over time , free (fT) and bioavailable testosterone (BioT) showed very low levels at T0  with respect to the normal range, while SHBG was close to the upper limit of the normal range (77.77 ± 12.12 nmol/L)  and TT, we calculated a percentage (%fT). The %fT tended to decrease at T3, but did not reach significance. SHBG did not change significantly Figure .The two metabolites of testosterone, DHT and E2, changed differently. DHT increased progressively, reaching significance at T12 (p < 0.02), whereas E2 did not vary. The ratio DHT/TT did not change while the ratio E2/TT was decreased significantly already at T3 and remained stable till T12 .Cortisol showed a slow, non-significant reduction during the one-year therapy Table .Evidence from this study suggests that one year of testosterone replacement therapy in male patients suffering from a severe form of chronic pain and diagnosed with morphine-induced hypogonadism (OPIAD) is able to positively change hormonal and behavioural 'indicators' chosen to measure different aspects of their condition.Although pain research is continuously coming up with new products to treat chronic pain, opioids remain the reference therapy. Unfortunately this approach involves several side effects, which increasing morbidity would induce the discontinuation of therapy . With coTestosterone replacement therapy is a common approach in ageing males with partial androgen deficit or in young hypogonadic men due to traumatic or surgical causes; in these subjects, testosterone administration via gel is known to increase total testosterone serum levels immediately, reaching a steady state in 1-2 weeks . Thus, iSeveral hypotheses have been advanced to explain OPIAD . One sugFinally, we cannot exclude either a direct effect of pain on the HPG axis, since observations have indicated a depressant effect of experimental pain on testosterone blood and brain levels in rats through the stress system, or the quite common use of other drugs able, like opioids, to inhibit the HPA axis ,33.While the psychological and somatic aspects of the painful condition are usually taken into consideration by physicians, the sexual aspect of the patient's life is generally disregarded. In the present study, as in a previous one by Daniell's group , the andWe provide preliminary data suggesting that the pain experience, as assessed by QUID , is affected by testosterone replacement. In fact, QUID dimensions improved by the third month, reaching the best values at the sixth month. This was a very substantial result present in all subjects. QUID was more sensitive than the other pain measurement tools administered , probably because the questionnaire is composed of a series of descriptors requiring patients to carefully analyse and define the ongoing pain experience. Furthermore, since this instrument studies the different dimensions of the pain experience , we were able to verify that all these components benefited from the testosterone therapy, albeit following different time courses.The morphine dose matched the change in pain shown by QUID. Although three subjects asked for escalating doses to complete the pain relief , the others maintained or reduced the morphine amount, thus implicitly expressing pain amelioration. The results of the SF-36 Mental Index agreed with these findings, as they indicated an improvement in the respective domains, i.e. daily activities, emotional competence and social relations. Of course, the improvement in these aspects may have positively influenced the pain perception and vice versa, since a virtuous circle was established.The extension and distribution of the body surface area in pain remained unchanged, as did the VAS scores. From the beginning of the epidural morphine administration, all the patients complained that the last week before the refill was the worst of the month, even though the dose of morphine was repeatedly verified to be constant in the last days of the cycle. Our interpretation of the high VAS scores involves two mechanisms, the one involving patient attitudes and the other the instrument itself. Very long-lasting and unresponsive pain is not easily consciously modified since a feeling of helplessness is unavoidable in these subjects, impeding their realization that any change has occurred, especially when it is positive. VAS does not contrast this attitude. Due to its oversimplified nature, it does not require the patient to analyse and weigh his pain, and it facilitates recollection bias. In the end, the patient under-evaluates the measurement and over-emphasizes the pain he is rating. The findings on QUID, which requires the patient to focus on his experience, match perfectly with this explanation, making this instrument more reliable in the setting described herein. Interestingly these results are very similar to those reported by Daniell and colleagues (2006) , in whicThe affective state of chronic pain is characterized by deep depression and high anxiety; sometimes such an affective condition depends not only on the pain severity but also on the underlying disease, especially when it is highly vexing and disabling. Our patients were affected by intense long-lasting pain and a serious illness. Thus, they were anxious and depressed, as shown by the POMS and CES-D scores. These ratings did not vary throughout the observational period, indicating that testosterone therapy did not influence the patients' affective state. It is likely that the sense of uncontrollability of their condition was so deeply rooted in their mind that it was not easily attenuated. On the other hand, the improvement of pain was incomplete and too recent with respect to its history for the attitudes toward it to be changed. Furthermore, the patients knew that their disease was incurable. Interestingly the persistent high levels of anxiety and depression indicate that the decrease of pain shown by QUID cannot be attributed to the psychological component of the pain experience, as may occur in purposely treated chronic pain patients.The present results, although carried out in a small number of subjects and with a constant treatment dose, underline the possibility of successful testosterone replacement therapy in chronic pain patients treated with morphine. Hypogonadism is a usual consequence of opioid treatment, but it is rarely taken into consideration. Our results strongly suggest that this therapy can positively modulate the dimensions of pain. This effect allows us to propose the use of testosterone in clinics as an adjuvant, in combination with opioid therapy.The authors declare that they have no competing interests.AMA, IC, VB and GP conceived and supervised the project and edited the manuscript.IC, GdP, MC, AS, GS, SM, VP, LR, GP participated in the experimental process and data analysis. All authors contributed to data interpretation. All authors read and approved the final manuscript.


The Pain is the most common complaint in various diseases. Postoperative pain is common complication and spatially in elderly patient because of exacerbation of heard and vessel was impotents. The aim of this study was evaluation of the effect of low-dose IV dexamethasone on postoperative pain in patients with lumbar discectomy.In a clinical trial that studied in neurosurgery wards of Shohada and Imam Reza hospitals affiliated to the Tabriz University of Medical Sciences on patients underwent lumbar discectomy, the effect of low-dose IV dexamethasone on postoperative pain was evaluated. 80 patients divided in 2 equal groups, we used IV morphine (present routine treatment) in group A and IV morphine in addition to 8mg IV dexamethasone in group B, for reducing post lumbar discectomy pain. 21 patients in group A, & 22 in group B were male and 19 patients in group A & and 18 in group B were female (P=0.823). Mean age of patients in groups A and B was 39.32 and 39.22 years, respectively . Mean of pain score (VAS) at 6 hours post-operation in group A and B was 6.97 and 6.75, respectively . VAS at 12, 18 or 24 hours post-operation in both groups didn’t differ significantly (P greater than 0.05).We didn't observe any significant reduction in post lumbar discectomy pain after adding 8 mg dexamethasone into morphine. Regarding other studies, it seems that higher doses of dexamethasone should be used to achieve a significant pain reduction.Lumbar discectomy, Dexamethasone, Postoperative pain, Pain measurement


Objective: A study is made of the influence of gender, educational level, marital status, income, social support, and perceived general and oral health upon pain intensity in a sample of patients with temporomandibular joint disorders (TMJD) explored in primary care (AP).Design: A review was made of 899 patients from Córdoba Healthcare District (Spain) referred to the primary care TMJD Unit by their primary care physician and/or dentist. Of these subjects, 151 failed to meet the inclusion criteria. The remaining 748 subjects were explored according to the corresponding research diagnostic criteria (RDC/TMJD). A bivariate analysis was made the association of pain intensity to the demographic and psychological characteristics of the patients, and to perceived general and oral health, followed by a multivariate linear regression analysis to explain pain intensity as a function of the rest of the variables. The SPSS version 19.0 statistical package was used.Results: The patient age ranged from 18-86 years, with a mean of 45.8 years (± 15.8), and a female predominance of 5:1. The characteristic pain intensity (CPI) score was almost 15 points higher on average in women than in men (p<0.05). A lower educational level, and separation or divorce, were correlated to an increased intensity of pain. Social support, depression and general and oral health also explained part of pain intensity. The regression model established with these variables accounted for 13.3% of the variability of pain (R2 = 0.133).Conclusions: Women suffer more intense pain than men. Perceived health partially explains the variability of the CPI score. However, it is empirically seen that the variables gender, educational level and marital status exert an important and independent influence upon pain intensity. Key words:Cranial-mandibular disorders, age, gender, educational level, primary care, research diagnostic criteria for temporomandibular joint disorders (RDC/TMD). Temporomandibular joint disorders comprise a large group of signs and symptoms affecting the temporomandibular joints (TMJs), the muscles that control these joints, or both . The mosPain has precise physical, anatomical and pathological dimensions , but is In this context, pain is conditioned by the personal and particular elements of the individual suffering the condition, and also by the social elements that identify the individual, such as his or her sociodemographic characteristics. Accordingly, pain as a social concept implies the intervention of educational, cultural, sociological and personal elements, and as such requires study based on the subjective perception of the individual . In otheTherefore, in order to explore pain from a subjective perspective, we must take both social  and psychological variables  into account.On the other hand, the research diagnostic criteria for temporomandibular joint disorders (RDC/TMJD) conform a dual-axis diagnostic classification system in which the first or clinical axis classifies the symptoms  into one of the three most prevalent clinical presentations of TMJD  ,6. The sThe prevalence of temporomandibular joint disorders has been extensively studied by many authors. However, on considering those that have used the RDC/TMJD -12, the Authors such as LeReshe the al.  have expThe rest of sociodemographic variables such as educational level, marital status, or income have been little investigated in relation to TMJD .The present study explores the relationship between patient perceived pain intensity and the sociodemographic variables gender, age, educational level, marital status and income, variables pertaining to the psychological domain, and self-reported general and oral health.The study sample consisted of 899 patients referred between January 2007 and July 2010 by primary care physicians and dentists ascribed to Córdoba Healthcare District (Spain). The following inclusion criteria were established: age: ≥18 years , with some of the following signs or symptoms: mandibular or TMJ pain, limitation or restriction during oral aperture or lateralization, or joint sounds with or without pain.The following exclusion criteria were applied: systemic rheumatological , neurological or autoimmune diseases, patients subjected to TMJ surgery or head and neck irradiation treatment, patients with head and neck injuries in the two months prior to the study, pregnant women, the use of psychoactive medication, muscle relaxants or corticosteroids not suspended at least one week before the study, antidepressant or nonsteroidal antiinflammatory drug use within the past three days, patients with antecedents of drug abuse, and subjects failing to give written informed consent to participation in the study.Of the original 899 patients, we excluded two who were under 18 years of age, while 149 declined to participate in the study. These subjects did not differ from the remaining 748 patients in terms of the demographic variables. The patients who agreed to participate returned for a second visit in which the two axes of the RDC/TMJD were evaluated.Patient data compilation and the clinical examination were carried out according to the RDC/TMJD guidelines, using a validated translated version ensuring intra- and inter-examiner reproducibility ,19.The study questionnaire addressed sociodemographic variables, psychological variables, clinical parameters and pain intensity. Regarding the sociodemographic variables, the main characteristics of the patient were considered: gender, age, educational level, occupational status at the time (employed or otherwise), marital status and income. In turn, two psychological variables were assessed: satisfaction with the social support received (persons from which help can be received in case of need), and degree of depression. The latter was rated according to the modified Symptoms Checklist-90 (SCL 90),21, compThe characteristic pain intensity (CPI) score was obtained from the GPS , applying the following formula: Fig.  where Q1 is the intensity of pain at the present time; Q2 is the worst pain intensity of the last 6 months; and Q3 is the average pain intensity of the last 6 months – based on a scale of 0 (no pain) to 10 (worst pain possible). The result of the sum is divided by the number of questions, multiplied by 10. In this sense, the result is a new variable with values from 0 (no pain) to 10 (intense pain).Lastly, patient perceived general and oral health was explored by means of a 5-point Likert scale.A univariate descriptive analysis was made of the different study variables. In turn, the influence of the sociodemographic, psychological and health variables upon pain intensity among the patients with temporomandibular joint disorders in the primary care setting was evaluated based on a bivariate analysis (contrasting of means using the Snedecor F-statistic) of each of the variables and pain intensity.After assessing the bivariate relationships between the CPI score and rest of the variables, we developed a linear regression model in which the mentioned score was taken to be the dependent variable, while the independent variables were those parameters found to show a significant association to the CPI score in the bivariate analysis.The SPSS version 19.0 statistical package was used throughout. The study was approved by the Ethics Committee of Reina Sofía University Hospital .The main descriptors of the CPI score are shown in The characteristic pain intensity (CPI) score was almost 15 points higher on average in women than in men (55.73 and 40.91 respectively). As can be seen from figure Another significant element in the bivariate analysis with respect to CPI was educational level. Those patients with a lesser educational level yielded higher CPI scores, while those with a higher education level yielded comparatively lower pain scores.Regarding marital status, separated or divorced patients reported higher intensity pain, followed by married subjects, while single or widowed patients yielded the lowest pain scores. The differences between the separated or divorced patients and the rest of the marital status categories proved significant Fig. .A higher or lower income, or being employed or not, implied no changes in CPI score.In reference to the psychological variables, the availability of social support was significantly correlated to the CPI score. In general, the patients were clearly dissatisfied with the social support received. While differences were observed, they were mainly circumscribed to those individuals clearly satisfied with the support received (satisfied or very satisfied) versus the rest of the patients – the latter exhibiting the highest CPI scores .On the other hand, a positive association was observed between depression and an increased intensity of pain.Lastly, regarding the two health variables, higher CPI scores were associated to poorer perceived health, as could be expected.The results of the regression analysis are reported in Regression 1: The variables found to be significant were gender, married or divorced status (confidence level 95%), and primary education or no education (confidence level 90%). The variables found to be significant in the bivariate but which lost significance in the regression analysis were age, university studies and single status. The model proved globally significant (F=8.180). The determination coefficient (R2) was not very high and accounted for 7.2% of the pain intensity. Considering that the analysis focused on the effect of the sociodemographic variables upon pain, this should not be interpreted as a low value. The coefficients (B) indicate the variation in pain intensity in response to unit variation in some of the variables, assuming that the rest of the variables remain constant. According to the model, gender increment  raised the pain intensity score by 14.7 points. The same was seen to apply to educational level, where only primary education or no education implied a pain intensity increase of over 5 points versus patients with higher educational levels. Lastly, married or divorced status implied a pain intensity increment of 11.8 and 23.3 points, respectively.Regression 2: This analysis furthermore included the variables of the psychological and social support axis of the RDC/TMJD. As a result, the R2 of the model increased 4.4%, and the global independent variables accounted for 11.6% of the variability in patient pain intensity. The variables found to be significant were gender, married or divorced status, and depression (confidence level 95%). Educational level, which proved significant in the previous model, was no longer significant in this second regression analysis. This may be due to the observation that the subjects with a lower educational level also showed the highest depression and lack of social support scores. Likewise, while the bivariate analysis revealed significance for the variable social support, this significance was lost in the regression study. The model proved globally significant (F=10.484). The coefficients (B) were similar to those of the previous analysis, with some differences in terms of the increment observed in the dependent variable. Regarding depression, the patient pain intensity score was seen to increase 8 points for each increment in depression (0 representing no depression and 4 indicating extreme symptoms of depression).Regression 3: Lastly, this third regression analysis included the above variables together with the two parameters related to patient perceived health. These variables were introduced in order to determine their effect upon the rest, allowing us to evaluate the influence of the sociodemographic and psychological variables upon pain intensity after inclusion in the model, independently of the effects of patient health proper. It is very interesting to note that there were no relevant changes in the determination coefficients of the previously included variables. The model proved globally significant (F=9.919), explaining 13.3% of the variability in pain intensity. An increase in perceived general and oral health was seen to be associated with a 5- and 4-point decrease in pain intensity (negative coefficients), respectively.The present study shows that women suffer more intense pain than men, in coincidence with the observations of other studies. According to Rohlfs et al. , the heaAccording to Bonjardin , there iHowever, Pereira et al.  reportedAn interesting observation in our study is that patient perceived health explained part of the variability of the CPI score, but did modify the effects of the sociodemographic and psychological variables included in the model when health was omitted. In other words, the effect of gender, educational level or marital status upon pain intensity is independent of perceived health.We did not observe a statistically significant relationship between pain intensity and age group, occupation at the time of the study (employed or otherwise), or income.As explained by Martins et al. , the obsIn conclusion, while we have found that there are biological elements that condition differences in patient health, it remains important to study the social and cultural differences responsible for certain concrete aspects of such differences. In this context, the primary care setting, as the first step in the provision of health care, offers an excellent scenario for the conduction of such research.


DETECT) to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain  do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile), i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1) The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2) The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD.Painful radiculopathies (RAD) and classical neuropathic pain syndromes  show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (pain Since the pain involves pathology of a peripheral nerve trunk it is thought to be mainly of neuropathic pain origin. In fact, the recently proposed new definition of peripheral neuropathic pain, i.e. Thus, the question arises whether pain generating mechanisms in patients with painful radiculopathy are different from those with other neuropathic pain syndromes although all patients have a nerve injury in common. In a recent study in patients with PHN and DPN we described five distinct subgroups of patients in both entities who are characterized by a specific sensory profile, a typical constellation and combination of neuropathic symptoms. We hypothesized that distinct pain-generating mechanisms are related to the specific sensory profiles in each of the patient subgroups DETECT) performed in collaboration with the German Research Network on Neuropathic Pain (DFNS).In the present investigation we used the same approach to define subgroups of patients according to sensory profiles in a cohort of 2094 patients with painful radiculopathy and compared these profiles with the classical neuropathic pain syndromes, PHN and DPN. We analysed epidemiological and clinical data of painful radiculopathy patients who were collected within a cross sectional cohort survey in Germany (painThe aims were (1) to describe demographic data and co-morbidities in painful radiculopathy and (2) to detect characteristic sensory abnormalities in patients with painful radiculopathy and compare them with other neuropathic pain syndromes.DETECT questionnaire , at least 18 years old, were given hand-held computers . They were requested to complete electronically questionnaires for the epidemiological and clinical survey and to mark their painful areas on a body drawing see . In addire PD-Q; . FurtherThe method of data acquisition was validated in an earlier study Patients with back pain may suffer from a variety of different pain syndromes which are mechanistically distinct In order to circumvent this problem and minimize overlap the following approach was used to detect patients with painful radiculopathy with the highest level of security:Only patients were included in the study in whom the leg pain was the predominant complaint whereas back pain was absent or of minor intensity. This selection was done based on pain body drawings performed by the patients on the palm top. The palm top device was equipped with a body drawing with 34 predefined body areas . All pat(Foot) OR (foot AND shank) OR (foot AND shank AND thigh).DETECT questionnaire  was used to evaluate differences in continuous variables between three groups of patients. Continuous variables were presented within tables by mean plus/minus standard deviation. Categorial data were tabulated using frequencies and percentages.In order to identify relevant subgroups of patients who are characterized by a typical constellation of sensory symptoms a hierarchical cluster analysis was performed. To eliminate inter-individual differences of the general perception of sensory stimuli  the intensity scores of the questions were re-calculated for the cluster analysis. In detail, the given 0–5 score of each question was subtracted by the mean of all values marked in the 7 questions. In this individual score values above 0 indicate a sensation which is more intensive than the individual mean pain perception, values below 0 indicate a sensation which is less intensive than the individual mean pain perception.As there are no special a-priori-assumptions about the distance measures and the number of clusters for this heuristic approach, we used the commonly recommended hierarchical WARD-approach with a squared Euclidian distance measure. As there are no objective and compelled rules for determination of an optimal cluster number we used 3 criteria: the development of values of the WARD fusion algorithm with respect to cluster numbers, practical decisions about minimal group numbers and decisions about sense of combining groups as regards content.Using these criteria we identified a 5-cluster solution to be the optimal compromise. We applied the 5-cluster solution in the radiculopathy cohort and in the cohort of DPN/PHN patients separately. To prove the evidence of the solution a k-means cluster analysis which rearranges cases for better fitting was performed. The clusters are represented by the patterns of the questionnaire scores, thus showing the typical pathological structure of the respective group. As this is a heuristic approach no statistical analysis was performed.A total of 2094 patients with painful radiculopathy took part in the survey and were compared with 2121 patients with other neuropathic pain syndromes (1623 DPN and 498 PHN patients). The latter data have been published elsewhere DETECT questionnaire address the quality and intensity of specific sensory symptoms  and PHN  and slightly less in DPN patients . The seven questions of the painsymptoms . The patBurning pain occurred least frequent in RAD (25%) followed by DPN and PHN . Prickling sensations also occurred least frequent in RAD (26%) compared to DPN and PHN . Importantly, clinically relevant touch evoked allodynia and thermal induced pain were very uncommon symptoms in RAD , followed by DPN  and PHN . Severe pain attacks were described similarly frequent in RAD and DPN and nearly in half of the PHN patients . Numbness was a prominent descriptor in DPN (30%) and evenly distributed in RAD and PHN . Pain induced by slight pressure occurred in RAD patients nearly as often as in DPN patients and half as often as in PHN patients . For detailed results of DPN and PHN analysis please see In addition to the frequencies of each of the sensory symptoms the patients also showed typical combination patterns of symptoms, i.e. typical sensory profiles. A cluster analysis was performed to identify relevant subgroups of patients who present with a characteristic constellation of sensory neuropathic symptoms and to detect these profiles in RAD. The aim of the present investigation was to compare three etiologically different neuropathic pain syndromes, i.e. painful radiculopathy (RAD), painful diabetic neuropathy (DPN) and postherpetic neuralgia (PHN) and to describe similarities and differences in demographic data, co-morbidities and sensory perceptions. The study revealed three main findings:The frequency and severity of common co-morbidities in neuropathic pain, i.e., depression, sleep disturbance and anxiety, are similar across conditions.Compared to other peripheral neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in painful radiculopathy (only about 10%).One distinct sensory symptom pattern (sensory profile), a combination of severe painful attacks and pressure induced pain with the lack of spontaneous pain, allodynia and thermal hyperalgesia, was found to be characteristic for patients with painful radiculopathy.The literature indicates a clear link between psychological variables and back pain Sensory disturbances were considered as clinically relevant if the patients replied to the questions with a score of >3  . AlthougTo demonstrate differences between the two lesion sites an animal model of radiculopathy was directly compared to a model of peripheral nerve lesion. Despite the fact that pinprick allodynia, a sensory phenomenon which was not part of the present survey, was similar in both animal models, significant differences in spinal cord gene expression could be depicted The different lesion sites also lead to specific distributions of sensory symptoms. In radiculopathy and radiculoneuropathy the distribution is dermatomeric and non length-dependent whereas polyneuropathies show a length-dependent distribution.Modern concepts hypothesize that sensory abnormalities and in particular the individual pattern of sensory symptoms might allow insight into the underlying pathophysiological mechanisms of pain generation. In light of this hypothesis we performed a cluster analysis to identify relevant subgroups of patients who demonstrate characteristic sensory profiles , Fig. 2.Subgroup 1 occurs nearly three times more frequently in PHN than in DPN and RAD . The prominent features in this subgroup are moderate to strong spontaneous burning pain in combination with slight to moderate dynamic mechanical allodynia. Numbness was nearly ever noticed in this subgroup which indicates a preserved innervation of the skin without any signs of degeneration.The dominant symptom of subgroup 2 is severe and clinical relevant pain attacks. This symptom constellation occurs in 16% of RAD, in 16% of DPN and in 11% of PHN patients. These patients very likely experience the classical neuropathic shooting pain which occurs spontaneously for seconds, comparable to the attacks in trigeminal neuralgia.Patients who have been classified into subgroup 4 suffer from considerable burning pain and paresthesias but do not have relevant mechanical allodynia, thermal hyperalgesia and pain attacks. In contrast, numbness is a very prominent symptom. This symptom constellation indicates a severe deafferentation of the affected skin. Patients with painful radiculopathy and DPN show this symptom pattern much more frequently than PHN patients . These findings are in line with results obtained in a group of patients with painful radiculopathy using quantitative sensory testing which revealed a selective loss of vibration detection, detection of v. Frey hair contact, and cold detection in the affected dermatomes. Allodynia and hyperalgesia was rare One sensory profile, however, was found to be characteristic for patients with painful radiculopathy and does not occur in the other neuropathic pain conditions. This subgroup is characterized by a combination of severe painful attacks and pressure induced pain whereas spontaneous pain, allodynia and thermal hyperalgesia are only mildly present. It could be found in 15% of patients with RAD. Obviously, painful symptoms in this group are fundamentally different from perceptions that are experienced by DPN and PHN patients. What makes this sensory perception so unique for painful radiculopathies?Many patients with back and leg pain use the descriptor “pain attacks” if they want to express that even the slightest movement of the affected lumbar spine is capable of inducing a very severe, short lasting pain which ceases immediately after seconds. Very similar sensory phenomena could be evoked in patients who underwent surgery for disc herniation. Sutures were placed around the nerves during surgery and led out through the wound The question arises whether this subgroup can really be summarized under the definition of neuropathic pain. It is believed that radicular pain is a classical feature of most radiculopathies, but clearly it can also occur in the absence of a neuropathy of the root, i.e., in the absence of any nerve damage These phenotypic differences are certainly not the only variables which might determine the response to analgesic treatments. This is also influenced by genetic susceptibility and psychological factors such as catastrophizing and expectation which were not assessed in the present investigation. However, it might be possible that differences in sensory phenotypes explain some of the variance in treatment response and might, thus, be one puzzle piece to establish a more personalized treatment approach in the future. It might be possible to use this information to select the optimal patients for treatment with neuropathic pain drugs by their individual sensory profiles.Despite many similarities in sensory symptoms there are two decisive differences between painful radiculopathy and other neuropathic disorders. (1) The site of the nerve lesion in radiculopathy is often located proximal of the dorsal root ganglion which might explain the paucity of mechanical allodynia and thermal hyperalgesia and distinct underlying pathophysiological mechanisms. (2) Patients with painful radiculopathy often describe an evoked unpleasant sensation of lancinating, shocking or electric quality whereas in painful polyneuropathies and postherpetic neuralgia spontaneous burning pain and allodynia dominate the clinical picture. The pathophysiology of pain generation in this subgroup of radiculopathy is likely to be different from other painful neuropathies and might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences might in part explain the failure of medications which are effective in classical neuropathic pain syndromes.


Cav2.3 (R-type) VACCs have been especially thought to play critical roles in pain pathways and the analgesic effects of opioids. However, unknown is whether single-nucleotide polymorphisms (SNPs) of the human CACNA1E  gene that encodes Cav2.3 VACCs influence the analgesic effects of opioids. Thus, the present study examined associations between fentanyl sensitivity and SNPs in the human CACNA1E gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. We first conducted linkage disequilibrium (LD) analyses of 223 SNPs in a region that contains the CACNA1E gene using genomic samples from 100 patients, and a total of 13 LD blocks with 42 Tag SNPs were observed within and around the CACNA1E gene region. In the preliminary study using the same 100 genomic samples, only the rs3845446 A/G SNP was significantly associated with perioperative fentanyl use among these 42 Tag SNPs. In a confirmatory study using the other 255 genomic samples, this SNP was also significantly associated with perioperative fentanyl use. Thus, we further analyzed associations between genotypes of this SNP and all of the clinical data using a total of 355 samples. The rs3845446 A/G SNP was associated with intraoperative fentanyl use, 24 h postoperative fentanyl requirements, and perioperative fentanyl use. Subjects who carried the minor G allele required significantly less fentanyl for pain control compared with subjects who did not carry this allele. Although further validation is needed, the present findings show the possibility of the involvement of CACNA1E gene polymorphisms in fentanyl sensitivity.Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, lead to different proper doses of fentanyl, which can hamper effective pain treatment. Voltage-activated Ca However, the analgesic efficacy of opioids is well known to vary widely among individuals 2+ channels have also been considered to play important roles in the analgesic effects of and tolerance to opioids. Ca2+ influx modulators have been shown to affect both the antinociceptive effects of and tolerance to morphine v2.3 knockout mice show enhanced analgesic effects of morphine v2.3 in the PAG has also been reported v2.3 in the PAG could affect the activity of the endogenous descending antinociceptive pathway by regulating the release of GABA or other endogenous neurotransmitters. Thus, the expression level of or functional changes in Cav2.3 may cause differences in the analgesic efficacy of opioids.Voltage-activated Cav2.3 is encoded by the CACNA1E  gene, which is located on chromosome 1q25-31. Many SNPs have been identified in the CACNA1E gene, and some of these SNPs have been reported to be associated with type 2 diabetes CACNA1E gene have any association with pain sensitivity or opioid analgesia. In contrast to animal studies that use standardized pain tests, the analgesic effects of opioids in humans are usually evaluated in patients with actual pain, particularly cancer pain or acute postoperative pain CACNA1E gene affect pain sensitivity and the analgesic effects of fentanyl, one of the most commonly used opioid analgesics, evaluated by a standardized pain test and fentanyl requirements in healthy Japanese subjects who underwent uniform surgical procedures.Human CaThe study protocol was approved by the Institutional Review Board, Tokyo Dental College, Chiba, Japan, and the Institutional Review Board, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Written informed consent was obtained from all of the patients and from parents if required.Enrolled in the study were 355 healthy patients  who were scheduled to undergo cosmetic orthognathic surgery  for mandibular prognathism at Tokyo Dental College Suidoubashi Hospital. Patients with chronic pain, those taking pain medication, and those who had experienced Raynaud’s phenomenon were excluded.Patients were premedicated with oral diazepam, 5 mg, and oral famotidine, 150 mg, 90 min before the induction of anesthesia. Patients had an intravenous (i.v.) line on the forearm on their nondominant side. The temperature in the operating room was maintained at 26°C. The cold pressor-induced pain test was then performed before and 3 min after an i.v. bolus injection of fentanyl, 2 µg/kg, as previously described After the cold pressor-induced pain test ended, general anesthesia was induced with a target-controlled infusion (TCI) of propofol using a TCI pump . Vecuronium, 0.1 mg/kg, was administered to facilitate nasotracheal intubation. After the induction of anesthesia, 10 ml of venous blood was sampled for the preparation of DNA specimens. General anesthesia was maintained with propofol at a target blood concentration of 4–6 µg/ml. Vecuronium was administered at a rate of 0.08 mg/kg/h. The lungs were ventilated with oxygen-enriched air. Local anesthesia was performed on the right side of the surgical field with 8 ml of 2% lidocaine that contained epinephrine, 12.5 µg/ml, and right mandibular ramus osteotomy was performed. Local anesthesia was then performed on the left side, and left mandibular ramus osteotomy was performed. The bilateral mandibular bone segments were fixed in appropriate positions. Whenever systolic blood pressure or heart rate exceeded +20% of the preinduction value during surgery, i.v. fentanyl, 1 µg/kg, was administered.At the end of the surgery, rectal diclofenac sodium, 50 mg, and i.v. dexamethasone, 8 mg, were administered at the request of surgeons to prevent postoperative orofacial edema/swelling. After emergence from anesthesia and tracheal extubation, droperidol, 1.25 mg, was administered i.v. to prevent nausea/vomiting, and i.v. patient-controlled analgesia (PCA) with a fentanyl-droperidol combination  commenced using a CADD-Legacy PCA pump . A bolus dose of fentanyl, 20 µg, on demand and a lockout time of 10 min were set. Continuous background infusion was not employed. Droperidol was coadministered with fentanyl to prevent nausea/vomiting because our preliminary study showed a high incidence (up to 30%) of nausea/vomiting with PCA fentanyl in young females. Patient-controlled analgesia continued for 24 h postoperatively. In the case of treatment-refractory adverse effects or inadequate analgesia, PCA was discontinued, and rectal diclofenac sodium, 50 mg, was prescribed as a rescue analgesic as required . The intensity of spontaneous pain was assessed 3 and 24 h postoperatively using a 100-mm visual analog scale (VAS), with 0 mm indicating no pain and 100 mm indicating the worst pain imaginable. Intraoperative fentanyl use and postoperative PCA fentanyl use during the first 24 h postoperative period were recorded. Doses of fentanyl administered intraoperatively and postoperatively were normalized to body weight. Additionally, perioperative fentanyl use was calculated as the sum of intraoperative fentanyl use and postoperative fentanyl use because the analgesic effect of the intermediate-acting opioid fentanyl, administered pre- and intraoperatively, could outlast the duration of surgery and thus affect postoperative fentanyl use, especially in patients who received large doses of fentanyl intraoperatively. Therefore, in the present study, we considered perioperative fentanyl use an appropriate indicator of fentanyl analgesia in addition to postoperative fentanyl use.Genomic DNA was extracted from whole-blood samples using standard procedures. The extracted DNA was dissolved in TE buffer . The DNA concentration was adjusted to 5–50 ng/µl for genotyping individual SNPs or 100 ng/µl for whole-genome genotyping using a NanoDrop ND-1000 Spectrophotometer .CACNA1E gene region, genotype data from whole-genome genotyping were used. Briefly, whole-genome genotyping was performed using Infinium assay II and an iScan system  according to the manufacturer’s instructions. Five kinds of BeadChips were used to genotype 40, 67, 6, 119, and 123 samples, respectively: HumanHap300 , HumanHap300-Duo , Human610-Quad v1 , Human1M v1.0 , and Human 1M-Duo v3 . Some BeadChips included a number of probes specific to copy number variation markers, but most were for SNP markers on the human autosome or sex chromosome. Approximately 300,000 SNP markers were commonly included in all of the BeadChips. After the whole-genome genotyping, the data for genotyped samples were analyzed using BeadStudio or GenomeStudio with the Genotyping module v3.3.7 (Illumina) to evaluate the quality of the results, and the genotype data for all of the SNPs with CACNA1E gene annotation were extracted. In the data-cleaning process, markers that had “Cluster sep” values  less than 0.4 and three genotype clusters that were not separate from one another were excluded from the subsequent association study.For the analysis of SNPs within and around the CACNA1E gene, among 1,199,187 markers of the Human 1M-Duo v3 Bead Chip for 100 samples using Haploview v.4.2 D′ and 2r values were pairwise calculated using the genotype dataset of each SNP. Linkage disequilibrium blocks were defined among the SNPs that showed “strong LD,” based on the default algorithm of Gabriel et al. D′ for strong LD were set at 0.98 and 0.7, respectively. Tag SNPs in the LD block were consequently determined using Tagger software with default settings, which is incorporated in Haploview and has been detailed in a previous report Single-nucleotide polymorphisms for the association studies were selected based on recently advanced tagging strategies U-test, Kruskal-Wallis test (with Steel-Dwass multiple comparison tests), or Spearman’s rank correlation test, were used to detect possible associations between any of the clinical or genomic parameters  and clinical endpoints related to pain sensitivity or the analgesic effects of fentanyl. Many factors other than the genotypes of the screened SNPs  may also influence the analgesic effects of fentanyl. Therefore, when a significant association between a genotype and clinical endpoint was found, factors other than genotype were compared between genotypes using nonparametric analyses according to the types of data to evaluate whether the genotype groups were controlled by other factors that might affect pain sensitivity, the analgesic effects of fentanyl, or fentanyl requirements, including age and sex. Furthermore, we conducted additional multivariate covariate analyses using the Stepwise method , although the nonparametric distributions of most of our data were not suitable for the application of such parametric techniques. Values of p<0.05 were considered statistically significant. The sample size of the present nonparametric data was higher than the estimated size that possesses statistical power (1 minus type II error probability) of 99% for the Cohen’s conventional “medium” effect size of 0.25, when power analysis was performed for analysis of variance with three genotype groups using G*Power v.3.1.3 Parametric and nonparametric data are expressed as mean ± SD and median [interquartile range], respectively. The statistical analysis was performed using IBM SPSS v.20.0.0 software . In the present study, none of the clinically measured endpoints that were related to pain sensitivity  or fentanyl analgesia  were normally distributed. Therefore, nonparametric analyses, including the Mann-Whitney CACNA1E gene, 223 SNPs among 1,199,187 markers included in the whole-genome genotyping (Human 1M-Duo v3 Bead Chip) were tested using genomic samples from 100 Japanese patients  tended to be greater in males than in females , 24 h postoperative fentanyl use (p = 0.042), and perioperative fentanyl use (p = 0.0036) were significantly associated with genotypes of the rs3845446 SNP (p<0.05) for pain management than those who did not carry this allele , 24 h postoperative fentanyl use , and perioperative fentanyl use  VACCs are classified as “resistant” to blockers of L-, N-, P-, and Q-type Ca2+ channels and have been poorly investigated compared with these types of channels. The development of mice that lack Cav2.3 VACCs v2.3 VACC antagonist SNX-482 derived from tarantula venom v2.3 VACCs to pain transmission and opioid analgesia. Cav2.3 VACC knockout mice showed normal pain sensitivity to acute mechanical, thermal, and chemical stimuli but exhibited reduced responsiveness to somatic inflammatory stimulation v2.3 VACCs by SNX-482 produced analgesic effects in the second phase of the formalin test, although it increased nociceptive behavior in the first phase v2.3 VACCs play differential roles in pain transmission, depending on the type of pain stimulus. In the present study, PPLpre evaluated with the cold pressor test was not associated with the genotypes of the SNPs in the CACNA1E gene, consistent with previous findings, and might suggest that Cav2.3 VACCs are not involved in cold pain transmission under naive conditions. Furthermore, Cav2.3 VACC knockout mice were reported to display enhanced morphine-induced analgesia in the tail-flick and hot-plate tests v2.3 VACCs may modulate the analgesic effects of opioids. In the present study, we found that fentanyl use for pain management was reduced, but the analgesic effects of fentanyl evaluated with the cold pressor test were not significantly altered in subjects with the minor G allele of the rs3845446 A/G SNP. Altogether, the rs3845446 A/G SNP or other polymorphisms in the same LD11 region may cause reduced expression levels of Cav2.3 VACC mRNA and protein or dysfunctional changes  and enhance the analgesic effects of opioids. However, the Cav2.3 VACC inhibition-induced enhancement of opioid-induced analgesia may depend on the type of pain stimulus or pain expression .The therapeutic potential of VACCs in pain management has been the subject of intensive recent investigations CACNA1E gene, and some of these SNPs have been reported to be associated with type 2 diabetes CACNA1E gene displayed a significant association with opioid analgesia, but still unknown is whether this SNP alters gene function or expression, which may be an important limitation of the present study. The rs3845446 A/G SNP represents LD11 from intron 46 to exon 47 that contains a stop codon of the CACNA1E gene. Interestingly, Cav2.3 VACCs reportedly contain several alternative splicing variants v2.3d, e, and f isoforms contain a 45-amino-acid insertion between exons 44 and 45 Click here for additional data file.


Chest wall syndrome (CWS), the main cause of chest pain in primary care practice,is most often an exclusion diagnosis. We developed and evaluated a clinicalprediction rule for CWS.Data from a multicenter clinical cohort of consecutive primary care patients withchest pain were used . A final diagnosiswas determined after 12 months of follow-up. We used the literature and bivariateanalyses to identify candidate predictors, and multivariate logistic regressionwas used to develop a clinical prediction rule for CWS. We used data from a Germancohort (n = 1212) for external validation.From bivariate analyses, we identified six variables characterizing CWS: thoracicpain , stabbing, well localized pain, nohistory of coronary heart disease, absence of general practitioner’sconcern, and pain reproducible by palpation. This last variable accounted for 2points in the clinical prediction rule, the others for 1 point each; the totalscore ranged from 0 to 7 points. The area under the receiver operatingcharacteristic (ROC) curve was 0.80  in thederivation cohort .Among all patients presenting CWS (n = 284), 71% (n = 201)had a pain reproducible by palpation and 45% (n = 127) were correctlydiagnosed. For a subset (n = 43) of these correctly classified CWSpatients, 65 additional investigations  had been performed to achieve diagnosis. False positives(n = 41) included three patients with stable angina . External validation revealed the ROC curve to be 0.76  with a sensitivity of 22% and a specificity of 93%.This CWS score offers a useful complement to the usual CWS exclusion diagnosingprocess. Indeed, for the 127 patients presenting CWS and correctly classified byour clinical prediction rule, 65 additional tests and exams could have beenavoided. However, the reproduction of chest pain by palpation, the most importantcharacteristic to diagnose CWS, is not pathognomonic. When evaluating a patient with chest pain, the initial diagnostic step aims to rule outa life-threatening cause such as acute coronary syndrome or a pulmonary embolism. HoweverCWS remains a diagnostic challenge . Due toWe used data from the TOPIC (Thoracic Pain in Community) cohort, a multicentre cohortof primary care patients with chest pain, to develop a clinical prediction rule forCWS. We then analyzed data from a German study , a multicentre cohort ofprimary care patients with acute chest pain, to validate our rule. The originalpurpose of both studies was to investigate the characteristics of chest pain inprimary care practice. Methods for both studies have been established previously anddescribed  in various publications ,10,19-30General practitioners (GPs) in 58 independent medical offices and the medicalresidents of one university hospital outpatient department in Western Switzerland participated in the TOPIC study. All consecutivepatients presenting with anterior chest pain over a three-to-nine-week period  from March to May 2001were included. Participating physicians had an average duration of experience inprivate practice of 12 years . They received detailedinformation on the study and were trained to complete the forms during a meeting. Thestudy protocol was approved by the Ethical Committee of the Canton of Vaud (Prot.41/2000) [Between October 2005 and July 2006, all attending patients with anterior chest pain were consecutively recruited to thisstudy by 74 participating GPs in the state of Hesse, Germany. The recruitment periodlasted 12 weeks for each practice. Patients were excluded when chest pain had lastedfor one month or had already been noted by the primary care physician. The overallstudy protocol was approved by the Ethical Committee of the Faculty of Medicine,University of Marburg [CWS is defined as a benign cause of chest pain localized to the anterior chest walland caused by a musculoskeletal disorder ,3. CWS iA literature review was performed for two purposes. First, we wished to determinewhether any clinical prediction rules for CWS had been generated for primary care.Bösner et al. developed a simple score containing four determinants, but it Information was recorded regarding GP activity, age, and experience, as well aspatient basic characteristics, key past history, pain characteristics, and associatedsymptoms. The first part of the case report form (CRF) included 70 questions onhistory and clinical examination of chest pain. With the exception of age, allvariables were dichotomized. Information about additional medical tests, thesuspected diagnosis, and treatment decision was also recorded . Follow-As described previously , GPs tooAll completed forms were sent to the study coordination centre. A set of predefinedcriteria was used for data entry checks, and the GPs were contacted to resolveinconsistencies or to complete missing data. Double data entry was used to identifytranscription errors. Data cleaning and validation was performed by a group ofphysicians experienced in research. When the diagnosis reported by the GP was notconsistent throughout the follow-up year, the final diagnosis for chest pain wasdiscussed and approved by a group of clinicians who were not aware of the aim of thisstudy. Quality control of the reported diagnosis was done using patients up to datemedical records at the GP’s office for a random ten percent sample of theincluded patients. No inconsistencies were identified.As described previously , particiUsing data from the derivation cohort alone, bivariate logistic regression analysiswas performed to detect variables associated with CWS. Odds ratios(ORs) ≥ 2.0 were retained as potentially relevant for themultivariate analysis. To prevent overfitting related to colinearity, we explored theadvantages of combining similar factors. For example, the variables “welllocalized pain ” and “well localized pain ” were combined to create the variable “well localized pain.” Variables were retained iftheir combination significantly improved the multivariate model compared to the useof either factor alone in the model . According to the regression coefficients in themultivariate analysis, weights (points) were attributed to each factor in order tobuild a score. The area under the receiver operating characteristic (ROC) curve wasmeasured as an indicator of the discriminatory power of the score. We arbitrarily setthe cut-off for specificity at ≥ 85%. Other researchers have usedthis cut-off for specificity .The retained score was then applied to the validation cohort for external validation.Clinical signs that were not reported by the physician were considered absent bydefault. A second analysis was performed by multiple imputation for missing values ofthe key variable . In the validation cohort, the bestproxy for "pain well localized" was "localized muscle tension". The extent of painfrom other tissues could not be taken into account. Area under the ROC curve,sensitivity, and specificity were calculated in both cohorts. All analyses wereperformed with StataCorp. 2009 Statistical Software .A total of 664 patients with chest pain, aged 18 years and over, were included in thederivation cohort . Of these, 618 (93%) completed a 12-month follow-up with anavailable diagnosis. For the 46 cases with no formal diagnosis at 12 months, 25 died,two moved, and 19 had no diagnosis. However, diagnoses were available for 26 of thesepatients, with the diagnosis known before death or retained at the 3-month follow-up.Therefore, the population analyzed in this study consisted of 644 patients Table . Only vaGiven its stronger regression coefficient (1.64) the variable “painreproducible with palpation” accounted for two points and the other variablesfor one point, for a total score ranging from 0 to 7 points. The area under the ROCcurve was 0.8 , stabbing pain, well localized pain, no history of coronary heart disease,absence of GP concern, and pain reproducible by palpation (2 points). In the derivationcohort, the area under the curve was 0.8 and the specificity was 88.6% (319/360). Theexternal validation showed 93% (604/647) specificity with an area under the curve of0.76 . In addition, we observed that the reproductionof chest pain by palpation is not pathognomonic of CWS.The strengths of our study include the large numbers of participating GPs and patients,allowing us to assume that our sample is fairly representative. We implemented apragmatic strategy by consecutively including patients through their GP practice. Weachieved an excellent follow-up at one year (96%), and more than half of the patientslost to follow-up had an available diagnosis. A key feature of our study was ourexternal validation, which allowed us to confirm our results. However, our study suffersseveral limitations. First, delayed diagnosis was used as a reference in the absence ofa panel of experts or an independent diagnostic process. It was not possible to performadditional tests systematically in all patients. Second, there is currently no consensusabout the determinants or the designations of CWS in the literature. Third, there was nospecific calibration for the variable “pain reproducible with palpation,”which may have induced differences in individual interpretations. Fourth, some variableswere not available for external validation, and although they were relevant to thebivariate analyses, they could not be included in the development of the clinicalprediction rule. Fifth, the two cohorts showed design differences, what could weakentheir comparison. Only patients with acute chest pain were included in the validationcohort; in addition, the reference diagnosis was made by means of a telephoneinterviewof the patient in the validation cohort. The TOPIC study was not originally designed forthe development of a clinical prediction rule for CWS; if it had been, then otherdiagnostic criteria may have been explored.Our requirement that the prediction rule be highly specific leads, unsurprisingly, to arelatively low rate of patients with CWS correctly classified in the derivation cohort(127/284 = 45%). A lower rate (124/565 = 22%) in the validationcohort can be partly explained by design differences and semantic limits. In thederivation cohort, the 41 false positives were not life-threatening cases; most of thesecases were easily identifiable and were associated with a plausible pathophysiologicalmechanism for chest pain such as trauma or thoracotomy. Interestingly, parietalmetastases were not classified as false positives. However, our score misclassifiedthree patients  with stable angina as CWS. For these threepatients, the GPs had noted symptoms and signs for CWS as well as for cardiovasculardisease, and we therefore suspect the co-existence of both diagnoses for these threepatients. Therefore, patients with a positive CWS clinical prediction rule in thepresence of other signs of chest pain must be carefully examined and monitored for thefinal diagnosis and evolution of chest pain.In the literature, we found no consensus about the classification or the determinants ofCWS, and the pertinence of some variables is ambiguous. This lack of clarity had alreadybeen identified ,3,35,36.Universal consensus requiresthe exclusion of a potentially life-threatening cause ofchest pain in the emergency department and in primary care practice ,39, and In conclusion, CWS is a frequent diagnosis in primary care that is well known by generalpractitioners but has been insufficiently studied in the literature. Our proposedclinical prediction rule constitutes a tool that can be used in addition to the usualprocess of diagnosing CWS by elimination. Moreover, because its high specificity, a highpositive score may help clinicians to avoid ordering additional tests. For instance,using this tool, 65additional exams for 127 patients could have been avoided in thederivation cohort. We propose that our clinical prediction rule should be included inthe clinical diagnostic reasoning of physicians encountering a patient with chest painin primary care, keeping in mind that it does not exclude the presence of concomitantdiagnoses.2, Coefficient of determination; ROC, Receiveroperating characteristic; 95%CI, 95% confidence interval.AUC, Area under the curve; CRF, Case report form; CWS, Chest wall syndrome; GP, Generalpractitioner; OR, Odd ratio; RThe authors declare that they have no competing interests.FV and LH conceived the study, participated in patient inclusion, were the principleinvestigators, and critically revised the manuscript. BB and BF participated in thedesign of the study and critically revised the manuscript. PV designed the statisticalanalysis, and participated in drafting the manuscript. AR performed the statisticalanalysis and wrote the manuscript. TB participated in patient inclusion and criticallyrevised the manuscript. JH, NDB and SB participated in the statistical analyses of theexternal validation and critically revised the manuscript. All authors accepted themanuscript after reading.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/13/74/prepub


Knee osteoarthritis is the most common type of arthritis, with pain being its most common symptom. Little is known about the psychological aspects of knee osteoarthritis pain. There is an emerging consensus among osteoarthritis specialists about the importance of addressing not only biological but also psychosocial factors in the assessment and treatment of osteoarthritis. As few studies have evaluated the effect of psychological interventions on knee osteoarthritis pain, good quality randomized controlled trials are needed to determine their effectiveness.We intend to conduct a 6-week single-blinded randomized controlled trial with a 12-month follow-up. Altogether, 108 patients aged from 35 to 75 years with clinical symptoms and radiographic grading (KL 2–4) of knee osteoarthritis will be included. The clinical inclusion criteria are pain within the last year in or around the knee occurring on most days for at least one month, and knee pain of ≥40 mm on a 100-mm visual analogue scale in the WOMAC pain subscale for one week prior to study entry. Patients with any severe psychiatric disorder, other back or lower limb pain symptoms more aggravating than knee pain, or previous or planned lower extremity joint surgery will be excluded. The patients will be randomly assigned to a combined GP care and cognitive-behavioral intervention group (n = 54) or to a GP care control group (n = 54). The cognitive-behavioral intervention will consist of 6 weekly group sessions supervised by a psychologist and a physiotherapist experienced in the treatment of pain. The main goals of the intervention are to reduce maladaptive pain coping and to increase the self-management of pain and disability. The follow-up-points will be arranged at 3 and 12 months. The primary outcome measure will be the WOMAC pain subscale. Secondary outcome measures will include self-reports of pain and physical function, a health related quality of life questionnaire, and various psychological questionnaires. Personnel responsible of the data analysis will be blinded.This study addresses the current topic of non-pharmacological conservative treatment of knee OA-related pain. We anticipate that these results will provide important new insights to the current care recommendations.Current Controlled Trials ISRCTN64794760 Osteoarthritis (OA) is the most common form of arthritis and a major contributor to functional disability . It reprKnee OA is the most common type of arthritis. The main symptom of knee OA is pain, which is generally related to joint use and relieved by rest. However, the association between radiological changes in knee OA and the severity of pain or the level of disability is not straightforward. As OA progresses, the pain may become more persistent and also manifest itself at rest. In addition to pain, loss of function and joint stiffness are typical symptoms of OA, which often lead to difficulties in performing daily activities.The assessment and treatment of pain is vital to the management of OA . It is kThe cognitive-behavioral (CB) perspective presented by Turk et al.  is the mAccording to several reviews, psychological factors influence not only pain and disability, but also in particular the transition from the presence of acute to chronic pain ,16. HoweThere are several trials that have used behavioral interventions with similarities to CB principles as well as studies that have integrated CB principles with other forms of rehabilitation in OA patients. For example, Hurley et al. conducted an RCT assessing the effects of a combined exercise, self-management, and active coping strategies rehabilitation program . They foOne CB-based approach in treating pain-related disability and chronicity is the 6-session group intervention model presented by Linton . The modThe present study aims to explore the effectiveness and cost-effectiveness of the CB group intervention described by Linton , modifieThe proposed research is a 6-week open study with follow-up-points at 3 and 12 months from the beginning of the study. The participants will take part in 6 group meetings each lasting 2 hours. The meetings will be supervised by a trained psychologist and a physiotherapist according to a CB intervention model presented by Linton . At the Our aim is to recruit 108 patients mainly from primary care providers in the Kuopio area of eastern Finland. Our primary recruitment strategy is to dispatch recruitment letters to patients aged from 35 to 75 years who have had knee radiographs with knee OA changes taken in public primary care locations . The study doctors will check the knee radiographs of each patient from an X-ray database and knee radiographs will be graded according to the Kellgren-Lawrence (KL) classification . The recAll study candidates will receive a recruitment letter containing information about the study as well as a preliminary questionnaire and an informed consent form. The preliminary questionnaire will contain a comprehensive list of other comorbidities, including psychiatric illnesses. In the preliminary questionnaire the patients will be asked if they have other back or lower limb pain symptoms that are more aggravating than their knee pain (yes/no). After receiving the signed informed consent and the questionnaire, the study doctors will check the knee radiographs based on KL classification and determine the patient’s eligibility according to the inclusion and exclusion criteria of the study Table . PotentiThe patients will be randomly assigned to either the GP care and intervention group (n = 54) or the GP care control group (n = 54). Randomization will be conducted in blocks of six, separately for men and women. A computer-generated code for randomization will be constructed by a statistician who will not meet the study patients, and it will be administered via sealed opaque envelopes. The personnel responsible for data collection will be blinded to group assignment and will not be involved in providing the interventions. The code for randomization will be opened only after the statistical analyses have been performed after the 12-month follow-up point.A CB group intervention with 6 weekly sessions will be supervised by an experienced psychologist and a physiotherapist. The sessions will take place in a group of 8–10 persons according to the model presented by Linton . Each seThe same psychologist and physiotherapist who are both experienced in group-based rehabilitation interventions as well as in pain management will arrange the CB program for all the intervention groups. They have been trained for this particular CB intervention by going through in detail the session manual for therapists  and its The assessment points of this study are the baseline and 3 and 12 months, at which time points the questionnaires will be sent by post to the patients with a pre-paid return envelope. At the baseline, information will be gathered on the demographics, comorbidities, work history, and previous rehabilitation measures. The primary and secondary outcomes and other measures are listed in Table The primary outcome measure of the study is the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) self-reported pain subscale ,29, whicSecondary outcomes of the study will include WOMAC stiffness and physical function subscales -31, as wThe mean (±SD) knee joint pain score  was estimated by using the results of the knee joint pain scores in previous studies ,61. SincDemographic characteristics and baseline data will be summarized by descriptive statistics. Randomly missing data in the longitudinal set-up will be imputed using expectation–maximization algorithm before the analysis in order to follow the intention to treat principle. Data on various psychological variables predicting reported knee pain will be assessed by multiple regression analysis. For outcomes measured on a continuous scale, differences between groups in the mean change from the baseline to 12 months will be evaluated using the linear mixed modeling. The model assumptions will be checked by standard diagnostic plots. The participant rating of the global assessment of change will be compared between the two groups using the two-tailed Student t-test.Cost-effectiveness of the intervention will be evaluated by cost-utility analysis which is a techniques that incorporates the expenses of the intervention as well as the costs of the use of health care services and pain medication, sick leaves, rehabilitation and pensions. Utility analysis is based on measurement of QALY from 15D . Life exThere are several reasons why this study will advance our understanding of effective interventions to improve conservative knee OA treatment. First, there have only been a few studies evaluating the effect of psychological interventions on knee OA pain. Thus, good quality RCTs are needed to determine their effectiveness. As present, very few studies have evaluated a CB intervention for knee pain treatment, as far as we are aware this will be the first study to tackle this particular CB intervention model in treating OA patients. Second, the proposed research will address the very current topic of non-pharmacological conservative treatment of knee OA, and the results may have a significant impact on current care recommendations. Since knee OA is the most common form of arthritis, representing a major economic burden on social welfare and healthcare systems for both society and individual patients, it is worthwhile to find novel cost-effective interventions promoting conservative treatment. Third, it is important to evaluate this kind of CB intervention since cognitive and psychological factors are known to play major roles in chronic pain, pain severity and disability. Moreover, evidence-based guidelines indicate that one should adopt a the combination of pharmacologic and nonpharmacologic modalities to achieve adequate management of knee OA -66. WithThe study protocol has some limitations. First, due to volunteer bias, the results of psychological intervention studies may have limited generalizability . Second,Another limitation of the study might be the different amount of attention paid to the two groups. As the group of patients in the intervention will receive 12 hours more attention, a Hawthorne effect -70 is prBDI-21, BAI, 13-item SOC scale, TSK, PSEQ and LS questionnaires have been used in several clinical studies in Finland ,50,52-55Obtaining and assessing KL grades are not simple tasks. Valid measures are dependent on knee flexed standing views ,72 and eNo significant side effects or adverse events are expected.The authors declare that they have no competing interests.E-EH, JA and SS designed the trial protocol. E-EH and JA will be responsible for patient recruitment. SS, RV-R, E-EH and JA adjusted the intervention program to OA patients. SS and RV-R will hold the intervention sessions for the participants. E-EH, JA and SS drafted the manuscript. AV translated the Session manual for therapists. E-EH translated the patient example of the Session manual for therapists. JA and E-EH applied for the project funding. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/46/prepub