Back pain is one of the most important causes of functional limitation, disability, and utilization of health care resources for adults of all ages, but especially among older adults. Despite the high prevalence of back pain in this population, important questions remain unanswered regarding the comparative effectiveness of commonly used diagnostic tests and treatments in the elderly. The overall goal of the Back pain Outcomes using Longitudinal Data (BOLD) project is to establish a rich, sustainable registry to describe the natural history and evaluate prospectively the effectiveness, safety, and cost-effectiveness of interventions for patients 65 and older with back pain.BOLD is enrolling 5,000 patients ≥ 65 years old who present to a primary care physician with a new episode of back pain. We are recruiting study participants from three integrated health systems . Registry patients complete validated, standardized measures of pain, back pain-related disability, and health-related quality of life at enrollment and 3, 6 and 12 months later. We also have available for analysis the clinical and administrative data in the participating health systems’ electronic medical records. Using registry data, we will conduct an observational cohort study of early imaging compared to no early imaging among patients with new episodes of back pain. The aims are to: 1) identify predictors of early imaging and; 2) compare pain, functional outcomes, diagnostic testing and treatment utilization of patients who receive early imaging versus patients who do not receive early imaging. In terms of predictors, we will examine patient factors as well as physician factors.By establishing the BOLD registry, we are creating a resource that contains patient-reported outcome measures as well as electronic medical record data for elderly patients with back pain. The richness of our data will allow better matching for comparative effectiveness studies than is currently possible with existing datasets. BOLD will enrich the existing knowledge base regarding back pain in the elderly to help clinicians and patients make informed, evidence-based decisions regarding their care. Back pain is a particularly important problem for older adults. The prevalence of severe, disabling back pain increases in older adults ,2. MoreoThe Back pain Outcomes using Longitudinal Data (BOLD) project establishes a large, community-based registry of patients aged 65 years and older presenting with new episodes of healthcare visits for back pain. BOLD’s primary aim is to establish an infrastructure that allows the conduct of prospective, controlled studies comparing the effectiveness of diagnostic and treatment strategies for back pain in the elderly. The importance of BOLD stems from the high prevalence, clinical impact and cost of back pain, combined with a relative lack of comparative effectiveness data, especially for older adults. Back pain, an Institute of Medicine priority condition , is one Although there are numerous guidelines regarding the diagnosis and treatment of back pain in general, these evidence-based guidelines do not focus on the elderly. Age-related differences in the causes of back pain highlight the need for specific guidelines for diagnosing and treating back pain in older adults. For example, back pain due to metastatic cancer has a higher prevalence in older adults. In a study of primary care patients with back pain, age older than 50 years was associated with a higher likelihood of having cancer (positive likelihood ratio = 2.7), although the absolute probability of having cancer remained small at 1.2% . This inThe overall goal of this project is to establish a sustainable and rich registry to evaluate prospectively the effectiveness, safety, and cost-effectiveness of diagnostic approaches and interventions for elderly patients with back pain. The registry can also be used to identify and recruit patients for additional studies. We plan to recruit 5,000 patients age 65 and older with new episodes of health care visits for back pain . Patients who enroll in the registry complete validated, standardized measures of pain, back pain-related disability, and health-related quality of life at enrollment and 3, 6 and 12 months later. Our project includes a demonstration comparative effectiveness study of early  imaging versus no early imaging for elderly patients with back pain. In this observational cohort study we will test the hypothesis that early imaging is associated with more interventions and adverse labeling , greater disability and higher levels of pain compared to matched controls who do not undergo early imaging. We will also test the hypothesis that racial and ethnic minorities will have lower rates of early imaging than non-minorities. In parallel with construction of the BOLD registry, we also are performing a double-blind, randomized controlled trial of epidural steroid with local anesthetic compared with a local anesthetic injection alone for spinal stenosis; this component of the study is described elsewhere .BOLD is recruiting patients at three integrated health care systems: Kaiser Permanente of Northern California (KPNC), Henry Ford Health System (HFHS), and Harvard Vanguard Medical Associates/Harvard Pilgrim Health Care (HVMA/HPHC). We chose these sites for their geographic and demographic diversity. Confining our registry to the integrated health systems with comprehensive electronic medical record systems allows us to take advantage of the well-defined populations that their patients comprise as well as the wealth of data available in these systems, including health care utilization.The University of Washington’s Comparative Effectiveness, Cost and Outcomes Research Center (CECORC) and Center for Biomedical Statistics (CBS) serve as the Data Coordinating Center (DCC) for BOLD. A collaborator at Oregon Health and Sciences University (RAD) is also part of the DCC.The IRBs at all participating institutions  reviewed and approved the protocols for the BOLD Registry and the Observational Cohort Study of Early Imaging.We identify patients at their health care visits for back pain using the Ninth International Classification of Diseases (ICD-9) codes . We recrWe screen for study eligibility patients ≥ 65 years old who have had a primary care visit (including by telephone) or urgent/emergency care visit and been assigned a diagnosis code indicating back pain within the past three weeks Table . In addihttp://www.backpainproject.org) that has additional information about the study.The exact method of the initial subject contact varies slightly at each site. The site research staff identify and contact potential subjects by telephone, email, mail or in person, describing the study and inviting them to participate using a standardized script. In the invitation we provide a web address . The total time for completing the study questionnaires at each assessment is approximately 15–30 minutes.Our data come primarily from two sources: subject questionnaires and electronic data records. We have attempted to minimize the questionnaire burden while still obtaining important information regarding the patient’s back pain. At baseline, trained research coordinators/interviewers administer the questionnaires either in person or over the telephone within three weeks of a subject’s index primary care visit.We contact each registry patient at three, six and 12 months after baseline to collect data on patient treatments and outcomes. For follow-ups, the questionnaires are either self-administered by the subject using a mailed hard copy or administered by a research coordinator over the telephone. We plan to develop an on-line version of the questionnaire as an option for subjects to complete after being sent a link by email.Follow-up questionnaires can be completed within a two-week window on either side of the follow-up time-point. We use a computerized tracking system to identify when patients enter the interview window and when interviews are complete. If patients withdraw from the study, we attempt to identify the reason.We collect demographic information and information regarding back pain duration and back pain recovery expectations at baseline. We also administer the following measures at each assessment: 1) Roland-Morris Disability Questionnaire (RMDQ) , modifiePain Duration: We ask subjects at baseline to categorize the length of the current episode of back or leg pain (sciatica) as follows: 1) less than 1 month; 2) 1–3 months, 3) 3–6 months; 4) 6–12 months; 5) 1–5 years; and 6) more than 5 years.Patient Expectations: We ask subjects to use a 0–10 NRS to rate their confidence that their pain will be completely gone or much better in 3 months.Roland-Morris Disability Questionnaire: Our primary outcome measure is the Roland-Morris Disability Questionnaire (RMDQ) [e (RMDQ) , a back e (RMDQ) . The orie (RMDQ)  .We use e (RMDQ)  or disabe (RMDQ) . Its inte (RMDQ) . Its cone (RMDQ) ,19. The e (RMDQ) .Pain Numerical Rating Scale (NRS): We ask subjects to rate separately their average back and leg pain within the past seven days on 0–10 scales, with 0 = no pain and 10 = worst pain imaginable. Investigators commonly use NRS’s of pain intensity as outcomes in clinical trials of pain therapies, and these ratings have been demonstrated to be valid, reliable, and sensitive to detecting change in pain intensity after treatment [reatment . The Inireatment . Furtherreatment . The IMMThe validated Brief Pain Inventory (BPI) Interference scale measures pain interference with activities .The scalThe PHQ-4 is a four-item screen for depression and anxiety that has good sensitivity and specificity for identifying depression and anxiety disorders .http://www.euroquol.com)[The EQ-5D is a standardized health outcome instrument consisting of five dimensions . In addition, the instrument includes a “feeling thermometer” to assess respondents’ current health-related quality of life (0–100). The EQ-5D has been extensively validated and studied for a wide variety of conditions and populations, including the elderly, and is used as a utility measure in cost-effectiveness analyses (quol.com).The BRFSS Falls screen is a two-item questionnaire that assesses the number of falls the respondent has had in the past 3 weeks and how many resulted in injury -29.In addition to the patient-reported outcome measures, we will use electronic medical record and administrative data that are available at these integrated health systems. These health systems have standardized administrative and clinical data collected across their systems Figure . We willFor all interviews, research coordinators enter data on specially formatted, paper data collection forms that are stored securely at each site. In addition, sites have the option of entering data directly into the on-line REDCap data system . This haResearch assistants check data from the interviews for missing or unclear responses while the subject is still available. The data coordinating center’s senior programmer directs the data management and re-checks the data for quality. We defined specific logic rules for establishing the internal consistency of responses across several variables. When necessary, we check the original data collection forms or re-contact the subject.In many registries, there may be a relatively small subgroup of interest  and a large number of controls available for a comparative analysis of outcomes. As a general analytic approach in BOLD, we will evaluate cases in comparative studies using 3:1 matched controls with the nearest propensity score .Propensity-based matching is a strategy for assembling similar groups of patients in the absence of randomization. We will use this method to select control patients who are similar to patients who have selectively received the intervention of interest (e.g. early imaging). If we do not appropriately match controls on important baseline characteristics to patients who receive the intervention, there is a risk of obtaining biased results when comparing cases with controls due to confounding -37. PropFor a given research question and set of patients, we will use logistic regression models  to generate a propensity score for each person, using variables that are significant predictors of the intervention of interest. We will then match the propensity score of each case who received the intervention to the nearest propensity scores (up to 3) available among control patients whose propensity scores lie within a caliper window of 0.2σ of the case index, where σ is a measure of variation in the propensity score distributions of cases and controls as given in Rosenbaum and Rubin . If no cWe will conduct an observational cohort study of early imaging in seniors with new visits for back pain as our first comparative study using data from the BOLD registry. Our goal is to test the hypothesis that imaging of the lumbar spine within 6 weeks of the index visit (early imaging) is associated with worse patient outcomes and increased health care utilization and costs. Patients who get early imaging may be those with the worst pain or most alarming clinical presentation. However, given the variability in clinician ordering patterns, there is also a reasonable likelihood that those patients who do and do not get early imaging have considerable overlap.Prior work has suggested an association between early imaging and subsequent interventions ,39 but lAll subjects enrolled in the registry will be eligible for the observational study of early imaging. Cases selected for the observational cohort will be registry patients who had early imaging of the lumbar spine. We will identify propensity score-matched controls from the registry (see below) who did not have early imaging of their spine.Our overall aim for the observational cohort study is to compare the pain, function, and resource utilization and associated costs of patients who have early  imaging , computed tomography (CT) and bone scans) to those who do not have early imaging. The sample will consist of registry patients with new episodes of back pain. Our primary hypothesis is that patients who undergo early imaging will have worse modified RMDQ scores at one year compared with those who do not receive early imaging, after controlling for baseline back pain-related disability, pain severity and pain duration. Our rationale is that imaging may lead to adverse labeling  or more We will construct a propensity score based upon the logit function of the probability of receiving early imaging  for a patient with specific characteristics or prognostic factors . We willOur primary outcome measure is back-specific disability measured by the RMDQ at 12 months. We have selected the 12-month assessment as the primary outcome because this allows adequate time for any intervention benefit to manifest, and is the final assessment opportunity for the initial registry study design.We will first assess comparability of baseline characteristics between the matched groups to gauge the effectiveness of the propensity matching and then address any residual covariate imbalances through model adjustment. Rosenbaum and Rubin suggested that an approach combining both the propensity score and covariate adjustment is superior to the use of either strategy alone .Using the propensity-matched pairs, we plan to use a paired t-test to compare the between-group 12-month change in RMDQ. In conjunction with this primary analysis, we will use multivariate linear regression models adjusting for the propensity score and baseline factors that appear to have residual imbalance in order to compare groups with and without early imaging.We will use multivariate linear regression models adjusting for the propensity score or conditional logistic models to identify predictors of patient outcome at the one-year follow-up. We will use interaction terms between the early imaging and baseline characteristics to identify variables that predict differences in the outcome associations between the two groups.We will include subjects who have subsequent imaging more than six weeks after entry to the study in the non-early imaging group. We will compare characteristics of subjects who receive later imaging to those who do not in a sensitivity analysis.We will conduct similar analyses for the RMDQ at three and six months as well as for the pain NRS and EQ-5D using all data through one year. We will use methods appropriate for the analysis of repeated measures such as linear mixed models or repeated measures ANCOVA , adjustiUsing the patient‐reported data and the electronic health system information systems, we will enumerate the number and type of invasive interventions that patients undergo following enrollment. These interventions are listed in Table Another hypothesis is that racial and ethnic minorities will have lower rates of early imaging than non-minorities. To test this hypothesis, we will use the registry to compare rates of early imaging between African Americans/ Blacks and Whites as well as between Hispanics and Whites. We will test for differences in rates using fixed effects conditional Poisson regression models, controlling for the propensity score and residual imbalances among important covariates. We will also examine subsequent invasive interventions as well as outcomes in each of these ethnic and racial subgroups. If early imaging rates are indeed lower in racial and ethnic minorities, we would expect subsequent invasive interventions to be fewer and functional status better.The primary economic hypothesis is that patients receiving early imaging will have higher health care utilization, higher costs, and worse outcomes at one year compared to those not receiving early imaging. The primary economic outcome will be one-year incremental cost per quality-adjusted life year (QALY) gained from the private/public payer perspective .http://marketscan.thomsonreuters.com/marketscanportal/) to obtain an estimate of 2012 private payer average unit costs for medications and medical procedures/services.The cost-effectiveness assessment will use the health systems’ electronic medical records and administrative data as well as patient-reported outcome data. We will use the electronic data to assess within-health system categories of resource utilization . We will use the Marketscan® data warehouse (We will report short-term costs and consequences (baseline to 3 months) and assess six-month and one-year outcomes incorporating the linear mixed-model approach used in the primary outcomes analysis. Sensitivity and specific scenario analyses will be undertaken to evaluate uncertainty on cost-effectiveness parameters .Prior studies suggest that approximately 15%–30% of back pain patients will have early imaging of the lumbar spine . Given aIn a matched study, missing data at follow-up in either the case or matched control imply that neither patient’s data will be included in a matched analysis. That is, if we anticipate between 10–15% loss to follow-up equally balanced between comparison groups, the number of missing data points can be as much as doubled in any matched or conditional analysis. To compensate for this, we will enrich the control sample with 3:1 matched sampling so that each case will have up to three controls followed in an identical manner. In Table An important advantage of a registry is the ability to detect relatively rare events due to the large sample size. We base our sample size estimates on the ability to detect and make inference on relatively rare events. In the primary care setting, examples of rare events would be subsequent surgery or adverse outcomes from interventions such as epidural steroid injections. While our first planned use of the registry is for the comparative effectiveness evaluation of early imaging vs. no-early imaging in the elderly, we envision other evaluations such as the comparative effectiveness of physical therapy vs. no physical therapy.http://www.backpainproject.org.As the registry progresses in size and maturity, we anticipate making the BOLD resources available to researchers interested in evaluating diagnostic tests, treatments, and outcomes among elderly patients with back pain. Detailed information regarding data sharing will be available at In the U.S., many spine-related registries are device- or procedure-focused and hence recruit patients primarily from specialists. Outside the U.S., several prospective spine registries/cohorts have been established to study various aspects of back pain and while somewhat broader in scope, most still have a specialist focus -50. In cThe Back Complaints in the Elders (BACE) consortium is an international group of investigators who have independently established prospective cohorts in a primary care setting to investigate back pain among seniors . InvestiA great advantage of registries is that patient enrollment is easier than intervention trials, so large sample sizes are feasible. This increases generalizability and the ability to detect rare events, such as complications.Roovers highlighted the limitations of registries, including lack of proper control groups, confounding, bias, poor data quality control, and potential conflicts of interest due to industry sponsorship . Due to Another limitation of registries is selection bias associated with enrollment. Physicians might be more likely to enroll uncomplicated patients who are likely to have better outcomes. We avoid this shortcoming by using the health information systems to identify potential patients and have a research coordinator contact and enroll them (without prior screening by the primary care physician). Limiting enrollment to integrated health systems somewhat limits generalizability, since the delivery of care within these systems is distinct from the fee-for-service delivery system, with unique incentives. Nevertheless, we believe that the advantages of integrated health systems  far outweigh the limitations.Patients and clinicians both tend to under-appreciate the disadvantages of diagnostic testing. The degree of potential controversy associated with this issue was recently emphasized by the release of the U.S. Preventative Health Services Task Force report on mammography . The panThe BOLD registry establishes an infrastructure for studying back pain in the elderly and performing future comparative effectiveness and cost-effectiveness evaluations. Strengths include accessing patients from a community-based setting and using integrated health plans to facilitate the tracking of resource use. Since the aims and design parallel studies by an international consortium of investigators, comparison with cohorts from the Netherlands, Australia and Brazil will be possible. Even without the potential for future collaborations with international collaborators, the BOLD registry is a valuable new resource for comparative effectiveness research in the United States.Dr. Jarvik has the following potential conflicts of interest, although they do not relate directly to the subject of this manuscript, he lists them in the spirit of full disclosure. He serves on the Comparative Effectiveness Advisory Board for GE Healthcare. He is a co-founder and stockholder of PhysioSonics, a high intensity focused ultrasound company, and receives royalties for intellectual property. He is also a consultant for HealthHelp, a radiology benefits management company.JGJ, BAC, ALA, BWB, RAD, JLF, PH, LK, SSN, DRN, SDS and JAT developed the original concept of the study and developed the design of BOLD Registry study. ZB and KJ participated in the design of as BOLD and are coordinators. All authors have read and approved the final version of the article.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/64/prepub


Many patients describe pain and other adverse feeling from their ICU stay and the impact of such feelings impacts long-term psychological morbidity. Presently no objective method for detecting pain or distress is available. Skin conductance variability has been investigated as a monitor of perioperative pain. The method has not been studied in adult ICU patients.Twenty-five (13 intubated and 12 non-intubated) patients were included in this observational study. Patients were monitored with the MED-STORM Stress Detector for 1 hour of intensive care treatment and care. Skin conductance variability (number of skin conductance fluctuations per second (NSCF)) was measured and patients were observed in parallel during rest and during procedures and staff-patient interactions. The sedation-agitation level was monitored with the Motor Activity Assessment Scale. Pain was monitored with the Numeric Rating Scale (0 to 10) in communicating patients and by observation of expressions of pain in patients unable to communicate verbally.In non-intubated patients, NSCF values were low when patients were unstimulated and comfortable and increased with increasing stimulation but also with increasing agitation without any apparent pain. The highest NSCF values were noted during combined pain and agitation. In intubated patients, a similar pattern was observed but with generally lower values, most likely due to sedation. Sensitivity and specificity of NSCF at a cut-off value > 0.13 for detecting expressed pain/discomfort were 74% and 55% for non-intubated patients and 61.5% and 68% for intubated patients.Skin conductance variability increases in critically ill patients with increasing stimulation but is also affected by the level of sedation/agitation, making the method unsuitable for detecting pain alone in critically ill patients, but possibly of value to more generally monitor emotional stress with different etiology. Further studies of the method in critically ill patients, over longer time and with validated pain instruments are warranted.HS is a co-owner of Med-Storm AS, the company responsible for the production and distribution of the Med-Storm Stress Detector. The other authors declare that they have no conflicts of interest.


Pain from cervical spondylosis (CS) may result from degenerative spinal canal stenosis ) or lateral recesses compromise, leading to nerve root compression ). Pregabalin was shown to be effective in randomized, placebo-controlled trials for post-herpetic neuralgia and diabetic neuropathy. We evaluate its efficacy in CS with underlying CSR or CSM in a prospective study comprising Asian patients for the first time.Patients with CS and CSR or CSM  presenting with neuropathic pain were recruited. We excluded patients with diabetes, underlying neurological disease or who were previously on antiepileptics. Pregabalin 75 mg bd was administered for 4 weeks, after which dosage was increased to 150 mg bd for another 4 weeks if the visual analog scale (VAS) was not reduced by 50%. In addition, we monitored the short form McGill pain questionnaire (SFMPQ) at baseline, 4 weeks and 8 weeks. Mood changes were monitored using the hospital anxiety and depression score (HADS) with an identical timeline. = 25.4, P < 0.0005), SFMPQ (sensory)  = 11.2, P = 0.003), and SFMPQ (affective)  = 10.9, P = 0.008). For VAS, there was significant reduction at 4 weeks (P = 0.001) and 8 weeks (P < 0.0005) compared to baseline. For SFMPQ (sensory), there was significant reduction at 4 weeks (P = 0.01) and 8 weeks (P = 0.006) in scores compared to baselines. For SFMPQ (affective), there was significant reduction at 4 weeks (P = 0.04) and 8 weeks (P = 0.008) in scores compared to baseline. No significant anxiety  = 1.3, P = 0.32) or depression  = 0.06, P = 0.82) changes were observed in the HADS.We recruited 50 patients, of which 23 completed the trial. Of the 27 who withdrew, 12 (44%) were for somnolence. Thirteen patients’ (54%) dosages remained at 75 mg and 11 patients’ (46%) dosages were escalated to 150 mg bd. There were significantly reducing trends from baseline for VAS (ANOVA, FPregabalin is efficacious in alleviation of pain symptoms related to CSR as a first-line single agent, evaluated by quantitative severity and other experiential scales. No significant mood changes reported in other studies were demonstrated. Somnolence was commonest adverse effect leading to high dropout rates, occurring early even at the lowest dose. The findings suggest the need for further studies of efficacy at lower dosages, particularly in the Asian population. Cervical spondylosis (CS) is characterized by degenerative lateral recesses compromise, leading to nerve root compression ), or more severe spinal canal stenosis and cord compromise ). Medical management is usually the initial step, often consisting of pharmacological treatment and rehabilitation , 2. The Pregabalin is structurally related to the anti-epileptic drug gabapentin. It binds strongly and selectively to the alpha-2-delta subunit of hyper-excited voltage-gated calcium channels, leading to a reduction in calcium influx and synaptic release of excitatory neurotransmitters. This mechanism is believed to be responsible for its analgesic and anticonvulsant properties , 4.Pregabalin has demonstrated efficacy in randomized, placebo-controlled trials for post-herpetic neuralgia and diabetic neuropathy , 6. Its In this study, we evaluate its efficacy for treating neuropathic pain in degenerative CSR/CSM patients in a prospective fashion for the first time. Self-evaluation and investigator-rated scorings were implemented to ascertain effectiveness and tolerability of pregabalin in a multi-racial Asian setting.The patients were recruited prospectively from a general neurology service in a tertiary hospital. They were referred for diagnosis or management of complaints relating to the cervical spine. We included patients presenting with neck pain, which may be associated with numbness or weakness in a cervical root distribution. Patients should have signs of dermatomal sensory loss or motor weakness, reflex changes or even myelopathy. All patients must have imaging evidence (plain radiograph or MRI) of CS. We excluded patients with diabetes mellitus, chronic renal impairment or neurological disorders presenting with polyneuropathy which may otherwise confound assessment of outcomes. The local ethics committee has approved the study protocol, which has also been registered with clinicaltrial.gov (identifier number: NCT01061697).ad-hoc basis. As these were short-acting agents, they were discontinued once the trial commenced. During the trial period, none of the patients had any other form of analgesia.Pregabalin was commenced at 75 mg twice a day for a 4-week period, after which patients returned for follow-up. If the VAS pain scale was not reduced by 50%, the dosage was increased to 150 mg twice a day for a further 4 weeks. Adverse events to the study drug were documented carefully. Apart from physiotherapy, patients who had prior usage of pain prophylactic agents, including antiepileptics, gabapentin, and pregabalin were excluded. Of the original 50 recruited patients, 12 were on paracetamol and 10 were on indomethacin on an Each patient observed symptoms for 1 week prior to starting medication to obtain average baseline score values. We assessed pain symptoms on an 11-point visual analog scale (VAS) as the primary outcome measure. In addition, the short form McGill pain questionnaire (SFMPQ), comprising both sensory and affective components, was the main secondary outcome measure . SFMPQ , of which 23 completed the trial. Of the 27 who withdrew, 12 (44%) were for somnolence. Thirteen patients’ (54%) dosages remained at 75 mg and 11 patients’ (46%) dosages were escalated to 150 mg bd. Of the 28 patients who completed 4 weeks of trial, 13 (46%) had experienced > 50% reduction in pain. Based on an intention-to-treat analysis pertaining to the proportion of the original 50 patients recruited, 13 patients (26%) experienced > 50% reduction in pain.There was no significant difference in age and weight when comparing patients who completed or dropped out of the study . The liver function tests were not routinely monitored during the trial as pregabalin  is not s = 25.4, P < 0.0005), SFMPQ (sensory)  = 11.2), P = 0.003), and SFMPQ (affective)  = 10.9, P = 0.008). For VAS, there was significant reduction at 4 weeks (P = 0.001) and 8 weeks (P < 0.0005) compared to baseline. Additionally, repeated contrast testing of VAS at each week compared to the previous revealed significant reduction up to week 2. No further reduction was evident beyond week 2. Paired t-test was used to compare VAS scores between week 4 (after which dosages were maintained or doubled) and week 8. This showed a modest reduction in mean VAS of approximately 0.62 (P = 0.04). Comparing responses from week 4 to week 8 (paired t-test), the 75 mg bd (P = 0.24) arm did not show significant additional pain reduction. However, the 150 mg bd (P = 0.04) arm showed mild additional reduction in VAS scores.There were significantly reducing trends from baseline for VAS , there was significant reduction at 4 weeks (P = 0.01) and 8 weeks (P = 0.006) in scores compared to baselines. For SFMPQ (affective), there was significant reduction at 4 weeks (P = 0.04) and 8 weeks (P = 0.008) in scores compared to baseline.The PGIC scoring of patients who completed the study showed that 13% experienced no change in symptoms, 43% having minimal improvement, 30% having much improved, and 13% experiencing very much improvement. Similarly, the CGIC scoring showed that 22% experienced no change in symptoms, 35% having minimal improvement, 35% having much improved, and 22% experiencing very much improvement. = 1.3, P = 0.32) or depression  = 0.06, P = 0.82) changes were observed in the HADS.No significant anxiety (FFor the most common adverse effects of somnolence, 33 of 34 patients already experienced it at 75 mg bd dosage, and only 1 more patient had complained of its onset at the 150 bd dose stage.This is the first Asian study of pregabalin for treating neuropathic pain in cervical spine disorders to our knowledge. It was designed as a prospective and observational trial as pregabalin has already been shown to be useful for treating neuropathic pain in Western settings , 6. HereOf the patients that continued medication after the initial 4 weeks , there wIn comparison, previous pregabalin trials for neuropathic pain , 6 utiliThere were no serious adverse events observed in this trial, such as anaphylaxis, cardiovascular collapse or gastrointestinal complaints. In spite of FDA alerts on mood changes associated with antiepileptic drugs , our HADOf the documented adverse events, somnolence and dizziness were by far most commonly observed, constituting 81% and 33% respectively. These proportions were much higher than those reported in two large pregabalin trials, which were in the 25% range . While iThe present study is limited by the lack of placebo, small sample size and heterogeneous patient study group comprising Chinese, Malay, and Indians. While the high patient drop-out rates were observed, they were not apparently related to age or weight. This suggests that other pharmacological or intrinsic patient factors may be responsible for this observation. Nonetheless, these findings may provide additional justification of a trial at lower starting dosages in Asians.In conclusion, this PARPS has shown that pregabalin has rapid onset and is efficacious for neuropathic pain related to CS as a first-line single agent. However, the high proportion of adverse effects justifies further investigations into a lower initial dosage for Asian patients.


The purpose of the study is to evaluate the self-reported outcomes in the first year after primary total knee arthroplasty (TKA), and to determine factors influencing the quality of life (QoL) 6 weeks, 3, 6, and 12 months after TKA.A cohort of patients with knee osteoarthritis undergoing primary TKA at two hospitals  was prospectively followed for 12 months. Patients were assessed preoperatively and at 4 postoperative time-points, with the use of self-reported measurements for pain, physical function and depression with the following evaluation tools: Western Ontario and McMaster Osteoarthritis Index [WOMAC], Knee Society Scoring system [KSS], Centre for Epidemiological Studies Depression Scale, [CES-D10] and visual analog scale [VAS] for pain). General linear modelling for repeated measures was used to evaluate the effect of each independent variable including clinical and sociodemographic data. Differences between groups at different time points were tested by the independent samples t-test.Of the 224 eligible patients, 204  were included in the analysis. Response rate at one year was 90%. At 6 weeks after surgery, despite improvement in pain and alleviation of the depressive mood, the physical function remained less satisfactory. Females presented lower scores in terms of quality of life, both preoperatively and 6 weeks after TKA. Significant improvement was already experienced at 3 months postoperatively. According to WOMAC, KSS, CES-D10 and pain VAS scores the Qol was significantly improved 12 months after TKA (P < 0.001). CES-D10 score was positively correlated with WOMAC and pain VAS scores at all the time points assessed (P < 0.001). Age, body mass index (BMI), place of residence, level of education and social support were not significant predictors of QoL after TKA.Patients experienced great improvement in their QoL after TKA in spite of a less satisfactory physical function in the first 6 weeks after surgery, with noticeable differences in the QoL among genders in the same time period. After that period all patients experienced significant improvement for all the measured parameters, until the third postoperative month with smaller changes thereafter. Osteoarthritis (OA) is one of the most common causes of chronic pain and functional disability in the elderly and is related to genetic predisposition, environmental factors, lifestyle changes and ageing. The increased life expectancy and the tendency for obesity in younger individuals have lead to an increased prevalence of the symptomatic knee OA with broad variation among different populations. It is rNumerous follow-up studies after TKA reported that several socio-demographic and clinical variables, such as pre-intervention QoL scores, age, gender, obesity, social support, the number of comorbidities and the status of the mental health, may influence the outcome -14.This study prospectively evaluates the QoL after TKA, in a cohort of Greek patients. The objectives of the present study are to investigate the effect of patients’ demographic and clinical characteristics on the three dimensions of QoL  preoperatively and in a 12-month post-TKA period, and to identify disparities in the clinical outcome based on location of residence, educational status and social support.The cohort consisted of patients from the orthopaedic departments of two hospitals: the University Hospital of Larissa, located in central Greece, and the Veteran’s Hospital, located in downtown Athens. The duration of the follow-up was 12 months. The patient population of the University Hospital covered a broad spectrum of origin from rural to urban areas of the region while the population of the Veteran’s Hospital of Athens originated from urban near by areas. In Greece, the municipalities in which the largest settlement has less than 2,000 inhabitants are considered rural areas, while semi-urban are considered the areas with 2,000-10,000 inhabitants, and urban the areas with population larger than 10,000 ,14. PatiDuring the recruitment period 252 patients underwent primary TKA, but 27 did not meet the criteria, 5 refused to participate, and 16 underwent contralateral TKA during the follow-up period and were excluded from the study. The remaining 204 patients, 162 women and 42 men, were included and further evaluated. All patients started walking on crutches or a walker the second postoperative day and they were able to walk independently and in good balance before discharge from the hospital.The study design was prospective, with baseline measurements at the day before surgery and postoperative follow-up with personal contacts at 6 weeks, 3, 6, and 12 months. The information on sociodemographic characteristics of the patients such as age, gender, educational level, place of residence and social support status were record on a structured questionnaire. The patients’ social support was determined by their marital and living status. Patients who stated in the pre-intervention questionnaire that there were married or were living with someone, were defined as having more social support than those who were single and living alone.The clinical parameters included specific diagnosis, body mass index (BMI), previous major joint arthroplasty on the contralateral knee and Charlson Comorbidity Index score . Data onOne investigator (IP), who was not involved in the direct care of the participants, administered the questionnaires in face-to-face interviews and evaluated the different parameters (e.g. range of motion). For patients who were unable to read Greek because of illiteracy the questions were read-out by the interviewer.Four validated measurement tools were used: the Western Ontario and McMaster’s Universities (WOMAC) Osteoarthritis Index, the Knee Society Score (KSS), the Centre for Epidemiological Studies Depression Scale, short form (CES-D10), and the visual analogue scale (VAS) for pain.The WOMAC is a well-known, disease-specific instrument for measuring clinical outcome in patients treated for knee osteoarthritis ,17. UsinThe KSS consists of two scores, a knee score and a functioning score, both ranging from 0  to 100  . The kneThe CES-D short form is a 10-item self-reported measure of depressive symptoms commonly observed in older adults with chronic pain and was employed for independent assessments of depression and pain at each evaluation in order to measure potential improvement of mood after the surgical intervention. Scores range from 0 to 30, with higher scores indicating a higher frequency of current depressive symptoms experienced during the past week. Investigators have used a validated cut off score of 10 to differentiate clinically depressed from non-depressed patients. -21.The VAS is a commonly used assessment tool measurement for pain ,23. Indi2), level of education (elementary/ less and high), place of residence , social support (married /living with someone and otherwise), preoperative WOMAC, KSS, CES-D10, and VAS scores. The data were summarised as means ± S.D. or percentages. The effect of each independent variable was analyzed separately for the WOMAC and KSS questionnaires, and the CES-D10 and VAS scores, in time  using general linear modelling for repeated measures and post-hoc tests with Bonferroni’s correction. A general linear model multivariable analysis was used to estimate the effects of all factors of interest  on each response variable (QoL questionnaires) at 12 months postoperatively. The corresponding preoperative scores were used as covariates. The independent-sample t-test was performed to compare two groups' scores on the same variable. Pearson’s correlation coefficients were calculated to examine the relation between changes in WOMAC pain and VAS pain scores with changes in CES-D10 score. Effect sizes (ES) were calculated for the different outcome measures using the formula ES = mean change/SD of preoperative scores. The effect size is a standardised measure that provides information regarding the magnitude of change before and after TKA. An effect size of 0.8 or greater is considered large [The independent variables were age, gender, BMI  went home after discharge and followed a rehabilitation program supported by a physiotherapist with 12 sessions of physical therapy in 6 weeks period, starting the day after discharge. The remaining 28 patients were transferred to rehabilitation centers with a mean length of stay 19.3 ± (3.3) days and received a similar program of physiotherapy.2 had worse preoperative bodily pain  and poorer preoperative physical function  than did the patients with BMI < 30 kg/m2. There were no statistically significant differences in WOMAC domains across age, educational status, and residence or social support categories.The preoperative scores of the studied domains are analyzed in Table Analysis of the KSS questionnaire showed that women had significantly worse scores as compared with men . No significant differences were detected in KSS domains across, age, BMI, educational status, place of residence or social support categories.According to CES-D10, depression (score of 10) was detected preoperatively in 44.5% of patients . Women and those without social support had more depressive symptoms compared to male patients and to those having social support; these differences were statistically significant . Finally, VAS pain detected significantly higher scores in women than their counterparts .Table All groups of patients showed a statistically significant improvement in WOMAC domains between the pre- and the 12-month post-operative assessments. Patients improved from a bodily pain score of 11.8 ± 4.0 units preoperatively to a score of 1.6 ± 2.4 units (P < 0.001) 12 months postoperatively. Similar gains were observed for WOMAC function score , and for stiffness score . All WOMAC domains showed improvement at each follow-up visit .Table Regarding the three WOMAC domains, the multivariable analysis showed that the only predictive variables of better outcome were the baseline scores for pain and function Table .The improvement compared with baseline was statistically significant at 3, 6, and 12 months. In Knee score, patients were improved from 40.9 ± 18.0 units preoperatively to 89.3 ± 10.9 units 12 months postoperatively (P < 0.001). Similar pattern was observed for Function score: it improved from 34.4 ±12.2 preoperatively to 68.6 ± 14.1 units (P <0.001) 12 months postoperatively. In both KSS domains, there is no significant effect for gender, age, BMI, social support, education and place of residence at any postoperative follow-up interval (Table Pain VAS score significantly improved from a preoperative score of 8.7 ± 1.8 units to 12-month postoperative score of 1.6 ± 2.1 units (P < 0.001). There were no statistically significant differences across age, BMI, education, residence or social support categories Table .Similar gains were observed for CES-D10 scores. Patients’ mean ± SD score improved from 9.1 ± 6.6 preoperatively to 2.5 ± 4.5 units (P < 0.001) at 12 months after surgery.High scores, indicative depression were not found among the different groups of the study, during the postoperative follow-up. However, women had significantly worse scores when compared with men over time  were not offered the option of TKA from the surgeons of the present series, during the study period.This study also demonstrated that older age does not affect negatively the functional outcome after TKA ,13,25,32In the present study, it was hypothesized that patients living in rural areas, which reflects a lower socioeconomic and educational status and limited or no access to rehabilitation facilities, were more likely to have access barriers or underutilization of health care services especially in the early postoperative period that would consequently impact their outcome after a TKA -39. AccoSome studies demonstrated that social support might play an important role in moderating the effects of pain, physical disability, and depression in patients with osteoarthritis ,41. In aChronic pain and depression are closely related to each other and many studies attempted to reveal the causality -47. BaseAt 12 months postoperatively the TKA lead to a significant reduction in pain, stiffness, functional disability and depressed mood with the pain dimension showing the greatest improvement, although only 5% of patients complained for mild chronic pain without obvious concomitant clinical or radiographic sights that might explain this symptom. The greatest improvement was seen in all measurements within the first 3 postoperative months with smaller changes thereafter. However, at 6 weeks after surgery patients still experienced functional limitations and stiffness despite significant improvements in pain. The finding of limited early functional recovery is consistent with the findings from other studies suggesting that after an initial period of functional limitation patients improved by 3 months after surgery ,33. ThesBased on our data, we can conclude that the baseline WOMAC pain and function scores are a strong determinant of the respective post-operative scores at 12 months. The same conclusions apply to the CES-D10 score.We acknowledge however that this study was presents certain limitations such as the involvement of only two centres; therefore a multicenter research is needed for generalization of the results. In addition, the low proportion of males and the narrow age range of our patients, limited the usefulness of the results with respect to gender and age. The social support variable was created based upon the patients-reported preoperative living and marital status, which is only a crude measure of social support. In addition, the patients’ postoperative living conditions and marital status was not specifically investigated. Further studies need to explore these variables. The strengths of the study are its prospective design, the high rate of return to follow-up (90.2% at one year) and the use of a trained independent research assistant who recruited patients and followed them at each assessment.Our results demonstrated that quality of life in 95% of the patients with severe knee osteoarthritis was significantly improved in the first three months after uncomplicated TKA and thereafter. Women presented with worst pain, physical function and depressed mood preoperatively and they should be informed for that benefit when considering TKA earlier in the course of their arthritis. However 5% of patients stated that they experienced some mild symptoms 12 months after surgery. Age, BMI, level of education, social support and place of residence do not seem to influence knee replacement outcomes. Despite significantly milder pain and better physical function in the first 6 weeks postoperatively, for both men and women, the patients may need another person’s assistance for this time period after surgery. Finally, the finding that depressed mood has a strong positive correlation with chronic and more severe pain and functional limitation warrants further examination.TKA, Total knee arthroplasty; QoL, Quality of life; WOMAC, Western Ontario and McMaster Osteoarthritis Index; KSS, Knee Society Scoring system; CES-D10, Centre for Epidemiological Studies Depression Scale, short form; VAS, Visual analog scale; BMI, Body mass index; OA, Osteoarthritis.The authors declare that they have no competing interests.IP participated in the concept and design of the study, and the acquisition and the interpretation of the data and wrote the manuscript. ZHD participated in the concept and design of the study, reviewed the findings, and revised the manuscript. TP participated in the design of the study and helped draft the manuscript. LL participated in the concept and design of the study and helped draft the manuscript. EZ participated in the concept and design of the study, performed the statistical analysis and revised the manuscript. TSK participated in the design of the study and helped draft the manuscript. KNM participated in the concept and design of the study, critically reviewed the findings and revised the manuscripts’ final version. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/116/prepub


Chronic pain has been associated with impaired cognitive function. We examined cognitive performance in patients with severe chronic pancreatitis pain. We explored the following factors for their contribution to observed cognitive deficits: pain duration, comorbidity , use of opioids, and premorbid alcohol abuse. The cognitive profiles of 16 patients with severe pain due to chronic pancreatitis were determined using an extensive neuropsychological test battery. Data from three cognitive domains  were compared to data from healthy controls matched for age, gender and education. Multivariate multilevel analysis of the data showed decreased test scores in patients with chronic pancreatitis pain in different cognitive domains. Psychomotor performance and executive functions showed the most prominent decline. Interestingly, pain duration appeared to be the strongest predictor for observed cognitive decline. Depressive symptoms, sleep disturbance, opioid use and history of alcohol abuse provided additional explanations for the observed cognitive decline in some of the tests, but to a lesser extent than pain duration. The negative effect of pain duration on cognitive performance is compatible with the theory of neurodegenerative properties of chronic pain. Therefore, early and effective therapeutic interventions might reduce or prevent decline in cognitive performance, thereby improving outcomes and quality of life in these patients. Chronic pancreatitis is a serious medical disease characterized by inflammation of the pancreas resulting in progressive and irreversible morphological changes and often end-stage exocrine/endocrine failure It is now well accepted that neuroplasticity, i.e. altered central pain processing, plays an important role in the development of chronic pain Many patients suffering from chronic pain report cognitive complaints. There is substantial evidence that chronic pain can impair cognitive abilities However, most of these studies included patients with unspecified pain and pain syndromes of varying etiologies In acute and chronic neurodegenerative diseases, neuronal cell death is also an important factor underlying the observed decline in cognitive functions Apart from severe pain, many chronic pancreatitis patients report also other factors that have been associated with a decrease in cognitive functions, such as depressive symptoms The objectives of this study were 3-fold. Firstly, we wanted to examine whether chronic pancreatitis pain is associated with cognitive decline. A second objective was to examine whether documented cognitive deficits are related to pain duration, supporting the hypothesis that chronic pain is a progressive neurodegenerative disorder. Thirdly, our aim was to examine to what extent other individual factors, e.g. depressive symptoms, sleep disturbance, opioid medication and a history of alcohol abuse, contribute to the cognitive decline of patients with chronic pancreatitis. To this end, the neuropsychological profile of chronic pancreatitis patients was documented by means of a complete neuropsychological test battery and compared with the neuropsychological profile of healthy controls matched for age, gender, and education.Over a ten-month period, sixteen patients with confirmed chronic pancreatitis and associated chronic pain were referred to the Brainclinics Research Institute, Nijmegen, the Netherlands, for standardized assessment of their cognitive abilities. The diagnosis of pancreatitis was based on a standard battery of history, laboratory tests and radiological findings. Patients were ambulant and randomly selected from the outpatient clinic. Patients with persistent alcohol use were excluded from the study. The control group consisted of 16 healthy volunteers who were matched to the chronic patient group according to age, gender, and years of education. For all participants, the standardized neuropsychological assessment protocol of the Brain Resource International Database was used For the healthy volunteers, medical ethical approval to collect the data was obtained . The patients were all referred by their physician in charge for neuropsychological testing, as part of their medical follow up. Written informed consent to use the data for scientific purpose was signed by all subjects, both healthy volunteers and patients.Cognitive abilities were assessed by means of the Integneuro test battery using an automated touch screen tool The period (in years) that the chronic pancreatitis patients were under medical control for pain treatment was taken as measure of pain duration. Matched controls were free of chronic pain and scored 0 on this variable.Apart from group  and pain duration, four covariates were included in this study; depressive mood, sleep disturbances, opioid use, and a history of alcohol abuse.In both patients and healthy volunteers, depressive mood was assessed by the short-form version of the Depression Anxiety Stress Scales (DASS-21) Information about sleep disturbance and opioid medication was obtained through a screening questionnaire leading to either the presence of sleep disturbances or not in both the patients and healthy volunteers. Information about a history of alcohol abuse in the past and or the use of opioid medication was extracted from the medical files of the patients  within participants (level 2) and the test scores from these measurements were clustered in three different cognitive domains: psychomotor performance, memory, and executive functions. From this we expected dependency within the data. Therefore, a multivariate multilevel analysis was applied for the current data www.bristol.ac.uk/cmm/software/mlwin/). For details of the analysis see A multivariate multilevel analysis with fixed occasion models was used. The models were set up using a one-by-one backward removal of non-significant fixed effects . Next, one-by-one non-significant covariances were removed using a deviance test. The last step consisted of the removal (once more) of non-significant fixed effects. We followed this procedure to ensure we did not overlook suppression effects and that the covariance matrix was, initially, as free as possible. For the analysis the package MLwiN (version 1.10.000.6) was used .These models were not nested, thus comparison of the models using the standard deviance test was not appropriate. We used the Akaike's Information Criteria corrected for small samples (AICc) to evaluate the multiple regression models and select the “best” model for cognitive functions for each cluster at two levels see .For the multivariate multilevel analysis the test score variables for the clusters psychomotor performance, memory, and executive functions, were standardized . The predictor ‘group’ was a dichotomous variable  and the predictor ‘pain duration’ was a continuous variable with standardized values within the patients group . All covariates were dichotomous variables, except for the depression score, which was continuous and these scores were standardized in the multilevel analysis .Effects (E) on the test scores of the neuropsychological tests were calculated and in order to compare the effects, effect sizes (ES) for the continuous and dichotomous variables were calculated see .For a comprehensive illustration of the calculation and interpretation of estimated effects and effect sizes of the predictors ‘group’ and ‘pain duration’ see The study sample consisted of 16 patients with chronic pancreatitis pain and 16 healthy controls. Patients and healthy controls were matched according to age, gender, and years of education . Mean duFor the cluster psychomotor performance, model 2 with the predictor ‘pain duration’ (period of pain in years) had a lower AICc value (366.8) compared to the AICc of model 1 (376.2) including the predictor ‘group’  . TherefoThe effects of ‘group’ were significant for all seven tests when ‘pain duration’ and covariates were included (i.e. model 4), meaning that chronic pain patients performed worse on all tasks within the psychomotor cluster compared to the healthy controls . Thus onWith respect to the domain of psychomotor performance which comprised seven tests, the covariate depression appeared to hold additional explanatory effects with respect to two tests: the “Variability’ in taps of the non-dominant hand and performance on the ‘Choice Reaction Time’ test. Similarly, a presence of sleep disturbance holds additional explanatory effects for two tests: ‘Tapping’ with the dominant hand and with the non-dominant hand. Finally, the use of opioid medication also holds additional explanatory effects for two tests: ‘Variability’ in taps of the dominant and the non-dominant hand. A history of alcohol abuse appeared to have additional explanatory effects with respect to the six tests: ‘Tapping’ with the non dominant hand, ‘Variability’ in taps of both the dominant and the non-dominant hand, ‘Choice Reaction Time’ test, ‘Target Detection’ test, and ‘Working Memory’ test. Alcohol abuse is therefore the covariate with the greatest impact.In the cluster memory, the ranking of the AICc values of the 4 different models showed that model 2 with the predictor ‘pain duration’ (AICc 572.3) was the better statistical model for explaining memory compared to model 1 with the predictor ‘group’ (AICc 584.6). Thus the predictor ‘pain duration’ was a better predictor than the predictor ‘group’  with respect to memory. However, this advantage disappeared when covariates were added in the model . Model 4The estimated effects of ‘group’ in model 4 were significant for both parts of the ‘Maze learning’ tasks (0.55) and (−0.59), ‘Delayed recall’ of the verbal word learning task (0.49) and ‘Recognition’ of the verbal word learning task (−0.67) tests. Thus pain patients scored less accurately on these tasks compared to healthy controls . In addition sleep disturbance had additional explanatory effects in one test: the ‘Visual span’ test. The use of opioid medication had additional explanatory effects with respect to three tests: ‘Maze learning A’, verbal word learning and recognition of verbal word learning. A history of alcohol abuse had additional explanatory effects in four tests within the cluster memory: maze learning A and B, verbal word learning and the delayed recall of verbal word learning.In the cluster executive functions, the model with ‘pain duration’ (AICc 480.9) better explained the test scores of executive functions than the model with ‘group’ (AIC 495.9). Multilevel analysis showed that duration of pain remained of importance when the covariates were included (model 4), according to the estimated effects . Again, The estimated effects of ‘group’ were significant with respect to the tests ‘Switching of attention 1’ (−0.80), correct responses on the ‘Verbal interference’ test (−1.06), ‘Intrusions’ on the verbal word learning task (0.58), and reaction times to the ‘Go-NoGo’ task (1.63), meaning that patients showed a significant decline in executive functions compared to the healthy controls  gave a better explanation for the variance in cognitive performance  than the predictor ‘group’ (model 1) did. However, variance in all three cognitive domains could be best explained with model 4 which included ‘group’ and ‘pain duration’ together with relevant covariates of depression, sleep disturbance, opioid medication, and a history of alcohol abuse. The mean performance of the patients, in those nine tests that were significant deviant from controls with respect of pain duration, was 73% of that of the controls  The findings of the current study related to the domain of psychomotor performance may further have been affected by all four covariates investigated. These factors have all previously been associated with a decrease in psychomotor speed Pancreatitis pain patients also showed impairments in executive functions. Significant effects of pain duration were found on tasks that highly depended on mental flexibility (i.e. switching of attention task), self-monitoring abilities (i.e intrusions on word learning) and withholding a response . Executive functions represent a high, more abstract level of processing, and are mainly supported by the prefrontal cortex Memory performance was the least affected cognitive function in patients with chronic pancreatitis. Mild problems with memory functioning have previously been related to depressive symptoms Depression, sleep disturbance, use of opioids, and a history of alcohol abuse, are all factors that have been associated with decreased cognitive abilities. Therefore, in the current study these factors were included in the models explaining the observed variance in neuropsychological test data. Indeed, with respect to a number of the tests, these factors did offer additional explanation for the observed cognitive decline in pancreatitis patients. Of these factors, a history of alcohol abuse appeared to be the most prominent factor. However, the effect sizes of a history of alcohol abuse were still modest in comparison with the effect sizes of chronic pain and pain duration (data not shown). This limited effect might be ascribed to the long duration of alcohol abstinence at time of testing in our patients, i.e. at least one year. Indeed, significant recovery has been found within one year of abstinence in most cognitive domains In this study a homogenous group of patients was recruited, all having a confirmed diagnosis of pancreatitis. Despite the patients being homogenous in the cause of the pain, it is still difficult to ascribe the observed cognitive deficits to just one underlying cause. This difficulty is not only due to the variation in the duration of their pain disease but also due to comorbidity with depression, sleep disturbances, the high prevalence of a history of alcohol abuse and a current use of opioid medication. However, by applying multivariate multilevel analyses we were able to entangle at least partially the differential influences of these contributing factors.The uniqueness of this study is that it is the first study to formally assess the cognitive performance of chronic pancreatitis pain patients. Previous studies in this field have focused on other chronic pain patients e.g. low back pain The direct detrimental effect of pain duration on cognitive performance in the present study is a new observation, which has not been reported previously. This negative effect of pain duration on cognitive performance supports the novel concept of viewing chronic pain as a disease with neurodegenerative properties. From a therapeutic perspective, the suggestion that neurodegeneration may be related to chronic pancreatitis pain is extremely relevant. Typically, chronic pancreatitis patients with pain are treated with pain medication including opioids over long periods of time, with limited treatment success and low health-related quality of life, predominantly as a result of persisting or relapsing pain despite medication Appendix S1(DOCX)Click here for additional data file.Appendix S2(DOCX)Click here for additional data file.Appendix S3(DOCX)Click here for additional data file.Appendix S4(DOCX)Click here for additional data file.


Spontaneous pain, hyperalgesia as well as sensory abnormalities, autonomic, trophic, and motor disturbances are key features of Complex Regional Pain Syndrome (CRPS). This study was conceived to comprehensively characterize the interaction of these symptoms in 118 patients with chronic upper limb CRPS (duration of disease: 43±23 months). Disease-related stress, depression, and the degree of accompanying motor disability were likewise assessed. Stress and depression were measured by Posttraumatic Stress Symptoms Score and Center for Epidemiological Studies Depression Test. Motor disability of the affected hand was determined by Sequential Occupational Dexterity Assessment and Michigan Hand Questionnaire. Sensory changes were assessed by Quantitative Sensory Testing according to the standards of the German Research Network on Neuropathic Pain. Almost two-thirds of all patients exhibited spontaneous pain at rest. Hand force as well as hand motor function were found to be substantially impaired. Results of Quantitative Sensory Testing revealed a distinct pattern of generalized bilateral sensory loss and hyperalgesia, most prominently to blunt pressure. Patients reported substantial motor complaints confirmed by the objective motor disability testings. Interestingly, patients displayed clinically relevant levels of stress and depression. We conclude that chronic CRPS is characterized by a combination of ongoing pain, pain-related disability, stress and depression, potentially triggered by peripheral nerve/tissue damage and ensuing sensory loss. In order to consolidate the different dimensions of disturbances in chronic CRPS, we developed a model based on interaction analysis suggesting a complex hierarchical interaction of peripheral (injury/sensory loss) and central factors (pain/disability/stress/depression) predicting motor dysfunction and hyperalgesia. Complex Regional Pain Syndrome (CRPS), mostly regarded as a neuropathic pain disorder, is typically evolving after a minor trauma of the limb All patients with a history of CRPS of more than 12 months diagnosed either by the IASP criteria or the research diagnosis criteria proposed by Bruehl  [2], whoPatients suffering from CRPS had been treated following the treatment guidelines of our pain clinic: Treatment invariably contained physical therapy, occupational therapy and lymph drainage as long as clinical signs of edema were present. Drug therapy contained a WHO ladder step I medication , as well as a drug recommended as a first line choice for the treatment of neuropathic pain conditions All patients received a standardized Quantitative Sensory Testing (QST) for characterization of a complete somatosensory phenotype. Testing contained establishment of sensory as well as thermal detection and pain thresholds, vibration thresholds, mechanical pain sensitivity, paradoxical heat sensation and pressure pain thresholds. All tests were performed under minimal distraction in a silent, air-conditioned room, with an ambient temperature of 25–26°C. Subjects were seated on a comfortable chair, and allowed to adapt to the test environment for at least 20 minutes. The course of assessments was explained to the subjects by written standard patient instructions. QST followed the protocol suggested by the German Research Network on Neuropathic Pain (DFNS). All sensory tests were demonstrated in a remote test area (forearm) not affected by the underlying disease. The hand affected by the disease was termed “ipsilateral”, while the other hand was termed “contralateral”. All tests were performed at the dorsum of the ipsi- as well as the contralateral hand, starting at the contralateral side. Thermal testing was performed using a Medoc Thermal Stimulus Analyser TSA-2001 device  with a computer-controlled Peltier-based probe. Thermal testing consisted of testing for Cold Detection Threshold (CDT), Warm Detection Threshold (WDT), Cold Pain Threshold (CPT) and Heat Pain Threshold (HPT) and Thermal Sensory Limen (TSL) by using the methods of limits. Furthermore, a testing for elicitation of Paradoxical Heat Sensations (PHS) was applied. Mechanical testing consisted of determination of Mechanical Detection Threshold (MDT), Vibration Detection Threshold (VDT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS), Wind-up Ratio (WUR) and Pressure Pain Threshold (PPT). Furthermore, the degree of Dynamic Mechanical Allodynia (DMA) was assessed. Total duration of sensory testing was about 60 minutes. For an elaborate discussion see Rolke et al. Infrared thermometry  was used for clinical assessment of sympathetic outflow Hand edema was assessed using a custom made Lucite volumeter (13.5*13.5*34.5 cm), with the patient in an upright position. The testing commenced as described by Stern A standardized clinical examination of CRPS symptomatology according to the IASP criteria was performed in all patients. The testing commenced in a given sequence in a silent air-conditioned room at 23–25°C. Patients were allowed to adopt the environmental terms for at least 15 minutes before testing. All clinical examinations were performed by one of three experienced examiners . Assessment started with clinical testing for mechanical hyperalgesia, mechanic dynamic allodynia as well as hypoaesthesia. Mechanical hyperalgesia was tested using a blunt copper wire with a diameter of 1 mm. Mechanic dynamic allodynia and hypoaesthesia were tested using a mounted Q-tip. All examinations were carried out on the dorsum of the ipsi- as well as the contralateral hand, beginning with the contralateral side. Mechanical hyperalgesia was accounted when painful sensation elicited on one examined area was considerably more pronounced than on the contralateral side.Mechanical allodynia was considered to be present if pain was evoked by slightly touching the examined areal. Mechanical hypoaesthesia (loss of touch sensation) was diagnosed when touch sensation on one side was diminished in side to side comparison. Sudomotor dysfunction was evaluated in a dichotomous way  in comparison to the contralateral side. Disturbances of hair as well as nail growth, changes in skin colour, presence of edema and skin gloss were judged in an identical manner.An 11 point Likert scale ranging from 0–10  was used to assess the patients' subjective intensity of spontaneous ongoing pain. Furthermore, evoked pain accompanying physical strain of the hand was evaluated in an assessed as either exaggerated by physical strain or not (i.e. present or absent). Moreover, presence or absence of shoulder or elbow pain was recorded.The assessment of hand motion took place in an analogous setting. Patients underwent goniometric measurements to determine active range of motion (AROM) of the wrist (extension/flexion) as well as thumb abduction by using a standard plastic transparent goniometer. AROM was defined as the maximum amount of joint motion attained by a subject during active performance of joint motion. Patients were instructed to move the respective joint as far as possible. For wrist extension and flexion a test-retest reliability of >0.90 and inter-observer reliability coefficients between 0.78 and 0.91 have been reported CITEC: Center of Innovative Technic BV; Netherlands) following a standardized protocol. The utilized dynamometer measures grip strength in Newton (N) with an accuracy of 0.1%. All measurements were performed on the ipsi- as well as the contralateral hand. During the tests, the display was invisible for the patient. Each test was performed three times each hand, and the respective arithmetic mean was used for further analysis. Testing commenced with the patient in a seated position in the environment described above. Patients were instructed to apply the maximal possible force. Full-fist grip, three point grip and pinch-grip were measured nd and 3rd fingers were positioned above it. Pinch Grip: The distal phalanx of the thumb was placed above the device, while the radial side of the index fingers' middle phalanx was positioned under it.The muscle strength was measured by means of a hand held dynamometer  The German version of the Pain Disability Index (PDI) was used to measure the pain-related interference with seven distinct domains of daily life Symptoms of depression were assessed by means of the German version of the Center for Epidemiological Studies Depression Test (CES-D). This test combines twenty questions designed to measure levels of depression Intensity and incidence of stress symptoms were measured using the German Version of the Post-Traumatic Stress Symptom 10-Questionnaire (PTSS-10) The German version of the Short Form 36 (SF-36) was employed to assess the overall health-related quality of life. The SF-36 is a generic measure independent of age and underlying disease, assessing the generic health-related quality of life (HRQL) in eight dimensions  aggregated into two summary scores . The eight scales and the two summary scores are scored from 0 to 100, with 0 indicating the worst health and 100 the best Nonparametric paired Wilcoxon signed ranks method test was applied to detect side-to-side differences for scores with nominal or ordinal data level. Paired t-test was used for side-to-side comparisons as well as for group comparisons for data on interval level.reference data base)/SDreference data base. Significance of differences from healthy controls was estimated comparing the patients mean ± SD obtained by this z-normalization vs. a standard normal distribution (i.e. mean ± SD = 0±1) of an equal number of healthy subjects of the DFNS reference data using the web-based statistical freeware  All QST data except CPT/HPT/VDT and PHS were transformed into decadic logarithms to achieve secondary normal distributions within functional blocks of parameters (e.g. motor parameters). Subsequently, multiple correlations using the stepwise forward method of building regression equations was calculated to analyse which parameters were the dominant partners determining correlations between functional blocks of parameters. When the dominating parameter(s) had been identified (in some cases more than there one parameter represented a block), median split analysis was used to assign a direction of prediction . For description of this complex network of interrelations we used the wording “correlated” or “predicted”  to signify correlations that operated either bi- or unidirectional.In order to explore functional interdependence between pain, sensory, motor and psychological parameters we developed a network of mutual relations by causal modelling using a modified method of path analysis following a similar reasoning as current dynamic causal modelling approaches used in imaging data A total of 118 patients  were enrolled in the study . PatientThe average limb volume of the contralateral hand was 480.4±81.5 ml, while the volume of the affected hand was significantly reduced  in 36/118 patients (31.3%), while only 16/118 (13.9%) exhibited pathological volume enlargement suggestive of hand edema. The quantitative assessments were corroborated by standardised clinical examination identifying 30/118 patients (25.4%) displaying clinically relevant signs of edema .Patients with chronic CRPS displayed a statistically significantly lower hand temperature at the affected hand albeit differences were small . A total of 48 patients (40.7%) displayed abnormal skin colour at the affected hand, with 15 patients exhibiting glossy skin (12.7%). Twelve of these 15 patients displayed combined skin discolouration and glossy skin.Clinical assessment of sudomotor or trophic changes revealed the presence of enhanced sweating at the affected hand in 24 patients (20.3%), and in two patients (1.7%) at the contralateral hand. One of the two patients was affected bilaterally. Nine patients (7.6%) complained of augmented hair growth at the site of chronic CRPS, while disturbed nail growth was found in 23/118 patients (19.5%). Two patients had disturbed contralateral nail growth (1.7%), in one patient affecting solely the contralateral extremity .The majority of patients (77/118 = 65.3%) reported spontaneous ongoing pain (44 patients with pain scores ≥4 = 37.3%). Only 41/118 patients were completely pain-free at rest  . A few pPatients exhibited a highly significant loss of thermal  and mechanical detection  at the affected hand compared to age and gender-matched healthy controls . Notably, the same highly significant thermal as well as mechanical hypoesthesia also occurred at the contralateral hand, albeit to a lesser extent . Thus, sensory loss was homogeneously encountered in any non-painful somatosensory modality. Average somatosensory loss was −1.38 standard deviations  at the affected hand, and −1.01 SD at the contralateral hand .Thresholds for cold and heat pain were significantly decreased, indicating cold and heat hyperalgesia . Additionally, a striking hyperalgesia to painful blunt pressure was found . Likewise, the pain threshold to pin prick was lowered, and pain ratings to suprathreshold pin pricks were increased . Moreover, a statistically significant, albeit small degree of dynamic mechanical allodynia occurred . However, pain summation at the affected hand remained unaltered . Significant hyperalgesia was also encountered contralaterally throughout all pain parameters . Although marginally more frequent, the incidence of paradoxical heat sensations (PHS) was indifferent from healthy controls . Thus, sensory gain, i.e. hyperalgesia was encountered in any painful somatosensory modality. Average pain sensitivity was above normal thresholds by +1.12 standard deviations at the affected hand, and +0.55 standard deviations at the contralateral hand. QST results are summarized in Hand force at the affected hand as measured by dynamometry was significantly reduced in any test. Force reduction (−35–40%) was homogeneous throughout all tests performed, namely 98.4±74.8 N vs. 163.4±83.38 N for fist grip, 46.2±30.0 N vs. 74.4±48.4 N for three point grip, and 25.4±17.6 vs. 39.1±19.9 N for pinch grip; affected vs. contralateral hand respectively; all p<0.001 .Patients with chronic CPRS displayed significant motor impairments as revealed by several measures, including the ability to clench a fist, to maximally extend the fingers, or to supinate the wrist and forearm . However, impaired pronation of the wrist or forearm, as well as a disability to rotate the ipsilateral shoulder was rarely seen . FurtherTotal SODA score amounted to 88.4±22.8, and average SODA pain-score was 2.1±3.2 (SODA pain-score ranges from 0 to 12). The overall score of the Michigan Hand Outcome Questionnaire (MHQ) was 53.0±15.0 (range: 22–84). Furthermore, all subscores of the MHQ displayed significant hand disability .Pain disability index averaged 24.2±20.3. Average CES-D scores were 37.0±11.3, thereby considerably exceeding the limit (CES-D: >27) to diagnose a depressive episode in pain patients. Notably, 97/118 patients (82%) had a CES-D score of above 27. Mean PTSS-10 sum score amounted to 28.7±12.7 (median score: 27). 32/118 patients (27.4%) displayed a PTSS-10 higher than the cut-off of 35 reported in the literature. The majority of patients with chronic CRPS (89/118 = 75.4%) reported multiple traumatic memories . Mean nuMerely three patients displayed a temperature difference of more than +1°Celsius and were therefore classified as warm CRPS, while sixteen patients had a temperature difference between the ipsi- and the contralateral hand of ≥−1°C and were therefore classified as “cold” CRPS. Patients with “warm” CRPS displayed more spontaneous pain,  than patients with “cold” CPRS ; but differences were not statistically significance probably due to the small number of patients in each group. Furthermore, no differences in hand volumes or significant differences in QST between patients with “warm” or cold CRPS could be detected. Contrariwise, patients displaying hand discoloration at the time of assessment, had significantly more spontaneous pain  compared to patients without signs of hand discoloration  (p<0.001). Furthermore, patients with hand discoloration displayed significantly more pressure pain hyperalgesia . Moreover, no other ipsi- or contralateral changes in QST parameters or significant differences in hand volume could be detected.Correlation analysis encompassing all estimated parameters revealed several functional complexes. Ongoing pain and pain-related disability (PDI) , as well as posttraumatic stress (PTSS-10) and depression (CES-D) were highly correlated . There were also highly significant correlations between these two blocks of parameters . Median split analysis suggested that none of these relationships was unidirectional . AdditioScores of both methods of comprehensive objective and subjective motor function assessment (SODA and MHQ) were strongly predicted by ongoing pain  and pain-related disability . Median split analysis revealed that VAS or PDI were highly significantly predictive for differences in SODA or MHQ , but not vice versa  suggesting that motor disturbances were predicted by pain and PDI rather than correlated.Hyperalgesia was analysed using the QST parameter exhibiting the most prominent gain, namely blunt pressure pain (PPT). Combined correlation and median split analysis revealed that hyperalgesia to blunt pressure stimuli was highly significantly predicted by motor dysfunction , and to a lesser albeit significant degree by pain or PDI (both p<0.0001). In contrast, hyperalgesia was only weakly predicted by posttraumatic stress  and not at all by depression . An overview on correlational and predictive interaction of sensory function, pain, hyperalgesia, and motor and psychological functioning is depicted in Chronic CRPS was characterized by chronic pain at rest and during exercise, combined with substantially limited hand force and impaired motor function. Accordingly, the resulting overall hand function was substantially disabled even several years after the initial trauma. Chronic CRPS patients exhibited pronounced bilateral sensory changes revealed by QST, namely hyperalgesia and sensory loss. Furthermore, patients exhibited a clinically relevant degree of chronic stress as well as signs of depression. In contrast, patients with chronic CRPS displayed only marginal vasomotor, trophic or sudomotor changes.The majority of patients with chronic CRPS complained about spontaneous pain. The observed proportion is comparable to outcome studies in patients with childhood-onset of CRPS and a median follow up after 12 years, Because motor dysfunction was not a “conditio sine qua non” in former diagnostic criteria of CRPS, many studies do not report the amount of motor changes in CRPS or confine to describe manifestations of existing motor deficits In contrast to the distinct somatosensory and motor alterations, other symptoms of CRPS were by far less present. Of these changes, skin discolouration was most frequently noted with an incidence of about 40%. In contrast to patients with acute CRPS, in which hand edema and clinical aspects of a “warm” hand dominates, the volume of the affected hand was significantly reduced when compared to the contralateral side, and on average the hand affected by CRPS appeared “colder” Recently, it has been suggested that patients with “warm” and “cold” CRPS , might be representatives of a more peripheral or central pathophysiology of the disease While only few patients displayed signs of significant temperature differences between both hands, a considerable proportion of patients with chronic CRPS showed hand discoloration, which can, like temperature differences, also be interpreted as a sign of an ongoing vasomotor instability While psychological factors do not seem to be associated with the onset of CRPS Chronic CRPS patients displayed a considerable degree of hand disability and impaired hand dexterity, comparable to patients with rheumatoid arthritis and mobile swan neck deformities Chronic pain disrupts the so-called “default mode network” of the brain As the study design is not prospective, a potential recruitment bias must be taken into account. Overall, 86 patients which had been contacted, refused to participate in the study. Moreover, 67 eligible patients could not be contacted, and six patients deceased . HoweverQST is a behavioural functional measure of somatosensory function, and none of the performed tests provides a direct evidence of structural changes in either the peripheral or the central nervous system Taken together, one can speculate about the following mechanisms interacting in the pathophysiology of CRPS: Initial sensory loss, possibly caused by a peripheral neurogenic inflammation, accounts for the inducting of ongoing pain. The degree of ongoing “central” pain, depression and stress, determines the development and degree of hand dysfunction and the amount of evoked pain in chronic CRPS . In summ