To describe the translation and cultural adaptation of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire into Brazilian Portuguese, and verifies the reliability and validity of this new version. A cross-cultural adaptation of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire was performed using the following steps: translation, back-translation, committee review, and pre-testing phase (50 subjects). The psychometric properties were evaluated by application of the questionnaire to 102 patients. Reliability was assessed by homogeneity and stability of measures. The criterion-related validity was tested by comparing scores of Japanese Orthopaedic Association Back Pain Evaluation Questionnaire to Oswestry and Medical Outcomes Study 36 - Item Short questionnaires. Excellent internal consistency was found in both test (Cronbach’s α of 0.90) and re-test (Cronbach’s α of 0.91). The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire showed good reliability and the correlations ranged from reasonable (0.64) to very good (r=0.91). The Brazilian Portuguese version of Medical Outcomes Study 36 - Item Short was easy to apply and understand. The questionnaire had a great impact on assessment and multidimensional care of patients with low back pain. This disease is an important factor that causes absences from work, therefore, massive economic and social impact. Strategies to treat chronic low back pain vary considerably from country to country or even in different areas within the same country.Low back pain is a common musculoskeletal disorder that affects mainly economically active adults.1 This Therefore, general aspects of low back pain have been studied, including disability, rehabilitation, and compliance. Several reports described different scales and questionnaires to assess a number of aspects of low back pain, including perceived disability, quality of life, severity, intensity, pain distribution, and functional status.(-)The prognosis of chronic low back pain is uncertain because it includes several interlinked variables, which stimulates the search for new approaches to deal with this problem.3 Ther(-) It is a simple and effective method to assess lumbar back pain. In addition, the need of comparing different ethnic groups motivated the development of a Brazilian version of the questionnaire.The number of publications on lumbar degenerative disorders has significantly increased in Asian countries in recent decades. In many studies, Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) published a review of this questionnaire that had improved outcomes assessment. After, several studies showed the efficacy of JOABPEQ to evaluate lumbar disorders.-12 ITo describe the translation and cultural adaptation of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire into Brazilian Portuguese, and verifies the reliability and validity of this new version.Santa Casa de Misericórdia de Santos between 2011 and 2013. All patients received explanation about the study and those who agreed to participate signed the Informed Consent. The study was approved by the Institutional Ethics and Research Committee, with CAAE: 21338713.3.0000.5478/670.821.The JOABPEQ was applied in patients from the outpatient clinic of orthopedic diseases of the In the pre-test evaluation we included 50 subjects  to apply the preliminary version of the questionnaire. In the second step, 102 adults were included  in the main study and they responded to the translated version of JOABPEQ.The inclusion criteria were presence of chronic lumbar back pain (minimum 7 weeks of symptoms) and patients aged 18 and 70 years. In order to homogenize the sample, we excluded all patients who underwent surgery. Patients were not classified by disease or type of treatment. We did not considered any correlation between nosological classification of diseases and JOABPEQ scores, because it was not the goal of our study.Santa Casa de Misericórdia de Santos School Hospital. Participants completed forms during their rehabilitation period. Patients’ clinical history were evaluated to verify if they met the inclusion criteria of the study, and those who fulfilled the criteria were invited to participate during their clinical follow-up visits.All the patients were selected from the Orthopaedic and Physical Therapy Departments of The JOABPEQ has 25 questions that analysis and interpretation were grouped in the following sub-scales: low back pain, lumbar function, walk ability, social life function and mental health. The higher the score the better the patient’s condition. The end of the questionnaire presents three visual scales so we can complete the assessment in relation to pain with degrees for low back pain, buttocks and lower limb pain, and numbness in buttocks and lower limb . and Medical Outcomes Study 36 - Item Short (SF-36) questionnaires.For the process of translation, cultural adaptation and validation of the JOABPEQ in the Brazilian population, we also used the Brazilian versions of Oswestry13 and allow the evaluation of functional disability presented by the patient, based on the level of pain, at different activities in daily life. This questionnaire includes ten questions about daily life activities and patient’s responses to the questions assessing the pain impact during these activities. Results range from zero (minimum disability) to 100 (disability).The Brazilian version of Oswestry13 all also validated for Brazilian population, was used to evaluate quality of life, through 8 areas divided into 12 questions. The impact of questions is measured according to the authors’ recommendation to classify patients. Results are given separately for each domain, ranging from zero to 100, and 100 is the best possible result.The SF-36 questionnaires,14 als(-) according to the following steps: the original English questionnaire was translated into Portuguese by two independent translators, both fluent in the target language with good understanding of source language (blinded translation); synthesis of the two Portuguese versions in a single version was done by a trained professional in languages who checked spelling, grammar and overall style and response options; retranslation into English was done by two independent translators who were fluent in the source language (blinded retranslation); synthesis of the two English versions was compiled in a single version by a native English speaker language professional, and this new version was compared to the original version of the questionnaire for consistence; review by committee composed by health professionals, English and Portuguese speaking professionals and members who participated in the questionnaire preliminary analysis, and its main function was to verify the interpretation of each question and the answers; pre-test application for individuals who had low back pain. This phase was important to identify the understanding, acceptance and emotional impact of the questionnaire items, in addition to detect items that were confuse or misunderstanding. After that, a consensus meeting was promoted to the needed minor semantic adjustments to final edition of the questionnaire new version (The translation of the JOABPEQ into Brazilian Portuguese followed the recommendations of American Association of Orthopedic Surgery (AAOS) and the International Quality of Life Assessment (IQOLA) guidelines,-17 a version . At leasThe validity of JOABPEQ was determined by the assessment of criterion-related validity, which verifies the association between the instrument with others questionnaires that are recognized as valid. The questionnaires we used were already described above.Santa Casa de Misericórdia de Santos and their data were strictly recorded to allow monitoring during the period of the study.The retest step was possible because patients who were part of the study were monitored periodically by the orthopedic diseases clinic of the t-test. The evaluation of the validity  was performed using Pearson’s correlation coefficient, ranging from 0.00 to 1.00 . The level of significance adopted was 5%.To statistical analysis we used the Statistic Package Social Science (SPSS) version 17. Internal consistency was checked with Cronbach’s α coefficient for JOABPEQ results in test and retest. The test-retest reliability was assessed using Pearson’s correlation coefficient with paired The cultural adaptation process occurred successfully, and all steps were followed. The questionnaire was applied in pre-test phase among fifty patients. After this step, we revised the questionnaire for data collection and statistical analysis. Reliability was assessed by internal consistency and stability (test-retest). Regarding internal consistency analysis, JOABPEQ showed excellent results in both test (Cronbach’s α of 0.90) and retest (Cronbach’s α of 0.91). The t-test results) showed that the agreement is weak for the lumbar function and mental health domains, which shows a weak reliability for these items. In the areas of lumbar pain, ambulation and social life, good reliability was found.Although high degree of association was seen between the results in the test and retest (Pearson’s correlation coefficient results), the mean difference between this score . These results can be seen in The association between results of JOAPEQ and the Oswestry questionnaire was statistically significant. In Association was statistically significant between questionnaires in all domains, except for JOABPEQ deambulation and SF-36 mental health. JOABPEQ mental health had high association with SF-36 vitality, social functioning, and mental health, and moderate association with functional capacity, pain and general health status. JOABPEQ social life had the best association with SF-36 functional capacity and pain. There was a high association between JOABPEQ deambulation and lumbar function in SF-36 functional capacity.The JOABPEQ is a questionnaire to assess various aspects of back pain, including perceived disability, quality of life, severity, intensity, pain distribution and functional status. The assessment tool score includes five categories (25 items) selected from the Roland Morris Disability Questionnaire, SF-36, and a Visual Analogue Scale. The results range from zero (worst pain) to 100 (no pain).This study described the translation and cultural validation into Brazilian Portuguese of the JOABPEQ. The JOABPEQ is a relatively new assessment tool, which was validated in Japan in 2007 by Fukui et al.10 TheRecently, the number of Asian publications has increased. This, added to the fact that the JOABPEQ is frequently cited in a number of studies, the translation into Brazilian Portuguese is relevant, particularly because it enables to compare treatments in different ethnic groups.Several rating scales have been used for the analysis of patients with lumbar back pain. In Brazil, a Portuguese version of Oswestry questionnaire is often the scale of choice. For this reason we compared Oswestry questionnaire to the new Brazilian Portuguese version of JOABPEQ. In addition, two other tools used worldwide for analysis of quality of life  were compared as valid measures.The Brazilian Portuguese version of JOABPEQ had excellent internal consistency. In our study, the Cronbach’s α values observed on test and retest were 0.90 and 0.91, respectively. These values are better than the one described by Azimi et al., .18 It is also important to note that these domains may be influenced by other aspects of everyday life that could not be measured by the instrument.Regarding results of measures of stability (test-retest), the Brazilian version of JOABPEQ had good reliability, excepting for the lumbar function and mental health domains. The hypothesis to explain might be that current version was applied exclusively to non-surgical patients, while the previous articles also evaluated surgical ones. Different diseases may lead to different scores results, and we have the influence of several factors on JOABPEQ results, such as sex, age and type of disease and treatment.12 It  Long periods can compromise the interpretation of results because of clinical changes that may occur with the subject. On the other hand, too short times results can suffer from “memory effect” and do not represent reliable values. In our study, the average interval between evaluations was 4 days, ranging from 3 to 5, which is desirable in this kind of research.Another factor that may have influenced these results was the time interval in test and retest. The interval between the test and retest assessment is an important factor to be considered.19 LonAnother hypothesis to explain these discrepancies in these two domains may fall on the impact of statistical analysis chosen, as, of all the variables considered in the calculation, only one is ordinal, and the remaining nominal can lead to the divergent results found for these domains. This aspect should be considered as a limitation of this study.To verify the validity of a questionnaire means to check whether it actually measures what it is intended to. For this evaluation, we analyzed the association of the JOABPEQ with other instruments already validated in the Portuguese language.Most of the associations found between the JOABPEQ domains with the Oswestry and SF-36 questionnaires were moderate and high, which agreed and assured good use of the instrument in the Brazilian population.The association of the JOABPEQ lumbar pain domain with the Oswestry questionnaire and all domains of the SF-36 questionnaire was considered low. This low association might occur because both Oswestry and SF-36 questionnaires do not directly assess pain intensity. In the Oswestry questionnaire only one of questions directly assessed the intensity of pain and the SF-36 questionnaire assessed pain through quality of life.These variations may have occurred because of the type of patients included in our study. Our patients did not have degenerative changes of the lumbar spine and their clinical presentation had small changes that were not found equally in all instruments used during the validation process. In the existing publications, only Thailand’s version performed the JOABPEQ validation comparing with the SF-36 questionnaire and found results similar to our study.We have not found in the literature many validation studies of the JOABPEQ to other languages.,,, InAnother aspect that can be observed by comparing our study with the three others that translated JOABPEQ was that statistical tests chosen can developed non-comparable interpretations. Our study sought to follow international recommendations already mentioned, even concerning data analysis.The qualitative advantage of the JOABPEQ questionnaire is that easiness and rapid application, to apply the questionnaire does not take longer than few minutes. Our study confirmed that no instrument applied alone is complete enough to evaluate a pain, mainly a complex pain such as chronic low back pain.Limitations of this study were the difficulty some patients to respond the questionnaires because of their low educational level and the latent presence of chronic lumbar pain in part of the sample, a fact that may have influenced our results.The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire adaptation process to the Brazilian Portuguese was adequate. The instrument had excellent psychometric properties and its application was reliable within Brazilian population.


Synovial membrane inflammation is the most common finding presenting during hip arthroscopy, and may play a role in hip pain. We sought to determine the relationships between synovial cytokine levels, hip pain, and arthroscopic findings of the hip joint.We prospectively included 33 patients who underwent arthroscopic hip surgery (34 hips). For all patients, radiographs and severity of pain were evaluated preoperatively. During arthroscopy, we classified the chondral injury and synovitis, noted the incidence of labral tear and its instability, and a sample of the synovial membrane was harvested for quantitative PCR to determine levels of TNFα, IL1β, IL6, ADAMTS4, MMP1, and MMP3. The relationships between the levels of these cytokines, severity of hip pain, and the pathological findings during arthroscopy were examined.r = 0.45, p < 0.01), while VAS score on walking showed a positive correlation with TNFα , and ADAMTS4 . The modified Harris Hip pain score showed a negative correlation with TNFα  and IL6 .Pain intensity and cytokine levels were not significantly different between patients with labral tear or instability and those without. By contrast, the expression of TNFα, IL1β, IL6, and MMP1 mRNA was significantly higher in patients with diffuse synovitis than in patients with focal synovitis. VAS score during rest showed significant positive correlation with IL6 (The severity of synovitis and chondral injury are considered to be more important in the pathology of hip pain than labral tear or instability. Inflammatory cytokines, especially TNFα and IL6 might play an important role in the pathogenesis of pain in patients indicated for hip arthroscopy, possibly depending on the severity of synovitis. Hip arthroscopy has become a common technique for both the diagnosis and treatment of painful hips  more often than in people with OA, but without pain , and the study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All patients included provided their written informed consent to participate in the present study. We prospectively included 33 patients who were about to undergo arthroscopic hip surgery (34 hips). Exclusion criteria were patients aged 60 years or older, patients diagnosed with OA severity of Tönnis grade 3 or higher, or with inflammatory disease such as rheumatoid arthritis and purulent arthritis, or synovial chondromatosis. All patients complained of groin pain, restricted hip motion on flexion and internal rotation, and had a positive anterior impingement test. Our indications for arthroscopic hip surgery were labral tears and/or increased synovial fluid identified with pre-operative magnetic resonance imaging (MRI), and pain relief with 10 mL injection of 0.5% procaine hydrochloride into the hip joint at the initial visit. All patients were resistant to conservative treatment with medication and physical therapy, which was indicated for at least 3 months. During these 3 months, no patients were medicated with non-steroidal anti-inflammatory drugs or steroids. For all patients, age, sex, and clinical history were recorded. Physical examination, antero-posterior (AP) and cross-lateral plain radiographs, and MRI were evaluated. The pain component of the modified Harris Hip Score (mHHS) and visual analog scale (VAS) score at rest and on walking were evaluated preoperatively Murray .The centre-edge (CE) angle of the hip joint was measured using an AP plain radiograph. AP plain radiographs of the hip joint were assessed for the presence of coxa profunda and protrusio acetabuli, and CE angle ≥40°, which are indicators of a deep socket, a crossover sign known as an indicator of acetabular retroversion. The femoral α angle was measured; hip joints with a femoral α angle ≥55° were defined as having cam deformity. Patients having hip joints with a deep socket, acetabular retroversion or femoral cam deformity, or both, were defined as having femoroacetabular impingement (FAI)  were used in all cases. Gentle traction was applied to bilateral legs and a spinal needle was used to establish the anterolateral portal over a guide wire using fluoroscopy. With the camera in the anterolateral portal, the spinal needle was introduced into the location of the mid-anterior portal. By way of these two portals, we assessed the incidence of any labral tear and its instability as reported by Lage et al., and classified any chondral injury using the Outerbridge classification  according to the manufacturer’s instructions, and was used as a template for first-strand cDNA synthesis using SuperScript III RT (Invitrogen). The PCR reaction mixture consisted of 2 μL cDNA, the specific primer set , and 12.5 μL SYBR Premix Ex Taq  in a final volume of 25 μL. The sequences of the PCR primer pairs are listed in Table Six molecular biomarkers of inflammation within the synovium were measured: tumor necrosis factor-α (TNFα), interleukin-1β (IL1β), IL6, A disintegrin and metalloproteinase with thrombospondin Motifs-4 (ADAMTS4), matrix metalloproteinase-1 (MMP1), and MMP3.We determined the correlations between VAS score or mHHS pain score and arthroscopic findings. The relationships between pain intensity or arthroscopic findings and cytokine levels in the synovial membrane were determined.n (%). A Pearson chi-squared test was used to determine the correlations between labral tear or labral instability and inflammation of the synovial membrane. A non-parametric Mann-Whitney U test was used for comparisons of normally distributed data among the groups . When the minimum detectable difference was considered as 2.5 for VAS on walking, with 80% power and an α level of 0.05 the sample size was calculated as 24. A p < 0.05 was considered significant. Correlation coefficients were analysed to assess the associations between VAS, pain score of mHHS, and synovial cytokine levels.Statistical analyses were performed using JMP version 11.0 software . Continuous variables are expressed as the mean and the standard error of the mean unless otherwise indicated, while categorical variables are expressed as In 33 patients (34 hips), there were 10 men (11 hips) and 23 women (23 hips) with an average age of 41.8 ± 2.5 years. Their mean pre-operative VAS score was 27.3 ± 3.2 during rest and 59.4 ± 3.5 on walking. Their pre-operative mean mHHS score was 57.5 ± 1.8 in total and the pain component was 25.6 ± 1.1. In plain radiographs, 22 hips (64.7%) were classified as Tönnis grade 0, 10 hips (29.4%) as grade 1, and 2 hips (5.88%) as grade 2. The radiographic findings related to FAI in 16 hips (47.1%) were investigated.Based on arthroscopic findings, 29 hips (85.3%) were identified as having labral tears. Of the 29 hips with labral tear, labral instability was identified in 18 hips (62.1%), which needed labral fixation. In the Outerbridge classification, 5 hips (14.7%) were grade 0 , 16 hips (47.1%) were grade 1 (cartilage with softening and swelling), 7 hips (20.6%) were grade 2 , 4 hips (11.8%) were grade 3 , and 2 hips (5.9%) were grade 4 . No hip was identified as grade 1 (no synovitis) by our classification, 16 hips (47.1%) as grade 2 , and 18 hips (52.9%) as grade 3 (diffuse synovitis). We found no significant correlations between labral tear or labral instability and inflammation of the synovial membrane.Based on the arthroscopic findings, none of the VAS scores during rest, VAS scores on walking, or mHHS pain score were significantly different between patients with or without labral tear or instability, or between patients with focal or diffuse synovitis Table . The sevp < 0.05).We compared cytokine levels with pathological findings during hip arthroscopy Table . Existenr = 0.453, p = 0.0071), while VAS score on walking showed a significant positive correlation with TNFα  and ADAMTS4 . mHHS pain score showed a significant negative correlation with TNFα , IL6 , and ADAMTS4 . The mHHS total score showed a significant negative correlation with TNFα  and IL6 .We determined the correlations between the pain, loss of function experienced by patients, and synovial membrane cytokine levels Table . VAS scoIn the current study, we examined the relationships between synovial cytokine levels, hip pain, and pathological findings during hip arthroscopy. We found pain tended to be more severe in patients with a worse grade of chondral injury or synovitis than in those with labral tear or instability. The expression of TNFα, IL1β, IL6, and MMP1 mRNA was significantly correlated with the severity of synovitis. We investigated the correlations between clinical pain scores and expression of IL6, TNFα, and ADAMTS4.In knee OA, synovitis is recognized as a secondary phenomenon related to the cartilage degeneration induced by the release of cytokines or matrix proteases from articular cartilage into the synovial fluid, inducing knee pain (Higuchi et al. Expression of TNFα, IL1β, IL6, and MMP1 mRNA was significantly higher in patients with diffuse synovitis, compared with patients with focal synovitis. Additionally, TNFα showed a tendency to be more highly expressed in patients with severe chondral injury. In knee OA, Smith et al. reported that the expression of TNFα mRNA in synovial membranes was positively correlated to the degree of articular cartilage degeneration and severity of synovitis (Smith et al. MMPs are important mediators in OA, and are in turn mediated by cytokines such as TNFα and IL1β, which are produced by synovial macrophages (Bondeson et al. TNFα sensitizes nociceptive neurons via the induction of a proinflammatory cytokine cascade involving IL-6, inducing inflammatory pain (Woolf et al. We did not find any significant correlation of labral tears or instability with either the severity of pain or synovial membrane cytokine levels in the present study. However, because of the small sample size used, the study may have lacked sufficient power to detect small differences in pain. Our results suggest that the severity of chondral injury and following synovitis, which reflects the severity of inflammation, might have more influence on pain severity than labral pathology in patients meeting the criteria for inclusion. Furthermore, our results suggest that labral tearing might not affect the severity of synovitis. In knee joints, asymptomatic meniscal tears are seen generally, and whether or not meniscal tears are symptomatic depends on the existence of local synovitis (Hunter et al. Limitations of this study include its small sample size and lack of controls, for example patient participants with another hip diagnosis, or healthy volunteer participants without hip pain. The inability to find a significant correlation between pain intensity and cytokine levels may have been because the study lacked sufficient power to detect small differences in pain intensity as a result of the small sample size. A comparable study using a larger sample size is warranted to confirm our findings and elucidate the pathomechanism of hip joint pain in more detail.Severity of synovitis and chondral injury are considered to be more important pathologies for the origin of hip pain than labral tears or instability. Inflammatory cytokines, especially TNFα and IL6, might play important roles in the pathogenesis of pain in patients indicated for hip arthroscopy.


COMT (Catechol-O-Methyl Transferase) gene may influence a person’s vulnerability to develop long-term pain and some COMT single nucleotide polymorphisms (SNPs) may associate with patterns of acute or chronic pain. Many patients with whiplash-associated disorders (WADs) suffer from long-term pain and other related symptoms, but it is less known if genetic factors play a role in the recovery process. The primary aim of this study was to evaluate whether self-reported non-recovery, including pain, was related to COMT genotype in patients with WAD. The secondary aim was to investigate whether or not background factors, including mental health, were related to genotype and non-recovery.The COMT gene; additionally haplotypes were estimated and haplogenotypes inferred. The patients were followed up after 12 months and asked to rate their recovery including pain, mental health and quality of life.A total of 133 patients with neck pain after a whiplash trauma were included. Background factors were collected and blood samples were taken during the acute phase after the accident. DNA was isolated from blood and used to genotype the SNPs rs6269, rs4633, rs4818 and rs4680 in the COMT haplotypes. High levels of self-reported pain (OR 7.2) and anxiety (OR 4.4) after the accident were associated with non-recovery, but not related to the haplotypes. None of the other background factors were related to the haplotypes or non-recovery.The overall reported non-recovery rate at 12 months was 44% with no significant differences in distribution of the COMT haplotypes in patients with acute whiplash injuries could be detected. Independent replications are necessary to discard the hypothesis that COMT haplotypes do not influence non-recovery or pain levels in patients with acute whiplash injuries. High levels of initial pain and anxiety were associated with non-recovery, thereby confirming previously published reports.No association between self-reported non-recovery or pain levels and  Despite several attempts to understand the differences in the prognosis of recovery after a whiplash trauma, the biological mechanisms remain unexplained. The main symptom in patients with a whiplash-associated disorder (WAD) is long-lasting pain . InitialO-methyltransferase (COMT) gene is one of the most well-studied ones [It has been suggested that genetic predisposition might play a role in the pathogenesis of WAD. In the field of pain genetics, the catechol-ied ones . It has ied ones , as wellied ones , 9, loweied ones  and alsoied ones . Tammimäied ones .COMT gene regulates formation of both soluble and membrane-bound protein isoforms. It contains many single nucleotide polymorphisms (SNPs), some of which have been investigated concerning their role in pain regulation. The COMT Val158Met SNP, rs4680, is the most frequently investigated variant [The  variant . The Met variant , as well variant . In addi variant .COMT gene contains functional polymorphisms that have been found to influence human pain [COMT variations could influence pain regulation and clinical outcome in this patient population.While the man pain –19, its man pain , it is pCOMT genotype in patients with WAD. The secondary aim was to investigate whether or not background factors, including mental health, were related to haplotypes and to non-recovery.The primary aim of this study was to evaluate whether or not self-reported non-recovery, including pain, was related to Patients were enrolled between September 2002 and January 2004. Potentially eligible patients had sustained a whiplash injury less than 24 h before arrival at the emergency department (ED). Exclusion criteria were WAD IV (fractures), age < 15 years, inability to read and understand the Swedish language and impaired cognitive function making the self-report impossible. The medical treatment was administered according to the routine protocols at the hospital. The patients were informed about the study and those who agreed to participate were invited to an out-patient visit for inclusion. The patients were originally part of a randomized controlled trial in which standard treatment was compared with an intervention .A blood sample for the genetic analysis was taken and the participants were asked to fill in questionnaires regarding socio-demographic information, including age <24, 25–65, >66), gender, educational level (high school or less or university), working status, marital status and ethnic background . They were asked to rate their health-related quality of life (HRQoL) the week before the accident  according to the Short Form-36 (SF-36) Health Survey . Visual –65, >66,http://www.qiagen.com/). The selected polymorphisms in the COMT gene were: rs6269, rs4633, rs4818 and rs4680. The COMT rs4680  polymorphism was genotyped using the TaqMan® Drug Metabolism Genotyping Assay, according to the manufacturer’s protocol [2O (Applied Biosystem®). An ABI PRISM®7900HT Sequence Detection System was used to perform allele discrimination PCR reactions according to the following thermal cycler conditions: initial step of 10 min at 95 °C, followed by 50 cycles of denaturation at 15 s, 92 °C and annealing at 90 s, 60 °C. The PCR products were analysed and allele sizes were determined using SDS 2.2 (Applied Biosystem®). On the other hand, a fluorescence-based competitive allele-specific PCR (KASPar) assay (KBioscience®), based on a public genome sequence (www.ensembl.org/), was used to analyse the SNPs rs6269, rs4633 and rs4818. Alleles were determined using SNPviewer2®. χ2 test or Fisher’s test was used to investigate deviations from Hardy-Weinberg Equilibrium (HWE). The EM algorithm was computed using SNP & Variation Suite 7 (Golden Helix) to estimate linkage disequilibrium (r2) and haplotype blocks. Three common haplotypes were found, as in Diatchenko et al. [Blood was used to isolate DNA using the QIAamp DNA MiniKit, according to the manufacturer’s protocol . Secondary outcome measures were the SF-36 responses  and pain and mental status measured by visual analogue scales .p was less than 0.05, two-tailed. The p-values were presented without adjustment for multiple comparisons. Logistic regression was used to identify variables associated with being risk factors for non-recovery at 12 months. First, crude associations for each selected variable were studied in univariable models. Secondly, a multivariable model was used to adjust the associations. The results were regarded as significant at p < 0.05. The associations are presented as odds ratios (ORs) with 95% confidence intervals [Nominal variables were tested with chi-square test. The Kruskal-Wallis and Anova were used for comparisons measured on interval and ratio scale variables. The results were regarded as significant if ntervals .The statistical analysis was performed using SPSS version 20.0 .The study was approved by the Regional Research Ethics Committee Stockholm, Sweden and all patients gave their written informed consent before inclusion (Dnr-240/01).A total of 133 patients were enrolled in our study, but the outcome analysis was based on 128 patients because five lacked 12-month follow-up data. The distribution of genotypes and haplotypes are presented in Table As shown in Tables No significant differences could be detected either between the distribution of haplotypes and the VAS and SF-36 results before (retrospective rating) or after the accident or at the 12-month follow-up .Fifty-six patients (43.8%) reported non-recovery at 12 months, with no difference in the recovery rate between the different COMT haplotypes in relation to recovery, but high levels of initial pain according to VAS  and anxiety according to HAD ratings  were associated with non-recovery at 12 months.Regression analyses with adjustments for confounding factors Table  showed nCOMT haplotypes and recovery after whiplash injuries, could not detect any differences in the recovery rate between the three COMT haplotypes. Nor were any significant differences detected between COMT haplotypes regarding the secondary outcome measures, i.e., level of pain and quality of life according to the SF-36 at 12 months. However, the multivariate analysis showed that high levels of pain and anxiety after the whiplash injury were significantly associated with non-recovery.This study, investigating the association between COMT haplotypes and musculosceletal pain [COMT genotype. In our study, pain and anxiety affected the outcome, but were not connected to the COMT haplotypes. It is possible that the finding that 20% of the respondents reported symptoms of anxiety and 9% had signs of PTSD prior to the accident affected the results. It has previously been shown that anxiety and PTSD symptoms can moderate pain sensations [In a meta-analysis by Tammimäki et al. of pain and psychological symptoms after motor vehicle collisions, an association was found between different tal pain . Furthertal pain  reportednsations , 30.COMT haplotypes varies between different settings and geographic locations [Another explanation for the findings in this study, as compared to previous research, could be the differences in ethnicity between the studies. Mclean et al. reported differences in pain perception in a European-American population , Xiang eocations , 32 and ocations . Indeed,ocations , 35. HowCOMT genotypes. This finding is in contrast to the findings by Bortsov and co-workers, who found differences between genotypes 6 weeks after a motor vehicle collision [COMT haplotyping and subgrouping compared to that cohort. Grouping into three haplotypes  was done as suggested by Diatchenko and colleagues [Nor could our study demonstrate any differences in pain ratings between patients with the most common ollision . One realleagues . Anotherlleagues , 37.COMT SNPs as possible candidates; however, more studies are needed to define the possible causality of this relationship.Pain recovery comprises a complex interplay between several systems, from sensory to immune to brain circuits . ResearcCOMT haplotypes in patients with acute whiplash injuries could be detected in this material. Nor did we find associations between psychological factors and the COMT haplotypes. High levels of initial pain and anxiety were associated with non-recovery, thereby confirming previously published literature.In summary, no relationship between the outcome regarding reported non-recovery or pain levels and


Postherpetic neuralgia (PHN) is a chronic neuropathic pain that results from alterations of the peripheral nervous system in areas affected by the herpes zoster virus. The symptoms include pain, paresthesia, dysesthesia, hyperalgesia, and allodynia. Despite the availability of pharmacological treatments to control these symptoms, no treatments are available to control the underlying pathophysiology responsible for this disabling condition.Patients with herpes zoster who are at least 50 years old and have a pain score of 4 or higher on a visual analogue scale (VAS) will be recruited. The aim is to recruit 134 patients from the practices of general physicians. Participants will be randomized to receive gabapentin to a maximum of 1800 mg/day for 5 weeks or placebo. Both arms will receive 1000-mg caplets of valacyclovir three times daily for 7 days (initiated within 72 h of the onset of symptoms) and analgesics as needed. The primary outcome measure is the percentage of patients with a VAS pain score of 0 at 12 weeks from rash onset. The secondary outcomes measures are changes in quality of life (measured by the SF-12 questionnaire), sleep disturbance , and percentage of patients with neuropathic pain (measured by the Douleur Neuropathique in 4 Questions).Gabapentin is an anticonvulsant type of analgesic that could prevent the onset of PHN by its antihypersensitivity action in dorsal horn neurons.ISRCTN79871784. Registered on 2 May 2013.ISRCTN Registry identifier: The online version of this article (doi:10.1186/s13063-016-1729-y) contains supplementary material, which is available to authorized users. The most frequent complication following an acute episode of HZ infection is postherpetic neuralgia (PHN), a chronic and debilitating neuropathic pain syndrome that is refractory to most therapeutic strategies.Herpes zoster (HZ), often called PHN is considered a clinically significant problem because it may last for years and because it negatively impacts a patient’s quality of life across all four health domains: physical, psychological, functional, and social. The symptoms associated with PHN are sleep disturbances, mood changes, depression, and anxiety .The authors of a recent systematic review reported that the incidence of HZ infection was between 3 and 12 cases per 1000 patient-years for individuals older than 50 years of age, and that the overall risk of PHN ranges from 5% to more than 30% [The development of PHN is associated with increased patient age and severity of acute pain . The divGabapentin, a structural analogue of γ-aminobutyric acid, has been used for the treatment of PHN for decades, and the results of several randomized controlled trials (RCTs) show that it is a well-tolerated and efficacious treatment in patients with PHN . HoweverThe primary objective of the present study is to evaluate the efficacy of an optimal dose of gabapentin added to the usual treatment—valacyclovir and analgesics as needed—in the prevention of PHN at 12 weeks in patients older than 50 years old who have moderate to severe pain.We designed a multicenter, parallel, randomized, double-blind, placebo-controlled trial with recruitment of 134 patients from 17 primary care centers in Mallorca, Spain. Participants will be randomly allocated to receive gabapentin or placebo for 8 weeks to evaluate the efficacy of gabapentin in the prevention of PHN. Figure Male or female patients who are at least 50 years old, have a clinical diagnosis of uncomplicated HZ, present within the first 72 h of vesicle formation, and have an average pain score of at least 4 on a visual analogue scale (VAS) before therapy will be recruited. Table Each participating primary care center will have at least one physician from the research team invite potential candidates to participate in the clinical trial and to perform all procedures. All patients diagnosed with acute HZ will be referred to this physician and will be invited to participate in the trial. Willing participants who meet the eligibility criteria will be enrolled after they read and sign an informed consent agreement  using an unblinded randomization code list. The link between the randomization code and the corresponding treatment will remain blinded for all other study team members. During the process of randomization, each subject will be assigned a randomization code and will be given the treatment package with that code. This sequential randomization will be generated in blocks of six. To assess the effectiveness of masking, patients and investigators will be asked to guess whether they think they received the treatment or placebo at the final visit, and then will be asked to indicate what led them to that belief.The primary goals in management of HZ are to inhibit ongoing viral replication, alleviate pain, and prevent complications such as local shingles infections or PHN . Local mAntiviral therapy is considered the firstline treatment for HZ and should be initiated within 72 h of onset. Thus, all participants will receive 1000-mg caplets of valacyclovir hydrochloride three times daily for 7 days. The World Health Organization three-step pain relief ladder will be used for pain management. In particular, if pain occurs, there will be prompt oral administration of drugs in the following order, until the patient is free of pain: nonopioids (paracetamol); then, as necessary, mild opioids (codeine); then strong opioids, such as morphine.Bottles of 300-mg gabapentin capsules and of matching placebos will be dispensed according to the randomization schedule, which is retained by the clinical trial pharmacist. The participants, research staff, and investigators who assess outcomes will be masked to treatment allocations.Gabapentin will be initiated at 300 mg/day and then increased in a stepwise manner according to the instructions for use. The dose will be increased, regardless of whether efficacy is achieved at a lower dose, to a ceiling daily dose of 1800 mg/day. In patients who develop intolerable adverse effects, the dose will be reduced. The optimal dose established during the titration period will be maintained throughout the remainder of the study and followed by 1 week of dose-tapering. Use of systemic corticosteroids and tricyclic antidepressants will not be allowed.The treatment will be monitored at every visit by the responsible physician at every participating health care center. We will ask the patients to comply with a medical diary that has to be followed until the next appointment or a daily medication box, if wanted. At the last visit, the participants must return their bottles, and a final count will be made by the physician. A biannual study newsletter will be sent to all the researchers, and an annual meeting will take place between the principal investigator and all the study collaborators.Case report forms will be used to record data for all participants. The researchers will receive training for standardized data collection procedure. All data will be stored in a locked cabinet of every researcher until the inclusion period finishes. Patient information will be coded using a unique numerical identification, and the data will be entered into an electronic database and its validity secured. Logical checks will be performed for missing data and to find inconsistencies. The researchers and data analysts will have full access to data.Measures and variables are summarized, with a timeline, in Table The response rate of the groups at 6 and 12 weeks is a secondary outcome measure. Responders will be defined as those with a 50% reduction in VAS pain compared with baseline. This outcome was chosen following a recommendation from the Committee for Medicinal Products for Human Use in their clinical guidelines on clinical medicinal products intended for the treatment of neuropathic pain .The change from baseline to the end of the study in the DN4 questionnaire (Douleur Neuropathique in 4 Questions) score will be used to assess changes in neuropathic pain. This scale includes ten items, with each “yes” response scored as 1, and is subdivided into descriptors (seven items) and signs relating to the sensory examination (three items). A score above 4 indicates neuropathic pain. This questionnaire has been validated previously , 13, andThe 12-item Short Form Health Survey (SF-12®), a short version of the SF-36®, will be used to assess quality of life. This questionnaire has two questions on physical functioning, two questions on role limitations because of physical health problems, one question on bodily pain, one question on general health perceptions, one question on vitality (energy/fatigue), one question on social functioning, two questions on role limitations because of emotional problems, and two questions on general mental health . The SF-12 is applicable in different cultures, and a validated Spanish version is available , 16.The Medical Outcomes Study Sleep Scale will be used to assess the quality and quantity of sleep. This questionnaire has 12 items that assess the key constructs of sleep. It is self-administered, and patients are asked to recall sleep-related activities over the past 4 weeks. It comprises scoring in six domains: sleep disturbance (four items), snoring (one item), awakening with shortness of breath or a headache (one item), quantity of sleep (one item), optimal sleep (one item), sleep adequacy (two items), and daytime somnolence (three items). This scale has been validated in Spanish for patients with neuropathic pain .The Patient Global Impression of Change Scale comprises a single question in which the patient is asked to rate his/her present condition relative to how it was prior to treatment on a scale from 1 (very much better) to 7 (very much worse). This scale has been used in previous studies in which researchers assessed patients’ impressions of improvement following PHN treatment .Medications taken for control of pain will be recorded at baseline and at every follow-up visit during the study period.Patients will be interviewed at each study visit regarding the occurrence of any adverse events (AEs), including type of event, time of onset, duration, and severity. Safety analyses will be performed on the safety population, which will consist of all patients who received at least one dose of the study drug. Safety data will include the incidence of treatment-emergent AEs, serious adverse events (SAEs), and the number and percentage of patients reporting one or more AEs in each group.Participants will be free to withdraw from participation at their own request at any time without giving reasons for their decision. Withdrawals will be documented in the case report forms and in patients’ medical records, with active follow-up for ongoing SAEs.All information regarding AEs will be presented in the case report form. The study investigators will investigate the causal relationship of the study drug and the intensity of AEs. Any SAE  in any patient during the course of the study will be reported to the ethics committee .The sample size calculation is based on the primary outcome measure and the primary analysis for the intention-to-treat population. Researchers in a previous nonrandomized, noncontrolled experimental study reported the incidence of PHN was 20% . Thus, wth percentiles for nonnormal distributions. All analyses of the effectiveness and cost-effectiveness will involve intention-to-treat populations . This approach reduces the bias that may occur when participants not receiving assigned treatments are excluded from analysis. All tests will be two-sided, and an α value of 0.05 will be considered statistically significant.We will test for significant baseline differences in the placebo and gabapentin arms by use of descriptive analysis, with continuous variables summarized by means and SDs for normal distributions and by medians and 25th and 75We will compare the proportions of patients in each arm with PHN at 12 weeks against the null hypothesis of no difference between the groups. We will use the chi-square test in multivariate analysis and will adjust for potential confounders, if any, using a logistic regression model. We will estimate relative and absolute risk reduction and the number needed to treat, defined as the estimated number of patients who need to be treated with gabapentin for prevention of PHN in one patient.The health economic analysis will be performed by calculating the incremental cost-effectiveness ratio (ICER) at 12 weeks. We will systematically collect data on use of all resources, including inpatient care, consultations with health care providers, use of drugs, and laboratory tests. To measure effects, the SF-12 scores will be transformed into EQ-5D utility scores and quality-adjusted life-years (QALYs) will be determined. The ICER will be calculated as the difference in the mean costs of the two groups divided by difference in the mean effects of the two groups:A nonparametric bootstrap procedure will be used to perform the uncertainty analysis for the ICER. This procedure considers the skewness of cost data and the covariance of costs and QALYs. To control for possible confounding variables and to account for clustering, an alternative procedure (net-benefit regression) will also be used. Cost-effectiveness acceptability curves will be created to illustrate statistical uncertainty. We will determine the safety of interventions in the safety population and use per-protocol analysis with the chi-square test by comparing the AEs among patients.All estimates will include 95% confidence intervals. The number needed to treat will be calculated as the reciprocal of the difference between the proportion of patients with PHN in the placebo and gabapentin arms.This study will follow the principles outlined in the Declaration of Helsinki. All patients will be asked to provide written informed consent and will be told that participation is voluntary and can be withdrawn at any time without any negative consequences concerning their current or future medical treatments. Our study protocol has been approved by the Primary Care Research Committee, the Mallorca Ethical Committee of Clinical Research (IB 1857/12), and the Spanish Agency on Drugs and Medical devices (for Agencia Española de Medicamentos y Productos Sanitarios). Any protocol modification will be approved by the executive committee, submitted to the ethics committee for approval, and noted to the ISRCTN registry. Trial participants will be notified if relevant protocol changes will be made.PHN is a persistent nerve pain that has an adverse effect on quality of life in patients with HZ. It has a high prevalence among patients with HZ who are older than 50 years old and in those with moderate to severe pain, although previous studies have used different definitions of PHN. The definition of PHN in the proposed study is persistent pain for more than 90 days since the onset of shingles, considered the most accepted definition for PHN , 22.Treatments for PHN attempt to alleviate the pain, and several pharmacological strategies are available. This includes tricyclic antidepressants, anticonvulsants, analgesics, and topical agents. However, no disease-modifying therapy is available , and preGabapentin acts on supraspinal region to stimulate noradrenaline-mediated descending inhibition –26. We hThus, gabapentin may provide pain relief, but whether pain relief could also prevent the onset of PHN is not yet clear. In our study, participants in both arms will receive analgesic treatments as needed to provide pain relief. There is a significant increase in the risk of PHN following acute zoster infection, including prodromal pain and severe rush. Thus, participants in both of our study arms will also receive valacyclovir within 72 h after rash appearance. Valacyclovir is preferred over other antivirals because it more easily produces consistently high levels in the blood, patient compliance is better, and less frequent dosing is required.The effectiveness of gabapentin for the prevention of NPH was previously evaluated in two studies. Researchers in an uncontrolled open-label study concluded that the combination of gabapentin and valacyclovir reduces the incidence of PHN ; howeverA prospective controlled study showed that low doses of gabapentin were not effective in the prevention of PHN . HoweverThe two main strengths of our study are that, as far as we know, it is the first RCT to examine the effect of gabapentin on prevention of PHN, and it is an independent clinical trial funded by a public research agency. The ceiling dose of gabapentin is 1800 mg/day because it has been established that a dose greater than 1800 mg/day does not generally provide greater benefit; the bioavailability of gabapentin varies inversely with dose, and high-dose regimens are associated with lower patient compliance . GabapenLimitations of our study include the possibility of a high discontinuation rate due to gabapentin’s potential side effects, possible interactions of gabapentin with other drugs, and the complex dosage regimen. The most recognizable side effects of gabapentin are dizziness, somnolence, and drowsiness, so their presence might compromise the blinding of patients and investigators. Although we considered the use of an active placebo , we finally decided to use a “pure” placebo because of ethical considerations for the patients included in the study.HZ and PHN have major impacts on patients’ lives  and consAt the time of this writing, 70% of the target population of 134 has been enrolled. The anticipated study completion date is January 2017.


N = 30) to receive either mobile health pain coping skills training intervention delivered via Skype or traditional pain coping skills training delivered face-to-face (PCST-trad). This pilot trial suggests that mPCST is feasible, presents low burden to patients, may lead to high patient engagement, and appears to be acceptable to patients. Cancer patients with pain in the mPCST group reported decreases in pain severity and physical symptoms as well as increases in self-efficacy for pain management that were comparable to changes in the PCST-trad group (p's < 0.05). These findings suggest that mPCST, which is a highly accessible intervention, may provide benefits similar to an in-person intervention and shows promise for being feasible, acceptable, and engaging to cancer patients with pain.Psychosocial pain management interventions are efficacious for cancer pain but are underutilized. Recent advances in mobile health  technologies provide new opportunities to decrease barriers to access psychosocial pain management interventions. The objective of this study was to gain information about the accessibility and efficacy of mobile pain coping skills training (mPCST) intervention delivered to cancer patients with pain compared to traditional in-person pain coping skills training intervention. This study randomly assigned participants ( In patients with cancer, persistent pain is related to poor physical functioning, increased physical symptoms, and low overall health-related quality of life , 2. HighMobile health  technology advances may decrease a number of the barriers to psychosocial cancer pain interventions. First, patients with chronic diseases report being too busy or not having enough time to attend in-person sessions; mHealth technology can make intervention delivery available at a time and place convenient for the patient . Second,N = 25), breast, lung, prostate, and colorectal cancer patients with pain participated in a four-session mPCST protocol using video conferencing on a tablet computer while in their home environment. Feasibility was demonstrated by a high average number of intervention sessions completed (3.36 sessions out of a possible 4) and 84% overall trial completion. Participants reported mPCST to be a highly acceptable intervention using a standardized satisfaction questionnaire and 95% reported that mPCST improved their pain management. Participants receiving the mPCST intervention also reported lower levels of pain severity, physical symptoms, psychological distress, and pain catastrophizing from the period before to the period after intervention.We recently conducted a single-arm pilot trial that examined the feasibility, acceptability, and value of mHealth psychosocial pain management intervention—mobile pain coping skills training (mPCST) . In thisBuilding on this single-arm pilot trial, the primary objective of the current small pilot randomized controlled trial was to gain additional information about the accessibility and efficacy of mPCST delivered to cancer patients when compared to traditional in-person pain coping skills training intervention. We hypothesized the following: (1) compared to PCST-trad, mPCST would improve intervention access as assessed by feasibility , patient's self-report of burden related to intervention, patient intervention engagement , and self-report of a standardized acceptability scale and (2) mPCST would lead to significant decreases in pain, pain catastrophizing, physical functioning, physical symptoms, and psychological distress and despair and increases in self-efficacy for pain management comparable to PCST-trad.N = 30) to either mPCST or PCST-trad. Pre- (prior to randomization) and postintervention assessments included measures of pain, pain catastrophizing, self-efficacy for pain management, physical functioning, physical symptoms, and psychological distress and despair. Patient burden, acceptability, and engagement were also assessed after intervention. The preintervention assessment was completed with the study team at the participant's first visit and the postintervention assessment was completed one to two weeks following their final study intervention session. Participants completed both pre- and postintervention assessments using a tablet computer and were compensated $20 per assessment for a total of $40. All participants continued to receive their usual medical care. Institutional review board approved the study. This small randomized controlled pilot trial randomly assigned participants  intervention developed by Keefe et al. . PCST usParticipants in this condition received the same 4 sessions and content as participants in the mPCST condition, but all of the training was conducted at in-person sessions at the medical center.We assessed feasibility by examining study attrition , adherence , and completion time for each study condition .r = 0.10 and scale reliability was 0.78 and 0.59, respectively.Patient burden was measured by assessing 13 burden areas associated with accessing care following a cancer diagnosis. Items were selected based on information gathered from focus groups asking cancer survivors about barriers and burdens to accessing cancer care. Patients rated on a scale from 1 = “not at all” to 4 = “very much” how difficult it was to complete the study intervention sessions based on each burden. Scale 1 (Symptom Burdens) included items (factor loadings) asking about fatigue (0.73), pain (0.68), time (0.64), anxiety (0.67), feeling down or blue (0.53), and feeling stressed and overwhelmed (0.57). Scale 2  included items on distance (0.51) and difficulties getting to session (0.98). Items asking about the cost of sessions, finding transportation to sessions, taking time off work, finding childcare, and forgetting about sessions had small factor loadings and they were dropped from analyses. The correlation between the two factor scales was Patient engagement was assessed at the postintervention assessment. Participants were asked how many days in the last seven days they had used each of the pain coping skills. They were also asked how often since their final intervention session they had used the pain coping skills or ideas taught on this scale 0 = “not at all” to 4 = “almost every day.”Acceptability was assessed at the postintervention assessment with the Client Satisfaction Questionnaire 10-item version . Sample Pain severity was assessed at the period before and the period after intervention with the Brief Pain Inventory (BPI) . The BPIPain catastrophizing was assessed at the period before and the period after intervention with the 6-item pain catastrophizing scale of the Coping Strategies Questionnaire . These iPain self-efficacy was assessed at the period before and the period after intervention with the pain self-efficacy subscale of the Chronic Pain Self-Efficacy Scale . This suPhysical functioning was assessed at the period before and the period after intervention with the 4-item physical functioning scale of the Patient Care Monitor (PCM) v2 , 24. ThePhysical symptoms were assessed at the period before and the period after intervention with the physical symptom scale of the PCM , 24. ThePsychological distress was assessed at the period before and the period after intervention with 4 items from the PCM asking about crying or feeling like crying, being worried, feeling nervous, tense, or anxious, and feeling sad or depressed , 24. IteDespair was assessed at the period before and the period after intervention with 6 items from the PCM asking about hopelessness, lost interest in people and activities, helplessness, guilt, and worthlessness , 24. IteParticipants' age, gender, race, cancer type, diagnosis date, and cancer stage at study entry were collected through the patients electronic medical record. Participants' marital status, education level, comorbid medical disorders, and cancer treatments in the last week were collected through patient self-report at the preintervention assessment.t-tests were used to examine if there were group differences in days to completion, patient burden, and patient engagement. Pearson or point biserial correlations were used to examine the relationships between demographic/medical information and study variables of interest. We used repeated measures analysis of variance (ANOVA) to examine intervention related changes.Descriptive analyses were computed for patient demographic  and medical variables  . We exam30 participants with breast, lung, prostate, and colorectal cancer were enrolled in this trial; 15 were randomized to each condition. Participants were M = 60 (SD = 11) years old, 50% were female, 80% reported being partnered, and most participants were White (97%). Descriptive information is summarized in r = −0.43; p < 0.05), suggesting that younger participants reported higher levels of pain. Psychological distress was associated with gender , suggesting women reported more psychological distress compared to men. Psychological despair was associated with cancer stage  and number of comorbid medical disorders . These relationships suggest that higher levels of psychological despair are associated with more advanced cancer and more comorbid disorders. Race was not examined in these analyses as the majority of participants were White (97%).N = 30) may not have had enough participants to detect equal events such as disease progression or death across groups; participants in the mPCST group were more likely to report non-study completion due to disease progression and in one case, death. Of note, disease status at study entry by group was as follows: Stage 0 , Stage 1 , Stage 2 , Stage 3 , and Stage 4 . The reasons for noncompleters in the PCST-trad group may have been due to the constraints of an in-person intervention .Thirty participants were enrolled into the study and randomized. Of these 30 participants, 4  participants never started the study intervention. An additional 3  participants did not complete the second study assessment. Reasons for the 7 noncompleters included the following: cancer progression and/or less than 1-month life expectancy (2 mPCST), death (1 mPCST), improved prognosis (1 mPCST), not traveling to cancer center (1 PCST-trad), traveling too far (1 PCST-trad), and being lost to contact (1 PCST-trad). It is possible that this small trial (n = 23) participated in an average of 3.83 (SD = 0.65) out of 4 possible sessions. mPCST study completers (n = 11) participated in an average of 3.64 (SD = 0.92) study intervention sessions, with 9 participants completing all sessions. One mPCST participant completed only one study session but agreed to complete the follow-up assessment; another mPCST participant completed 3 out of the 4 sessions. The 12 PCST-trad study completers participated in all four study intervention sessions.Participants in both conditions who completed the study (n = 21) that completed all four intervention sessions, the average time from session 1 to session 4 was 46.81 (SD = 28.46) days. mPCST patients (n = 9) took an average of 29.67 (SD = 11) days and PCST-trad participants (n = 11) took an average of 59.67 (SD = 31.01) days. The average number of days to completion was significantly different between groups (t(19) = 2.76; p = 0.01).Among all study participants  to intervention participation were created and examined. All participants scored an average of M = 1.51 (SD = 0.55) on the Symptom Burden scale and M = 1.37 (SD = 0.57) on the Practical Burden scale. The reported barriers to intervention were low and there were no differences between groups. The three barriers with the highest individual averages were being tired or fatigued , pain , and distance from the medical center .p's > 0.17).At the postintervention assessment, all participants reported practicing the skills over the last 7 days as follows: progressive muscle relaxation with provided audio, M = 2.43 (SD = 1.95); progressive muscle relaxation without audio, M = 3.78 (SD = 2.54); activity-rest cycling, M = 4.17 (SD = 2.72); pleasant activity planning, M = 4.09 (SD = 2.13); cognitive restructuring, M = 4.77 (SD = 2.22); imagery, M = 4.13 (SD = 2.52); and minirelaxation, M = 3.70 (SD = 2.58). Following treatment, participants reported using pain coping skills learned in the intervention on average several days a week . There were no group differences reported in specific pain coping skills use or all skills use (n = 14) rating it excellent, 35% (n = 8) rating it good, and 4% (n = 1) rating it poor.All participants rated the program to be highly acceptable with an average rating of 3.5 (SD = 0.59) (1 = “low acceptability” to 4 = “high acceptability”). There were no significant differences in acceptability between groups. Participants rated the pain coping skills program overall with 61%  = 14.23; p = 0.001) and physical disability  = 13.59; p = 0.001). Mean scores suggest that the PCST-trad group experienced decreases in pain catastrophizing and physical disability not seen in the mPCST group. The statistics reported are for the between-groups interaction. No other pre- to postintervention differences between groups were found.There were between-group differences for pain catastrophizing  = 6.43; p = 0.20), pain catastrophizing  = 25.93; p < 0.001), self-efficacy for pain management  = 6.44; p = 0.02), physical symptoms  = 4.72; p = 0.04), and physical disability  = 5.16; p = 0.03). Mean scores  as participants in the mPCST condition (M = 30 days). The pain coping skills training protocol in this study was designed and intended to be delivered weekly over four weeks. This finding may suggest that providing cancer patients with pain the option to receive pain coping skills training intervention in their home with mobile technology may increase treatment fidelity . It may be that, in a clinical setting where providers are faced with the challenges of timing, billing, and scheduling compared to this formal research trial in which we used multiple resources to retain patients, many of the PCST-trad participants would not have completed the 4-session in-person intervention. Second, we found that study attrition in the PCST-trad condition appeared to be due to difficulties with distance to the medical center as one participant reported they could not complete sessions because they were no longer traveling to the medical center, one reported it was too far to travel, and a third was lost to contact. Attrition in the mPCST randomization group was largely due to worsening disease prognosis/death that may not have been equally represented in both groups due to the small sample size. As shown in We found that overall participants in this trial reported pre- to postintervention improvements in pain severity, pain catastrophizing, self-efficacy for pain management, physical symptoms, and physical disability. Participants in both groups experienced similar benefits in decreased pain and increased self-efficacy for pain management. This finding is significant for two reasons. First, patients with cancer often have progression in disease and/or receive intense cancer-related treatments that can lead to increased pain levels. The fact that patients in this study reported significant decreases in pain from the period before to the period after intervention may suggest that pain coping skills training protocols can help cancer patients with pain to improve their pain and pain coping even in the face of disease progression and cancer-related treatments. Second, self-efficacy for pain management has emerged as one of the most important psychosocial constructs in predicting patients' pain and their pain-related disability. Increasing patients' self-efficacy for pain management may be particularly important as cancer patients with pain often experience persistent pain even following cancer treatment . Interestingly, our data suggests that PCST-trad led to greater decreases in pain catastrophizing and physical disability when compared to the mPCST group. This finding may suggest that the mPCST protocol did not target these outcomes as well as a traditional in-person intervention and that further iterations of the intervention protocol should be altered to more intensely intervene in these areas.This study is a small, randomized pilot trial and future work with larger sample sizes is necessary. This work has several limitations. This study is limited by the small sample size, multiple assessment measures, and the possibility that patients who participated may have been more open to use of mobile health technology compared to patients who dropped out or chose not to participate. Future work should examine these relationships in larger samples of patients and patients with varying comfort levels with mobile technology. Also important to note is that medical-related factors such as illness severity/progression, medication effects, and cognitive limitations may limit a patient's ability to participate meaningfully in cognitive-behavioral coping skills training protocol; future research should consider this issue and work to identify those patients who are appropriate candidates and most likely to benefit from this treatment approach. Finally, given the significant difference in time to intervention completion but the absence of difference in outcomes  between groups, it will be important to consider optimal time for intervention in future trials.This small, randomized controlled pilot trial is one of the first trials to examine the accessibility and efficacy of mPCST intervention for cancer patients with pain compared to an in-person PCST intervention. Our findings suggest that pain coping skills training intervention that capitalizes on the advantages provided by mobile technologies is accessible to cancer patients with pain and is likely to lead to improved pain, self-efficacy for pain management, and other important pain-related outcomes. More work is necessary in this area to provide definitive information on the value of mobile health behavioral pain interventions.


Low cortisol levels are associated with several functional pain syndromes. In patients with secondary adrenal insufficiency (SAI), the lack in endogenous cortisol production is substituted by the administration of oral hydrocortisone (HC). Our previous study showed that a lower dose of HC led to an increase in reported subjective pain symptoms. Whether different doses of HC substitution alter somatosensory functioning in SAI patients has not been established yet.In this randomized double blind cross-over trial, forty-six patients with SAI participated. Patients randomly received either first a lower dose (0.2–0.3 mg HC/kg body weight/day) for 10 weeks followed by a higher dose (0.4–0.6 mg HC/kg body weight/day) for another 10 weeks, or vice versa. After each treatment period, blood samples were drawn and somatosensory functioning was assessed by determining the mechanical detection threshold (MDT), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS) and the pain pressure threshold (PPT), according to the Quantitative Sensory Testing (QST) battery by the German Network on Neuropathic Pain.The administration of the higher dose of HC resulted in significantly higher levels of cortisol (mean [SD] 748 [245] nmol/L) than the lower dose . No differences were found in MDT, MPT, MPS and PPT z-scores between the two doses of HC. Furthermore, the number of patients showing sensory abnormalities did not differ between the two different doses.The results suggest that the dose of HC has no impact on somatosensory functioning in response to mechanical stimuli in patients with SAI, despite previously found altered subjective pain reports. Stress hormones are known to play an important role in stress-related bodily disorders, such as functional pain syndromes. Stress, i.e. internal or external threats to the maintenance of homeostasis, activates the hypothalamic-pituitary-adrenal (HPA) axis in order to reestablish homeostasis. Activation of the HPA axis results among others in the secretion of cortisol. There is some evidence that cortisol increases the tolerance of pain ,2. SeverThe relationship between cortisol levels and sensory functioning using mechanical stimuli has been studied in healthy volunteers . HoweverAs shown previously by our group, patients with SAI reported more pain symptoms as assessed by daily diaries during treatment with a lower dose of HC  when compared to treatment with a higher dose of HC  . HoweverThis study is part of a randomized double blind cross-over study . PatientPatients were randomly assigned to either group 1 or group 2. Group 1 received first a low dose of HC  for 10 weeks, followed by a high dose of HC  for another 10 weeks. Group 2 received the two doses in reversed order. Randomization to one of the two treatment groups was performed by Tiofarma Inc, The Netherlands, with a block size of 4. The total daily dose was divided into three doses, administered before breakfast, before lunch and before dinner, with the highest dose given in the morning. After each treatment period patients returned to the hospital for evaluation. On testing days, patients were instructed to take their morning dose at 0700 hour. At 0800 hour the first blood samples were drawn in a fasting state in sitting position after a short period of rest, followed by physical, neuropsychological and sensory functional examination. Approximately five hours after the morning intake of HC a second blood sample was drawn.3 as internal standard [Total cortisol concentrations in plasma was measured by isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) and was performed essentially as described by Hawley et al., using cortisol-13Cstandard . Intra- The QST battery utilized in the present study consisted of four tests and was applied on the hand (dorsum) according to the standardized protocol of Rolke et al. . The QST2-Set, Marstock Nervtest, Germany). Using the ‘method of limits’, five ascending and five descending series of stimulus intensities were applied, resulting in ten thresholds. The final threshold is the geometric mean of these ten thresholds. The mechanical pain threshold (MPT) was measured using a set of seven pinprick devices (flat contact area of 0.2 mm in diameter) with fixed stimulus intensities that exerted forces of 8, 16, 32, 64, 128, 256 and 512 mN. Using the ‘method of limits’, patients were instructed to indicate whether or not they perceived a sharp sensation. The final threshold was determined in equivalence to the procedure described for MDT, i.e. the geometric mean of ten thresholds. Mechanical pain sensitivity (MPS) was assessed using the same set of seven pinprick stimuli to obtain a stimulus-response function for pinprick-evoked pain. Five runs were performed and in each run the pinpricks were applied in balanced and pseudo-randomized order. Patients were asked to give a pain rating for each stimulus on a numerical rating scale ranging from ‘0’ (“no pain”) to ‘100’ (“most intense pain imaginable”). MPS was calculated as the geometric mean of all numerical ratings for pinprick stimuli. The pressure pain threshold (PPT) was determined over muscle with a pressure gauge device  with three series of ascending stimulus intensities, each applied as a slowly increasing ramp of 50 kPa/s (0.5 kg/cm2 s). The final threshold was the geometric mean of three stimulations.The mechanical detection threshold (MDT) was measured with a standardized set of modified von Frey hairs . A similar difference was found five hours after administration of the morning dose .There were no differences in z-scores on the MDT, MPT, MPS and the PPT between the two doses of HC . Effect In this randomized double blind cross-over study, the effect of dose of HC on mechanical pain perception were studied. The administration of two different doses of HC for a period of 10 weeks did not result in a difference in mechanical QST parameters. This suggests that dose of HC does not alter mechanical pain perception in patients with SAI.Other studies using drug administration to investigate the relationship between cortisol and pain sensitivity have revealed conflicting results. Some studies reported an association between cortisol administration and reduced pain , whereasDespite the previously observed difference in subjective pain reports as assessed by daily diaries comparing both doses of HC , sensoryThe complete QST battery is a comprehensive test battery for somatosensory functioning across the full spectrum of nerve fibers: Aβ-fiber function, Aδ-fiber function and C-fiber function ,17. Aβ-fA strength of the present study is the unique patient population enabling a comparison of the direct relation between cortisol levels and mechanical pain perception by excluding potential interference of the negative feedback mechanism of the HPA axis. A limitation is the small number of patients, which should be considered when interpreting the results of this study. However, given the negligible effect sizes, we do not expect to find different results in a larger sample. Even though we’ve performed multiple tests, we did not adjust for the inflated type I error. However, the null findings of the results even without adjusting for multiple testing underscores that there is no effect. Furthermore, 10 weeks of treatment might be too short to find dose-dependent effects of HC on mechanical pain perception. However, the study by Kuehl et al. (2010) showed significant differences in sensory perception as soon as six hours after induced hypocortisolism, so a lack of differences due to a too short treatment period is in our opinion unlikely. One can speculate that plasma levels are of importance, but the main effects of hydrocortisone are genomic and temporal relationships with several endpoints including somatosensory functioning may therefore differ from plasma concentrations.To the best of our knowledge, this is the first study examining the effect of two different doses of HC on mechanical parameters in patients with SAI. Our results indicate that the dose of HC has no impact on mechanical pain perception in patients with SAI, even though a difference in subjectively experienced pain symptoms was reported previously by the same patient group .S1 Text(DOCX)Click here for additional data file.S2 Text(PDF)Click here for additional data file.


Over 300,000 patients in the United States sustain low-trauma fragility hip fractures annually. Multidisciplinary geriatric fracture programs (GFP) including early, multimodal pain management reduce morbidity and mortality. Our overall goal was to determine the effects of a GFP on the emergency department (ED) pain management of geriatric fragility hip fractures.We performed a retrospective study including patients age ≥65 years with fragility hip fractures two years before and two years after the implementation of the GFP. Outcomes were time to (any) first analgesic, use of acetaminophen and fascia iliaca compartment block (FICB) in the ED, and amount of opioid medication administered in the first 24 hours. We used permutation tests to evaluate differences in ED pain management following GFP implementation.We studied 131 patients in the pre-GFP period and 177 patients in the post-GFP period. In the post-GFP period, more patients received FICB  and acetaminophen  in the ED. Patients in the post-GFP period also had a shorter time to first analgesic  and received fewer morphine equivalents in the first 24 hours  than patients in the pre-GFP period.Implementation of a GFP was associated with improved ED pain management for geriatric patients with fragility hip fractures. Future studies should evaluate the effects of these changes in pain management on longer-term outcomes. Every year over 300,000 Americans sustain low-trauma fragility hip fracturesOur overall goal was to determine the effects of a multidisciplinary GFP on the emergency department (ED) pain management of fragility hip fractures. We hypothesized that the implementation of a GFP in the ED would be associated with increases in the use of regional anesthesia and acetaminophen and decreases in the time to first analgesic and amount of opioid medication.This was a retrospective, before-and-after cohort study using data from the University of California, Davis Health System’s electronic health record (EHR). This study was approved by our institutional review board.We performed this study at a single urban, academic ED with an annual volume of approximately 60,000 adult patients. Our hospital is a tertiary care facility with 619 licensed acute care beds and serves a 65,000 square-mile area that includes 33 counties and six million residents. Our hospital implemented the GFP on January 1, 2014. The GFP was developed by the departments of orthopaedics, internal medicine, anesthesiology, pharmacy and emergency medicine and was started as a quality improvement program on January 1, 2014. The program includes osteoporosis screening, medical co-management, operative fixation within 48 hours, early physical/occupational therapy including mobilization and early discharge planning, as well as strategies to recognize, prevent and manage delirium. The GFP team meets weekly to discuss patient and system issues. In the ED, the GFP includes a multimodal pain-control order set consisting of early acetaminophen, opioid medication, and fascia iliaca compartment block (FICB) regional anesthesia.What do we already know about this issue?Geriatric fracture programs (GFP) reduce mortality, morbidity, and hospital costs for geriatric patients with hip fractures.What was the research question?Does a GFP improve ED pain management for geriatric patients with hip fractures?What was the major finding of the study?A GFP was associated with enhanced ED pain management for geriatric patients with hip fractures.How does this improve population health?A GFP was associated with decreased variability in analgesia timing and use and with more patients receiving evidence-based pain management.We included all patients age 65 years and older who presented via the ED with a unilateral, native, non-pathologic, low-energy, proximal femur fracture  who were admitted to the hospital. We excluded patients under 65 years of age, fractures resulting from high-energy mechanisms , periprosthetic fractures, isolated trochanteric fractures, femoral shaft fractures and patients with multiple injuries.Eligible patients were initially identified based on an International Classification of Diseases (ICD)-9-CM code of 820.xx, 821.xx, or 733.14 prior to October 1, 2015, or an equivalent ICD-10 code  after Oc22Our primary outcomes were FICB use in the ED, acetaminophen use in the ED, time to first analgesia, and IV morphine equivalents administered in the first 24 hours. We also evaluated race and sex differences in these outcomes.We defined ED length of stay as the time from ED triage to the time that the patient physically left the ED. ED acetaminophen was defined as any administration of acetaminophen  while the patient was in the ED. Time to first analgesic was defined as the time from ED triage to first administration of any analgesic. IV morphine equivalents in the first 24 hours included all opioid medications administered outside the operating room within 24 hours of ED arrival. We used a calculator approved and used by the UC Davis Medical Center Pharmacy and Therapeutics Committee to convert all other opioid medications to IV morphine equivalents .We calculated summary statistics. To evaluate inter-rater reliability, we used kappa coefficient for the binary outcome and Pearson’s correlation coefficient for the continuous outcome. Chi-square and Fisher’s exact tests were used to compare patients in the pre-GFP and post-GFP periods. We compared binary outcomes between the pre-GFP and post-GFP period using two-sample binomial Z-tests. Both time to first analgesic and IV morphine equivalents had skewed distributions. Hence, we used regression models and permutation tests to assess the statistical significance for independent variables. To compare mean differences in these outcomes between periods, we fit regression models to these outcomes and applied permutation tests to the resulting regression coefficients to obtain valid p-values.Of 325 patients with eligible diagnosis codes, 17 patients were excluded from the study due to non-isolated injuries (6), high-energy mechanism (5), peri-prosthetic fracture (2), femur fracture with no hip involvement (2), lack of an acute fracture (1), and pathologic fracture (1). We studied 131 patients in the pre-GFP period and 177 patients in the post-GFP period. The majority of patients in the study were female  and White . Median age was 82 years. Demographic and clinical characteristics of the two groups are shown in The two reviewers had perfect agreement for ED acetaminophen use  and excellent agreement on outcomes for morphine equivalents (correlation coefficient 0.94). In the post-GFP period, more patients received FICB  and acetaminophen  in the ED. Patients had shorter time to first analgesic  and received fewer morphine equivalents in the first 24 hours . Differences in time to imaging, ED length of stay, and time to surgery were not statistically significant between the pre-GFP and post-GFP periods. No cases of local anesthetic systemic toxicity or other complications were reported for patients who received FICB . Seventy patients  in the post-GFP period did not receive FICB. Of these 70 patients, the procedure was contraindicated in 40 patients (57%) due to anticoagulation therapy, nine patients (13%) due to refusal, and one patient (1%) due to anesthetic allergy. In 20 of the 70 patients (29%) there was no documented contraindication to FICB in the EHR.We observed less variance in amount of opioid medication used (p=0.006) and time to first analgesic (p=0.03) in the post-GFP period  and 2.Notably, seven patients in the pre-GFP period but no patients in the post-GFP period received over 60mg IV morphine equivalents for pain control in the first 24-hour period. Twelve patients in the pre-GFP period but only three patients in the post-GFP period received their first analgesic over 600 minutes after ED arrival.In univariable analysis, non-White patients received less opioid medication than White patients (p=0.03). This association persisted (p=0.03) in a multivariable analysis adjusting for pre- vs. post-GFP period and sex. There was no interaction between race and pre- vs. post-GFP period (p=0.07) with regard to opioid timing. No differences were found in time to first analgesic, acetaminophen use or FICB use between White and non-White patients (data not shown). No sex differences were found in any of the four outcomes (data not shown).We provide one of the first reports of a GFP’s effect on ED pain management of fragility hip fractures in the United States. Overall, our results suggest that patients received earlier and more comprehensive ED pain management following the implementation of a GFP as evidenced by increased usage of regional anesthesia and acetaminophen along with decreased patient opioid requirements and time to first analgesia. The decrease in opioid use was likely due to pain relief provided by the FICB and acetaminophen. Pain management in this population is important because good pain control is associated with increased mobility, fewer complications resulting from immobility, and decreased rates of delirium. Rapid pain management in this population is also important because time to administration of oral, parenteral or intranasal pain medication is a Medicare quality measure for patients presenting with a long bone fracture.24Our data demonstrate the feasibility and safety of FICB performed in the ED by emergency physicians (EP). We adopted conservative guidelines from the American Society of Regional Anesthesia and Pain MedicineThe GFP’s multimodal pain management education for resident and attending physicians regarding FICB was critical to the program’s success. We held annual FICB training sessions with didactic and practical components for EPs. We discovered a need for continued re-education, particularly in July with the arrival of new EPs who were unfamiliar with the FICB clinical pathway.We found less variability in the post-GFP period in both opioid requirements and time to first analgesia. These differences are likely multifactorial. First, the GFP included an EHR order set that included acetaminophen and set doses of opioid medication. Second, ED provider education emphasized early pain relief. Third, the use of oral or rectal acetaminophen was stressed with occasional use of IV acetaminophen. In our ED, acetaminophen can be ordered by a physician in triage and administered prior to IV access. This decreased variability suggests that more patients are receiving the evidence-based, high-level standard of care included in our GFP clinical pathway.17Non-White patients received less total opioid medication than White patients; however, no racial differences existed in other ED pain management measures. The existence of racial disparities in ED opioid prescribing for long bone fracture is controversial.Our study has several limitations. While we used strategies to minimize bias, our study is subject to limitations inherent in retrospective studies.Implementation of a GFP was associated with improved ED pain management for geriatric patients with fragility hip fractures via ED use of FICB and acetaminophen. Future studies should evaluate the effects of these interventions on longer-term patient outcomes.