Percutaneous liver biopsy (PLB) is the “gold standard” in the diagnosis of liver diseases. A pilot trial has shown pethidine may reduce anxiety and the need for post-procedural pain relief. The aim of this study was to investigate the role of pre-procedural pethidine.A double-blinded, randomized, placebo-controlled trial was conducted to assess the need for pethidine prior to PLB. 98 patients were randomly assigned to receive either 50 mg pethidine i.v. (n = 48), or an equal volume of 0.9% normal saline (n = 50). PLB was performed with ultrasound guidance after adequate local anaesthesia with xylocaine. Patients were asked to self-evaluate pain experienced using a visual analogue score (0–10) immediately and an hour after PLB. Patients were then followed up 24 hours after the procedure to assess their pain score, retrospective pain score and willingness to have a repeat procedure.Pethidine administration resulted in significantly lower pain scores  and required less analgesia  immediately after PLB in comparison to the placebo group. There was no significant difference in the pain score and analgesia requirement one hour after the procedure, the pain score at 24 hours after procedure and retrospective pain score. 94% of all patients of either group are willing to under go a repeat liver biopsy (NS).The administration of pethidine routinely prior to PLB reduces the immediate post procedural pain but has no lasting effect and does not influence the patients’ decision making process for future investigations.ACTRN12614001194651, 13 November 2014 Percutaneous Liver biopsy (PLB) remains an essential tool in the diagnosis and management of parenchymal liver disease. It is still considered as the “gold standard” in the diagnosis, assessment and staging of various diseases.As an invasive procedure, PLB has been associated with several complications including post-procedural pain . Liver bA randomized, placebo-controlled, double blind study approved by the Lower South Regional Ethics Committee and undertaken at Dunedin Public Hospital (DPH), New Zealand. DPH is a tertiary teaching hospital with 350 inpatient beds covering a population of more than 190,000 people over 32,000 square kilometers of land in the lower South Island of New Zealand [One hundred consecutive patients consented to be enrolled in the trial between March 2009 and May 2011, two patients withdrew their consent. All patients were given information sheet and written consents were obtained. Patients were randomly assigned to the pethidine (N = 48) or placebo group (N = 50)  abdominal ultrasound revealed a contraindication to PLB such as massive ascites, intrahepatic duct dilatation, or focal lesion; 4) patients without a telephone for study follow up; and 5) patients with a solitary lesion that required target biopsy under ultrasound guidance.were as follows: 1) Patients with previous allergic reaction to pethidine or metoclopramide; 2) Patients with clotting disorders and abnormal prothrombin time with international normalized ratio (INR) of greater than 1.5 or thromcytopenia with platelet less than 50 × 10At Dunedin Public Hospital (DPH), a single consultant oversees the liver biopsies performed both by the consultant and advanced trainee in gastroenterology. Current blood results including full blood count and INR were reviewed and informed consent was obtained one day prior to the procedure. Patients were asked to fill in a Penn State worry questionnaire .For the procedure, patients were placed in the supine position, and the ideal location for the liver biopsy on the lateral aspect of right thoracic site was established by both percussion as well as immediately prior to the investigation by abdominal ultrasound . Patients were randomly (using randomization table) assigned to receive either 50 mg pethidine i.v. or an equal volume (1 ml) of 0.9% normal saline as premedication. All patients received 10 mg of metoclopramide i.v. The premedications were prepared by an independent nurse who was not involved with the care of patient before and after the procedure. The prepared medications were identical in volume and appearance and labeled with randomization number and patient details. The patients, assisting nurse and the operator were unaware of what premedication the patient received. The metoclopramide was given to mask the side effect of pethidine that patients may experience. Following disinfection of the skin with iodine, the patients were given the assigned premedication. The skin and subcutaneous layers of the thoracic wall were locally anaesthetized with 10 ml of 1% xylocaine containing 1:100,000 adrenaline. A small incision into the skin was made using a disposable scalpel. The liver biopsy was performed using a modified Menghini  biopsy sp value of less than 0.05 was considered significant.The two groups were compared by Student t-test or Fisher’s exact test for qualitative variables. A There were 63 male and 35 female patients with a mean age of 47.6 ± 8.5 years (range 17–81 years). The indications for PLB are hepatitis C (50%), hepatitis B (11.2%), autoimmune hepatitis (7.1%), alcoholic hepatitis (1%) and others (30.6%). Both groups were similar with respect to age, sex, body mass index and indication for liver biopsy. There were no significant differences in pre-biopsy anxiety score, current analgesic use, liver function test, INR, MELD (Model for End-stage Liver disease) score and number of passes to obtain a sample between the two groups (Table Pethidine administration resulted in significantly lower pain scores immediately after the procedure than the placebo group: 0.60 ± 0.1 versus 1.2 ± 0.2 (p = 0.006). The range of pain score for the pethidine group was 0 to 2 compared to 0 to 4 in the placebo group.No patient in the pethidine group required any additional analgesia immediately after the procedure in comparison to five (10%) patients in the placebo group (p = 0.03).One patient from the pethidine group required pain relief compared to four patients in the placebo group an hour after the procedure however, there was no statistical difference in the pain score or pain relieve requirement an hour after the procedure.There was no significant difference in the pain score and the retrospective pain score between the two groups at 24 hours after the procedure. 94% of the overall patients were willing to undergo a repeat PLB if clinically indicated; there was no significant difference between the two groups   is still considered as the “gold standard” in the diagnosis, assessment and staging of various diseases. It provides an accurate diagnosis in approximately 90 percent of patients with unexplained liver function test abnormalities . A signiThe attitude toward post-procedure pain and its prophylactic use of analgesics, anxiolytic, or sedative drugs is a matter of uncertainty and controversy. Consequently, there is variation between centers in techniques and guidelines for liver biopsy ,3. In ouWe conducted a randomized, placebo-controlled, double blind study to evaluate the need for pethidine in PBL. The results show that the use of pethidine provided a statistically significant pain relief in the immediate post procedural period in comparison to the placebo group but has not long-term effect.In more detail, the mean VAS score was 0.6 in the pethidine group in comparison to 1.2 in the placebo group immediately after the procedure. Although there is statistically significant difference in the VAS score between the two groups, the VAS score of 1.2 in the placebo group is not considered as a clinically significant pain score as patients with VAS score of 2–3 are still usually quite functional.Our results also showed that the use of pethedine had no long-term effect and did not impact on the pain score at one hour and 24 hours. With use of local anesthetic and good liver biopsy technique patients tolerated the PLB procedure with minimal pain.More importantly, the result showed that overall 94% of patients were willing to undergo a repeat procedure if required regardless of whether they have received pethidine or not.Administration of pethidine did not affect the rate of complications; there were no significant complications observed during the study period. These were consistent with our previous pilot study . The useIn conclusion, based on our results, we consider the use of pethidine as unnecessary and liver biopsy can be performed under good local anaesthesic technique. The use of pethidine before percutaneous liver biopsy resulted in better pain score and less analgesia requirement immediately after the procedure. However the use of pethedine had not impacted on the pain score and retrospective pain score at 24 hours after procedure. 94% of patients were willing to undergo a repeat procedure if required regardless of whether they have received pethidine or not. Pethidine use before procedure can be discussed with the patient; however its use may not enhance patients’ compliance with future biopsies.


Chronic musculoskeletal pain and depression are very common in primary care patients. Furthermore, they often appear as comorbid conditions, resulting in additive effect on adverse health outcomes. On the basis of previous studies, we hypothesise that depression and chronic musculoskeletal pain may benefit from an integrated management programme at primary care level. We expect positive effects on both physical and psychological distress of patients.Objective: To determine whether a new programme for an integrated approach to chronic musculoskeletal pain and depression leads to better outcomes than usual care.Design: Cluster-randomised controlled trial involving two arms: a) control arm ; and b) intervention arm, where patients participate in a programme for an integrated approach to the pain-depression dyad.Settings: Primary care centres in the province of Tarragona, Catalonia, Spain,Participants: We will recruit 330 patients aged 18–80 with moderate or severe musculoskeletal pain  for at least 3 months, and with criteria for major depression (DSM-IV).Intervention: A multicomponent programme according to the chronic care model. The main components are care management, optimised antidepressant treatment, and a psychoeducational group action.Blind measurements: The patients will be monitored through blind telephone interviews held at 0, 3, 6 and 12 months.Outcomes: Severity of pain and depressive symptoms, pain and depression treatment response rates, and depression remission rates.Analysis: The outcomes will be analysed on an intent-to-treat basis and the analysis units will be the individual patients. This analysis will consider the effect of the study design on any potential lack of independence between observations made within the same cluster.Ethics: The protocol was approved by the Research Ethics Committee of the Jordi Gol Primary Care Research Institute (IDIAP), Barcelona, (P14/142).This project strengthens and improves treatment approaches for a major comorbidity in primary care. The design of the intervention takes into account its applicability under typical primary care conditions, so that if the programme is found to be effective it will be feasible to apply it in a generalised manner.NCT02605278; Registered 28 September, 2015.ClinicalTrials.gov:  Pain and depression are common and relevant conditions in primary care patients , 2. At tWhen depression and pain co-occur, both disorders can have an additive adverse effect on health and its management: the pain increases the complexity in the treatment of depression and interferes with recovery, while depression has a similar effect on the therapeutic response for the pain , 10.Treatment of individuals with chronic pain and depression is complex. For example, antidepressants, which are a well-established and effective treatment for depression, have also been used for musculoskeletal pain disorders but the evidence for their usefulness when applied in this way is controversial . Care maIt therefore seems that a strategy for the joint management of chronic pain and depression is a reasonable option that could be expected to produce a synergistic effect on clinical outcomes. Based on this premise, in a study performed in primary care settings Kroenke et al. developed and tested a programme that integrated optimised antidepressant therapy (actively managed by a nurse care manager) and a psychoeducational behavioural intervention for pain self-management. There was evidence for substantial improvement in the depression symptoms as well as moderate improvements in the pain and the functional interference they were causing . HoweverOur hypothesis is that both depression and chronic musculoskeletal pain will benefit from an integrated management programme for pain-depression comorbidity, established at the primary care level in our health system. Positive effects can be expected, with regard to the physical as well as psychological adjustement of patients.The general objective is to study whether a programme to manage chronic musculoskeletal pain and depression in primary care results in better outcomes when compared to those achieved through the usual approach. The specific objectives are to determine, over the course of a 12-month monitoring period, the effectiveness of this programme on depression severity, pain severity, and therapeutic response rates for pain and depression.A controlled trial will be conducted involving a random assignment of clusters (patients registered with the same primary care physician) to two study groups: a) control group undergoing usual care; and b) treatment group, where participants will undergo a program for the integrated management of chronic pain and depression Fig. .Fig. 1FlThe study will be conducted at the Institut Català de la Salut  primary care centres in the province of Tarragona, Catalonia, Spain.Patients will be selected from the rosters of the participating physicians using the following inclusion criteria: aged 18 to 80 years old, experience moderate or severe musculoskeletal pain  scale ≥ 5 points) for at least three months despite analgesic treatment, and have diagnostic criteria for major depressive episode (DSM-IV).The following patients will be excluded: those suffering from any physical, psychological, or language-related limitation, or any concurrent illness that impedes their comprehension or participation in the evaluations; patients with a psychotic disorder, bipolar disorder, or alcohol or drug dependencies; and patients who are pregnant or lactating. Also considered as ineligible will be patients with an established diagnosis of fibromyalgia or somatization disorder; those with a workplace disability claim currently in progress; and those expecting an intervention for a joint prosthesis during the next 12 months. If a patient is being treated with antidepressants, this will not be a criterion for exclusion as long as the patient shows major depression criteria at the time of entering into the study.To avoid potential contamination between the intervention and usual care, which could take place if the same physician were attending patients from the intervention group and the control group, the patients will be assigned to the study groups by clusters, with each cluster comprising patients belonging to the same physician’s roster.www.random.org. The physicians will commit to participate in the study prior to this assignment, and the patients will accept their recruitment without knowing which study group they will be assigned to.The clusters from each primary care centre will be assigned to either the intervention group or control group by someone not otherwise involved in the study , following a simple randomised procedure using the List Randomiser tool at The intervention consists of a programme that integrates and organises several components, designed according to the basic premises of the chronic care model  includinDepression will be managed based on the algorithms and recommendations of the comprehensive clinical guide in the computerised primary care clinical records. This is a computerised system used to support clinical decisions that has been developed based on the most recent clinical practice guidelines for major depression , 21. It The care manager is a psychologist who, based on the algorithms and recommendations from the computerised guideline, will support and collaborate with the treating physician in managing the patient, while also providing support for suitable compliance with the treatment by the patient and preventing discontinuities in the care. The care manager will also participate in the monitoring of the patients. Periodic follow-up will be carried out by telephone. Typically, these phone contacts will occur monthly during the first two months of the study, then every other month after that. The content of the telephone contact is structured and includes: monitoring of symptoms with the PHQ-9  scale, the MINI scale for suicide risk , and the GAF scale  to evaluate the impact of the depression on the patient’s functioning; as well as evaluating the patient’s compliance with treatment and identifying any difficulties in this area. These contacts will also provide the patients with therapeutic advice and reminders about upcoming visits.On the basis of the information available through the computerised system, the care manager will provide the treating physician with information that will allow him or her to take the best decisions about health care. The care manager will also collaborate with the attending physician to ensure that these decisions  are taking place effectively. Supervision and approval of this activity will be performed on a weekly basis by an expert member of the research team.This is a group-based psychoeducational programme with a cognitive-behavioural orientation. It promotes understanding and self-management of depression and pain as well as the related difficulties, in order to facilitate the acquisition of adaptive strategies for managing these conditions on a day-to-day basis and provide incentives for the patient to play an active role in their illness management , 24.The programme is structured into 9 weekly sessions of 2 h, led by the care manager. These sessions include a presentation of the content and dialogue, as well as interaction between the participants. In order to promote the active and independent role of the patient, “homework” is assigned after each session, which will be reviewed at the beginning of the following session. The content of the psychoeducational sessions covers the following areas: understanding of pain; managing emotions; basic relaxation techniques; cognitive restructuring strategies; problem solving; establishment of life goals; relationships between pain and physical activity, healthy postures, and sleep; maintenance of the strategies learned; and preparation of plans to be applied in the event of temporary setbacks.In order to facilitate the sessions, a teaching manual is made available along with other supporting materials .The physicians will treat the patients assigned to the usual care group based on their own, unrestricted criteria, using any resources available that they may consider appropriate.th Edition) will be: M15 (polyarthrosis), M16 (coxarthrosis), M17 (gonarthrosis), M19 (other arthrosis), M47 (spondylosis), M50-M51 (disc disorders), M54.2 , M54.3 to M54.5 (lumbago), M54.6 to M54.9 , M25.5 (joint pain), M79.6 (limb pain), R52.1-R52.2 (chronic pain).Using the list of active diagnoses in the computerised clinical records, a search will be performed for cases among the rosters of the participating physicians. The search codes and diagnoses  for at least 3 months, as well a positive screening for major depression (PHQ-9).Patients positively screened for chronic pain and depression will be selected for an in-person interview with an independent interviewer to confirm whether they meet the inclusion/exclusion criteria and to obtain their informed consent in writing.The following procedure will be used to select and recruit the patients:Standardised self-report scales will be given in person (during baseline interview) and on the telephone . Questionnaires will be administered by an independent qualified interviewer. The interviewer will be blind to participant’s group.In accordance with the aims of this study, the major outcome variables are the measurements of depression and pain severity as continuous variables, pain response rate, and depression response and remission rates.severity of depressive symptoms will be measured by means of the HSCL-20  [The 0 items) . The iteClinical remission of depression is defined as complete relief of symptoms and return to full functioning [ctioning  An averactioning .Depression response to treatment is a defined as a 50 % reduction in the severity of the symptoms with respect to the baseline HSCL-20 score [20 score .pain intensity and pain interference will be measured using the 15-item version of the Brief Pain Inventory [The nventory , 29. Thetherapeutic response of pain is considered relevant when a 30 % reduction is observed with respect to the baseline score [A ne score .Health-related quality of life will be measured with the EuroQol-5-D questionnaire [ionnaire , 31. TheSociodemographic information: sex, age, marital status, education, labour status, and social class based on occupation .The severity of physical comorbidity will be measured using the Duke Severity of Illness Checklist (DUSOI) , 34. ForTo assess the most common psychiatric comorbidity in depressed patients we will use the dysthymia and anxiety sections of the Primary Care Evaluation of Mental Disorders (PRIME-MD). This interview can generate a range of diagnoses of mental disorders according to DSM-IV criteria , 36.We will establish how long the current depressive episode has been evolving and any previous history of depression.At baseline:The degree of disability caused by the psychological disorder will be evaluated using the Sheehan Disability Inventory (SDI) , 38. ThiThe patient’s perspective on the efficacy of treatment will be assessed using the self-report Patient Global Impression of Change (PGIC) . This isPatient satisfaction with the care will be evaluated using a single item: “How would you rate the quality of the care you have received  for your pain and/or depression problems?” with five response options in a Likert scale, from “excellent” to “bad” .Pharmacological treatments for pain and depression and use of health resources will be determined by means of interviewing the patient and exploring his/her computerised clinical records .At the baseline and the follow-up interviews, we will also measure:We will consider the response rates to treatment for depression and pain as reference variables. We will assume that the proportion of patients achieving a therapeutic response will be 50 % for both outcomes in the control group , and we The randomisation will take place at the level of the primary care physicians (clusters), while the results of the intervention will be analysed at the individual-patient level . The priWe will compare the intervention group with the control group in order to verify that they are comparable in their baseline characteristics.The main outcomes (dependent) variables are depressive symptoms (HSCL-20 score), response rate to the depression treatment, remission rate for depression, severity and interference of the pain (BPI), therapeutic response rate for the pain, and health-related quality of life at 3, 6, and 12 months.p < 0.05. We will use STATA-12 and SPSS v.15 software for these calculations. This analysis strategy takes into account the design effect (randomisation by clusters) for any potential lack of independence among observations within the same primary care centre.In order to evaluate the effects of the intervention on the dichotomous variables we will use multilevel logistical regression models with mixed effects, adjusted by cluster, and employing an estimation of the Odds Ratio (95 % CI) of the intervention group with respect to the control group as a measurement of the effect. In order to measure the effect on the continuous variables we will use linear regression models with random effects (cluster), estimating the differences in adjusted averages (95 % CI) for the intervention group versus control group. For the main outcome variables we will calculate the intracluster correlation coefficient (ICC). Statistical significance will be established as current = 130, out of a foreseen total sample of n = 330).Initial recruitment of patients: June 2015; deadline for recruitment of patients: December 2016; deadline for period of patient monitoring: December 2017; publication of the results: January-June 2018. The study is ongoing and currently we are recruiting patients .The Study Protocol was approved by the Research Ethics Committee of the Jordi Gol i Gurina Primary Care Research Institute (IDIAP), Barcelona, on December 17The study design involves the need to obtain informed consent at two levels: a) from the collaborating primary care physicians; and b) from the participating patients.The information provided by the research team to the healthcare professionals will include the voluntary nature of participation and the ability to leave the study without any negative consequences for the health care of their patients. The participating professionals will sign a document stating their commitment to keep patients informed, verifying the absence of conflicts of interest, and specifying that their participation in the study will promote the interests of their patients.The written information provided by the study interviewer to the patients prior to their consent will include a general overview of the study’s objectives and activities; the voluntary nature of his or her participation; the right to leave the study at any time with a guarantee that they will continue to receive the treatment their physician considers most appropriate; and the guarantee that patients included in the control arm will receive the treatment that their physician considers to be the most appropriate, with no restrictions.If the patient withdraws consent to receive periodic study assessment, they will be considered to have dropped out and will not be contacted for periodic assessment in the future.All data will be securely held with restricted access and clinical information will not be used beyond the objectives of the study.A study performed in the United States has demonstrated that a programme for the integrated care of depression and chronic pain can produce improved health-related results . HoweverThis project raises some methodology issues that should be commented upon. Firstly, randomised assignment by clusters has been chosen  because Secondly, the procedure used to identify and recruit patients eligible for the study is based on a screening. This prevents any possible selection bias that could exist if the participating physicians themselves recruited the patients . The drawback is that this way of identifying patients does not correspond with the manner to diagnose chronic pain and depression established in usual practice, and this could have a certain effect on the representativeness of the sample. Furthermore, the fact that individuals are recruited at a point in time when they are not actively seeking medical care could cause the sample to include patients who are not strongly motivated when it comes to the intervention, particularly towards the psychoeducational programme which requires a certain level of commitment and personal effort by the patient.Thirdly, the intervention incorporates several components. It will not be possible to determine which one is responsible of any observed change/improvement, or even whether the results are due to the non-specific effects.The designed intervention relies upon a structured package of multiple strategies: structured and optimised management of depression following clinical guides, the care management, and a psychoeducational intervention used to provide patients with the resources and skills to self-manage their pain and depressive symptomatology. One of the most innovative aspects is that of defining and promoting the role of the care manager in the systematic, structured management of the chronic health problems experienced by our patients. The innovations incorporated into this intervention take into account its feasibility under the typical primary care conditions found in Spain, so that if the results of the evaluation are favourable, generalised implementation of the programme will be feasible.th, 2014 (ref:P14/142). The study design involves written informed consent from the collaborating primary care physicians and from the participating patients.Study Protocol approved by the Research Ethics Committee of the Jordi Gol i Gurina Primary Care Research Institute (IDIAP), Barcelona, on December 17http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (


Multiple epidemiological studies show that headache is less prevalent in elderly people. Despite this, there is evidence that headache has a significant impact in elderly quality of life. There are few studies evaluating characteristics of elderly patients with headache. Aim of the present observational study was to evaluate the characteristics of elderly patients reporting headache in an outpatient geriatric service in Italy.Data were collected from October 2014 to March 2015 in patients over 70 years of age. We used the Pain Detect Scale, a previous validated instrument, to investigate presence of any type of non cancer pain. The scale detected presence of pain, including headache, and assessed intensity of pain during the last month, using a numeric rating scale. We also collected data about comorbidity, number of drugs taken and cognitive status (using MMSE score).Mean age of 94 participants was 81 years, 65 (69.1%) were women and 29 (30.8%) were men. Eight (8.5%) patients reported headache with significant pain intensity (VAS > 5). Patients with headache had high comorbidity (mean of 6 different diagnoses) and took multiple drugs (mean of 6 different drugs). Two of the 8 patients had a significant cognitive decline (MMSE < 23) .


HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune mediated myelopathy caused by the human T-lymphotropic virus type 1 (HTLV-1). The efficacy of treatments used for patients with HAM/TSP is uncertain. The aim of this study is to document the efficacy of pulsed methylprednisolone in patients with HAM/TSP. Data from an open cohort of 26 patients with HAM/TSP was retrospectively analysed. 1g IV methylprednisolone was infused on three consecutive days. The outcomes were pain, gait, urinary frequency and nocturia, a range of inflammatory markers and HTLV-1 proviral load. Treatment was well tolerated in all but one patient. Significant improvements in pain were: observed immediately, unrelated to duration of disease and maintained for three months. Improvement in gait was only seen on Day 3 of treatment. Baseline cytokine concentrations did not correlate to baseline pain or gait impairment but a decrease in tumour necrosis factor-alpha (TNF-α) concentration after pulsed methylprednisolone was associated with improvements in both. Until compared with placebo, treatment with pulsed methylprednisolone should be offered to patients with HAM/TSP for the treatment of pain present despite regular analgesia. The preA minority of HTLV-1 infected persons develop symptoms and estimates of risk of HAM/TSP among HTLV-1 carriers vary from estimated life time risks of 0.25% in Japan and 1.9%HAM/TSP is characterised by perivascular lymphocytic infiltrates in the brain and spinal cord, initially CD4+ lymphocytes, followeThe most common clinical findings in HAM/TSP are lower limb weakness and hyperreflexia. Lower let al reported sustained benefit following high dose methyl prednisolone in one patient (out of 23), with recent onset symptoms[Nearly 35 years after the discovery of HTLV-1 there is still no standardized treatment for HAM/TSP. The evidence underlying current therapy principally originates from case reports or small cohorts and only two randomised controlled studies have been completed,31. The  symptoms.Pulsed methyl prednisolone has been used in a variety of immune-mediated diseases. A clinical trial in children with lupus nephritis concluded that the benefits of pulsed methylprednisolone were equivalent to high dose oral prednisolone but with fewer adverse effects. In a doBased on the limited reports of steroid use in patients with HAM, the anti-inflammatory effects reported in other conditions and an established safety profile, pulsed methyl prednisolone has been offered to patients with HAM/TSP attending the National Centre for Human Retrovirology. To test the hypothesis that one course of pulsed IV methylprednisolone is beneficial in patients with HAM a retrospective analysis of data from treated patients was conducted. Key symptoms, signs, HTLV-1 proviral load and markers of inflammation were used to measure the effect of pulsed IV methylprednisolone in a well characterised population of patients with HAM/TSP.Patients attending the National Centre for Human Retrovirology (NCHR) at St. Mary’s Hospital, London are invited to participate in HTLV research through the Communicable Disease Research Biobank (Oxford REC C Committee Ref: 09/H0606/106). After giving written informed consent, allowing clinical data analysis, patients donate blood for research purposes, which is stored under The Human Tissue Act licence on the St. Mary’s Campus.Since its foundation in 1991, 111 patients have attended the centre for management of HAM/TSP. Pulsed IV methylprednisolone has been offered as a treatment since 2004 with 28 patients treated up to May 2014. Notes from two patients could not be retrieved. The diagnosis of HAM/TSP in the remaining 26 was in accordance with WHO criteria with chaTo ascertain whether patients had stable, improving or worsening symptoms of HAM/TSP in the period leading up to treatment, data from the appointment immediately preceding D0 (Pre) were also collected. The duration of any effect attributed to treatment was determined from three follow up (FU) appointments: FU1 at week 4 ± 2 weeks, FU2 at week 12 ± 5 weeks and FU3 at week 24 ± 6. As not all patients were included for all parameters studied or at every time point the mean number of weeks between D0 and FU1-3 varied marginally for each parameter.The clinical parameters assessed were pain, gait, urinary frequency and nocturia. Lower back/limb pain was measured using a self-reported visual analogue 11 point scale (VAS) with 0 representing no pain and 10 the most severe pain that the respondent could imagine. Gait was assessed by a standardised 10 meter timed walk (10m TW) measurement whereby the time taken by the patient to walk 10 meters on the level, with the assistance of their usual walking aid, from a standing position, was recorded in seconds. Patients were asked to recall the average number of micturition and/or intermittent self-catheterisation (ISC) episodes per day (frequency) and after retiring to sleep (nocturia) since the previous assessment. A change in the use of walking aid and catheterisation was not included in the analysis of continuous data but was instead incorporated into the analysis of categorical data. A change in walking aid or catheterisation was considered to represent a larger clinical change than any contradictory increase or decrease in 10m TW, frequency or nocturia. The following laboratory parameters were routinely documented and measured by a clinical pathology accredited laboratory according to standard methodology: alanine aminotransferase (ALT), creatine kinase (CK), haemoglobin (Hb), lactate dehydrogenase (LDH), white blood cell count. HTLV-1 proviral loads (pVL) were quantified using a real-time polymerase chain reaction and expressed as a percentage of PBMC infected. The preA cytokine profile was conducted in a subset of nine patients with suitable, undiluted, peripheral blood plasma samples available from D0, D2 and a single follow-up appointment, a mean of 10 ± 4.3 weeks from D0. IFN- γ, IL-10, IL-12 p70, IL-13, IL-1B, IL-2, IL-4, IL-6, IL-8 and TNF-α were measured using the Meso Scale Discovery Multi Spot Assay System proinflammatory panel 1 assay, according to the instructions provided by the manufacturer . All assays were duplicated and the mean was taken for the cytokine concentration at each time point.Continuous parameters were analysed using paired T tests to assess whether the difference between Pre, D2, and FU1-3 compared to D0 was statistically significant (p<0.05). The data from Pre, D2, and FU1-3 were categorised into small (0.1–30%) or large (>30%) improvements and deteriorations in comparison to D0. Chi squared goodness of fit tests were used to assess categorical change after treatment at D2, and FU1-3 with the pre-treatment change from Pre to D0. Linear correlation between two parameters was assessed using Pearson product-moment correlation coefficient of the sample, ‘r’. Correlation was considered strong if r>0.5, weak if 0.20<r<0.49, and minimal if r<0.19. A table of critical values for Pearson’s correlation using p<0.05 was used to determine whether the correlation was statistically significant.Of the 25 patients treated with 1g IV Methylprednisolone on three consecutive days, 24 completed the treatment without any side effects. One patient became hypomanic and discontinued treatment after the first dose. The patient originally prescribed the single 500mg dose tolerated the treatment well.Eighteen patients  had documented pain at baseline and were thus included in the pain analysis. Eight patients were excluded including seven that were pain-free at D0 and one patient whose relevant volume of medical records could not be retrieved. Pain scores improved at D2 in 17/18 patients with a mean maximum improvement of 3.8 points at D2 (p<0.0001) . The paiAll the patients with pain were on analgesia at time of infusions and during follow up. To determine whether the observed improvement in pain might be attributable to changes in analgesia rather than associated with the methylprednisolone infusions analgesia at each visit was reviewed. During follow up, ten patients increased their use of analgesia and in five cases this was followed by an improvement in pain score. However, with the one exception, analgesia was modified at or after FU2 (12 weeks) i.e. after the effect of methyl prednisolone had been documented.Twenty-two ambulant patients were included in the 10m TW analyses. The improvement in 10 TW was maximal at D2 with a mean 8.0 seconds per 10m improvement (s/10m) (p = 0.024)  but thisNo significant changes in urinary frequency or nocturia were observed, these remaining constant at four and two episodes respectively. Four patients, of whom two had SPCs, had documented UTIs during three day infusions and two additional patients, not using catheters, reported UTIs at FU1. All of which were adequately treated without further complications and there was no report of UTIs beyond FU1.Fluctuations in creatine kinase, alanine transaminase, lactate dehydrogenase and haemoglobin were observed but with no consistent pattern and these were not statistically significant (data not shown). Temporary neutrophilia and lymphocytopaenia at D2 were statistically significant (p<0.0001) with a greater decrease in CD4+ T-cells than CD8+ T-cells as shown in The median concentration of each of the eight pro-inflammatory cytokines  decreased from D0 to D2 and the anti-inflammatory cytokine IL-10 increased. Only the reductions in IFN-γ (p = 0.003), IL-6 (p = 0.044) and TNF-α (p = 0.004) were statistically significant at D2 . The decPain at baseline correlated moderately with IL-6 (r = 0.36), weakly with TNF-α (r = 0.13), and not with IFN-Ɣ (r = -0.09) concentrations at D0 (data not shown). The 10m TW at D0 correlated moderately to IFN-Ɣ at D0 (r = -0.30), weakly with TNF-α (r = 0.24), and minimally with IL-6 (r = 0.16) concentrations at D0 (data not shown). As shown in Pain is a common symptom of HAM/TSP, reported in up to 88% of patients. The effIt is unlikely that a change in other medication was responsible for the statistically significant reduction in pain observed prior to 12 weeks. Of the 10 patients who reported increased use of analgesia during follow up, only five reported an improvement in pain and in four of these patients the medication was altered at or after FU2, 12 weeks after treatment, by which time the majority of the pain effect observed with methylprednisolone had waned. The immediate effect of pulsed IV methylprednisolone was not influenced by a change in analgesia however the prolonged improvement in pain seen in a subset may in part be attributed to the addition of other analgesia.et al. speculated that patients with a shorter history would benefit more from treatment[The effect of pulsed IV methylprednisolone on gait was less striking. The improvement in walking time for 10m was only statistically significant on the last day of treatment and not thereafter. However, the magnitude of the effect on gait was predicted by both the duration of disease and the baseline 10m TW. Patients with shorter duration of disease and more severe gait impairment had the greatest improvement in gait. Araujo treatment. In the Changes in plasma cytokines in relation to pulsed IV methylprednisolone have been reported in other diseases such as Stevens Johnson Syndrome but theyBaseline cytokine values did not predict more severe gait deficit but reductions in TNF-α, and IL-6 were linked to an improvement in gait. One interpretation of these observations is that the neurological deficit that is associated with impaired gait is either more fixed or less steroid responsive than the inflammation that is associated with pain. These observations, suggest that more targeted therapies might be selected for the treatment of HAM/TSP. Whilst anti-TNF therapies would be a natural choice based on these findings limited experience with infliximab monotherapy was tempered by a high rate of adverse events and cessation of the study for futility. TargeteSteroid sparing agents can also be considered—in an open pilot study ciclosporin was associated with sustained improvement in pain and mobility.Since glucocorticoids are immunosuppressant and HTLV-1 pVL is associated with the risk of both HTLV-1-associated inflammatory disease and ATLL, HTLV-1 pVL was monitored during, and for six months after, the high dose IV methylprednisolone therapy. A transient decrease in pVL was observed during the three days of the infusions, which was initially attributed to glucocorticoid induced redistribution of the intravascular lymphocyte pool to the bone marrow–46. HoweUTIs are common in patients with HAM/TSP especially those who practice intermittent self-catheterisation. AlthougThe literature underlying the use of IV methylprednisolone in HAM/TSP is limited and to our knowledge has only been described in case reports–50 and tet al[et al. treated their patients every 3–4 months, for an average of 3.4 cycles, with most improvement observed following the first two cycles and decreasing benefit thereafter [et al did not measure pain outcomes.These data support the use of pulsed IV methylprednisolone in patients whose motor abilities deteriorate rapidly as reported by Nakagawa et al who usedereafter . ImportaThis retrospective study has a number of weaknesses including potential for placebo effect, potential for selection bias and reliance on data collection at routine clinic visits. However, methyl prednisolone is widely accessible and the data indicate an effect which should now be tested in a randomised control trial to accurately assess its use in patients with HAM/TSP.A three-day course of 1g IV methylprednisolone was associated with a significant improvement in pain in patients with HAM/TSP lasting at least three months with benefit independent of duration of HAM/TSP. The effect of methyl prednisolone on gait was limited with no benefit apparent four weeks after therapy. The clinical benefits coincided with reductions in plasma concentration of pro-inflammatory cytokines TNF-α and IL-6 Pulsed steroid therapy was not associated with any long term effect on HTLV-1 proviral load.


Objectives. In some rheumatoid arthritis (RA) patients, joint pain persists without signs of inflammation. This indicates that central pain sensitisation may play a role in the generation of chronic pain in a subgroup of RA. Our aim was to assess the degree of peripheral and central pain sensitisation in women with active RA compared to healthy controls (HC). Methods. 38 women with active RA (DAS28 > 2.6) and 38 female HC were included in, and completed, the study. Exclusion criteria were polyneuropathy, pregnancy, and no Danish language. Cuff Pressure Algometry measurements were carried out on the dominant lower leg. Pain threshold, pain tolerance, and pain sensitivity during tonic painful stimulation were recorded. Results. Women with active RA had significantly lower pain threshold (p < 0.01) and pain tolerance (p < 0.01) than HC. The mean temporal summation- (TS-) index in RA patients was 0.98 (SEM: 0.09) and 0.71 (SEM: 0.04) in HC (p < 0.01). Conclusion. Patients with active RA showed decreased pressure-pain threshold compared to HC. In addition, temporal summation of pressure-pain was increased, indicating central pain sensitization, at least in some patients. Defining this subgroup of patients may be of importance when considering treatment strategies. Rheumatoid arthritis (RA) is a chronic inflammatory disease causing synovial joint destruction, disability, and pain . DespiteCentral pain sensitisation is defined as “an increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input” . ClinicaPain in RA is usually assessed either by self-reported questionnaires or by simple palpation of the joints. Computerized Cuff Pressure Algometry (CPA) is a more precise method for quantitative pain testing which primarily assesses sensitivity of muscle and deep tissue. CPA is less influenced by inter- and intraexaminer bias than handheld pressure algometry . CPA is Based on the hypothesis that some RA patients with a high DAS28 suffer from central pain sensitisation, our aim was to use CPA to study pain properties in patients with active RA. The main outcomes of interest were pain threshold and pain tolerance, indicating the degree of peripheral pain sensitivity and degree of temporal summation  assessed by tonic painful cuff pressure stimulation .This clinical study was cross-sectional and noninterventional carried out according to the Helsinki Declaration and accepted by the Capital Region of Denmark's Ethical Committee (KF01-058/02). All assessments were performed the same day and in the same order by the same persons. All participants gave informed written consent to participate.age ≥ 18;RA diagnosed by a rheumatologist according to the ACR criteria ;active RA according to the EULAR definition, DAS28 ≥ 2.6 .Exclusion criteria were polyneuropathy, pregnancy, and patients not able to understand Danish or to follow instructions. Patients were recruited from the Rheumatology Department, Bispebjerg and Frederiksberg Hospital, Denmark, from June 2011 to September 2012, and were screened according to the following inclusion criteria:The following parameters were measured: A 28-joint count , plasma The device consisted of a 61 cm tourniquet cuff (placed on the widest part of the lower leg on subject's dominant side), a computer-controlled air compressor, and an electronic 10 cm visual analogue scale (VAS)  . The subSend(see ). The TSskew and kurtosis/SEkurt.For data analyses, SAS software  was applied. In order to evaluate the empirical distributions of the continuous outcomes, we tested for normal distribution looking at skewness/SEThe PROC MEANS statement was used for summarizing the data. T-TEST procedure was used to compare the two groups, analysed as two independent samples. The CORR procedure, based on Spearman's rank-order correlation, was used as a nonparametric measure of association between various variables.The median age of patients was 56 years (IQR 46–69) and 39 (IQR 32–44) of the controls. Characteristics of RA patients are shown in Data from Cuff algometry measurements are shown in All RA patients had active disease at the time of assessment, with median DAS-28CRP of 4.3 (IQR 3.6–5.0). The median number of swollen joints was 5 (IQR 3–11) and the number of tender joints was 7 (IQR 4–13). The disease duration varied from 4 to 444 months with a median of 33 months.p < 0.01) compared with the healthy controls  in the RA group had a TS-index above 1.09, with a maximum of 2.46.p < 0.01)  than in HC  ( < 0.01) .rs = −0.003; p = 0.99; RA: rs = −0.122; p = 0.46), disease duration , number of tender points , tender joint count , and swollen joints count , or DAS28 .There was no correlation between TS-index and age (HC: Earlier studies have reported concomitant fibromyalgia in a subpopulation of RA patients , 17, 18,In addition, post hoc analyses indicated that the degree of temporal summation was more pronounced in some of the RA patients, where 29% had a TS-index above the upper limit of that of HC. This suggests that degree of central sensitisation is more pronounced in a subgroup of RA patients .Computerized Cuff Pressure Algometry has previously been applied in other chronic rheumatic pain conditions , 13, 21.In RA, pain is the major determinant of patient global assessment of disease activity . In subjDue to limited sample size, subgroup analyses were not possible. Our results, however, point towards a necessity of a large scale study assessing the relationship between treatment response and underlying pain mechanisms. Since this study was on women only, we cannot generalize our results to the pain condition in men with RA.In patients with active RA, signs of central pain sensitisation were found as indicated by a higher TS-index compared to the group of healthy controls. This indicates that assessment of pain and the underlying mechanisms may be of importance when considering treatment strategies in the individual subjects with RA.


Pain following hip arthroscopy is highly variable and can be severe. Little published data exists demonstrating reliable predictors of significant pain after hip arthroscopy. The aim of this study was to identify influence of intraoperative factors  on the severity of postoperative pain.A retrospective review of 131 patients who had received a variety of arthroscopic hip interventions was performed. A standardized anaesthetic technique was used on all patients and postoperative pain was analysed using recovery pain severity outcomes and analgesic use. A multivariate logistic regression analysis was performed on intraoperative factors including patient age, sex and BMI, arthroscopic infusion pressures (40 vs 80 mm Hg), amount of fluid used, length of surgery and types of arthroscopic interventions performed. Thirty six patients were also prospectively examined to determine arthroscopic fluid infusion rates for 40 and 80 mm Hg infusion pressures.Use of a higher infusion pressure of 80 mm Hg was strongly associated with all pain severity endpoints (OR 2.8 – 8.2). Other significant factors included hip arthroscopy that involved femoral chondro-ostectomy (OR 5.8) and labral repair (OR 7.5). Length of surgery and total amount of infusion fluid used were not associated with increased pain.80 mm Hg arthroscopic infusion pressures, femoral chondro-osteoectomy and labral repair are strongly associated with significant postoperative pain, whereas intraoperative infusion volumes or surgical duration are not. Identification of these predictors in individual patients may guide clinical practice regarding the choice of more invasive regional analgesia options. The use of 40 mm Hg arthroscopic infusion pressures will assist in reducing postoperative pain. Pain following hip arthroscopy is highly variable and in some cases can be severe, with high patient Numerical Rating Scale (NRS) pain scores up to 8/10 and associated high postoperative opioid requirements –5. AlthoWe performed a retrospective study  of 140 consecutive patients in 2013 who had undergone therapeutic hip arthroscopy by a single surgeon and anaesthetist with combined subspecialty experience in the procedure of more than 8 years. From May 2013, the treating surgeon changed the routine arthroscopic infusion pressures used from 80 mm Hg to 40 mm Hg for all hip arthroscopies. Arthroscopic infusion pressures were kept the same throughout the entirety of each patient’s procedure. Inclusion criteria were all patients undergoing hip arthroscopy who had received the same standardised anaesthetic and postoperative pain regime. Patients who had contraindications to any component of the standard anaesthetic technique such as medication allergy or opioid tolerance were excluded from the study.All patients were ASA (American Society of Anesthesiologists Preoperative Assessment Score) 1 or 2 and were elective admissions planned for overnight stay. Each patient received spontaneous ventilation volatile agent general anaesthesia with a laryngeal mask airway and sevoflurane. All patients also received 1 g IV paracetamol, 1.5 mg/kg IV tramadol and 40 mg IV parecoxib analgesia intraoperatively, as well as pre-emptive antiemesis of 8 mg IV dexamethasone and 1 mg IV granisetron. Alfentanil was titrated intraoperatively in 250mcg boluses to a respiratory rate of 10–12 at the end of the procedure. Patients in recovery received further IV morphine boluses of 1–2 mg 5 minutely titrated primarily to (1) patient’s satisfaction with their level of analgesia such that patients declined further opioid administration; (2) lack of signs of impending opioid narcosis  and (3) patient’s reported NRS score of 6 or below. All opioid doses were converted to IV morphine equivalents as per MacIntyre .All patients underwent hip arthroscopy in the lateral position under general anaesthesia. Under fluoroscopic guidance, traction was applied  and the instruments were placed through mid-trochanteric and anterior paratrochanteric portals using the Arthrex Continuous Wave 3 Arthroscopy Pump . At the end of the surgical procedure, the joint was lavaged and injected with ropivacaine 200 mg and morphine 5 mg.Pain outcomes assessed were the highest and lowest NRS scores in recovery, and the total intraoperative and recovery room opioid requirements. These endpoints were used as markers of significant postoperative pain as (a) the complex relationship between pain scores and opioid use requires both endpoints to be measured and (b) the highest pain score in recovery is a marker of initial pain following a standardised intraoperative analgesic regimen, whereas the lowest pain score reflects the degree of residual pain after maximum safe doses of opioid analgesia have been administered to the patient. Patient demographics and specific surgical interventions were also recorded Table . Nine paAs total arthroscopic fluid volumes infused are not charted routinely, we also prospectively observed the fluid volumes used per unit time in a series of 36 patients, half of which had received infusion pressures of 80 mm Hg and the other half who had received 40 mm Hg throughout the entirety of their procedures. Once mean point estimates of ml/ min in each prospective group had been calculated, these were used to derive fluid volumes given/ min in our study sample.P values of <0.05 were considered statistically significant. The total number of variables included in the regression model did not exceed the conservative ratio of 1 variable per 10 samples [Statistical analysis was performed using SPSS version 21 . Association between continuous variables was analysed by linear regression and correlation. Prediction bands were calculated around the regression lines to estimate dependent variable outcomes for a given value of any independent variable. Patient characteristics of age, sex and BMI as well as likely operative predictors for severe postoperative pain were analysed by a multivariate logistic regression model against outcomes of highest recovery room NRS >4, lowest recovery room NRS <2 and intraoperative/ recovery room IV morphine requirements of over 0.15 mg/ kg. NRS outcome cutoffs were selected based on accepted definitions of “moderate-to-severe” and “mild” postoperative pain , and theThe demographics and perioperative information of the 131 patients included in the study are presented in Table 2 0.91–0.97 at p < 0.0001 for 40 and 80 mm Hg infusion pressures respectively, Fig. Duration of arthroscopic infusion was strongly correlated with total infusion volumes . However, there was only minor correlation between total volumes infused and the pain severity outcomes of NRS scores and IV morphine requirements  into the hip joint and surrounding tissues compared with 210 ml/min for those whose infusion pressure was 40 mm Hg  and achieved statistical significance across all pain severity outcome measures, whereas operative intervention types influenced perioperative IV morphine use alone. An 80 mm Hg infusion pressure is frequently used amongst hip arthroscopy specialists as the commonly held belief is that a high pressure allows superior surgical access, however there is no evidence that the use of this infusion pressure confers any advantage. Indeed, the surgical author found that less periarticular soft tissue swelling developed during long cases where 40 mm Hg was used, resulting in less restriction of arthroscopic instrument mobility within the joint.Although volumes infused vs. highest and lowest recovery pain scores achieved statistical significance with regards to correlation, the strength of correlation was weak (highest pearson’s R = 0.36) and the prediction bands around the regression lines too broad to be considered useful in clinical practice (NRS range of +/- 4 for a given amount of fluid infused). Correlation between arthroscopic infusion volumes and perioperative morphine requirements did not reach statistical significance; this result may be explained by the confounding effects of the routinely co-administered analgesics  as well as the common observation that in situations of intense postoperative pain and escalating opioid dosing, early signs of sedation and respiratory depression contraindicate further opioid administration even though patient reported NRS scores may remain elevated. Surgical duration and hence total volumes infused also did not achieve statistical significance in the multivariate logistic regression model for independent predictors of analgesia outcomes. It is possible that the ratio of amount of fluid absorbed into soft tissue as opposed to that lost out of surgical access portals is affected by arthroscopic infusion pressure.Although the findings of Baker et al  suggestep < 0.0001) and with a precise point estimate (95 % CI +/- 10 ml/ min). Intra-articular fluid pressures can potentially vary significantly despite arthroscopic pump settings and continuous measurements performed by arthroscopic pumps are made by an internal systems pressure gauge, and hence may not reflect true intra-articular pressure. Future studies using continuous direct measurement of intra-articular fluid pressures during surgery would be warranted.Our study was limited by its retrospective design and moderate sample size. The use of multivariate logistic regression modelling however is robust in the face of non-normally distributed data and lack of randomisation; nor are direct cohort comparisons required. Although our study design was based on a single centre sample, it has ensured that a standardised approach to anaesthesia and surgical technique had been applied. The use of derived values for total arthroscopic fluid volumes infused may introduce some degree of error, but it is clear from our results that infusion volumes at 80 versus 40 mm Hg are significantly different (Qualitatively we observed that the use of lower fluid infusion pressures did not compromise surgical view quality and access. Indeed, the use of 80 mm Hg infusion pressure led to decreased mobility of arthroscopic instruments due to a greater degree of soft tissue swelling around port access sites.A higher arthroscopic fluid infusion pressure of 80 mm Hg is strongly associated with significant postoperative pain, whereas total infusion fluid volumes and surgical duration are not. Arthroscopic interventions involving extensive bony resection and soft tissue repair – femoral chondro-ostectomy and labral repair – also have a significant influence on postoperative pain. Identification of these predictors in individual patients may guide clinical practice regarding the choice of more invasive regional analgesia options. If a lower arthroscopic infusion pressure of 40 mm Hg does not impair the surgeons view and access, we recommend its use to reduce the risk of patients developing severe postoperative pain.Written informed consent was waived by the Austin Health Human Research & Ethics Department for the purposes of this study.


The aim of this study was to investigate augmented pain processing in the cortical somatosensory system in patients with fibromyalgia (FM). Cortical evoked responses were recorded in FM (n = 19) and healthy subjects (n = 21) using magnetoencephalography after noxious intra-epidermal electrical stimulation (IES) of the hand dorsum . In addition, healthy subjects were stimulated using the amplitude corresponding to the average stimulus intensity rated 6 in patients with FM . Quantitative sensory testing was performed on the hand dorsum or thenar muscle  and over the trapezius muscle (tender point), using IES  and mechanical stimuli . Increased amplitude of cortical responses was found in patients with FM as compared to healthy subjects. These included the contralateral primary (S1) and bilateral secondary somatosensory cortices (S2) in response to intensity-equivalent stimuli and the contralateral S1 and S2 in response to perceptually-equivalent stimuli. The amplitude of the contralateral S2 response in patients with FM was positively correlated with average pain intensity over the last week. Quantitative sensory testing results showed that patients with FM were more sensitive to painful IES as well as to mechanical stimulation, regardless of whether the stimulation site was the hand or the trapezius muscle. Interestingly, the slope of the stimulus-response relationship as well as temporal summation of pain in response to IES was not different between groups. Together, these results suggest that the observed pain augmentation in response to IES in patients with FM could be due to sensitization or disinhibition of the cortical somatosensory system. Since the S2 has been shown to play a role in higher-order functions, further studies are needed to clarify the role of augmented S2 response in clinical characteristics of FM. Fibromyalgia (FM) is commonly associated with chronic wide-spread pain, but is notorious for its multi-modal symptoms such as anxiety and depression, sleep disturbances, fatigue and cognitive symptoms . TypicalPrevious studies of FM have shown that pain sensitivity –7, tempoWhat remains largely unclear from studies assessing sensory symptoms and signs in patients with FM is how different outcome measures relate to each other. This is particularly important since patients with FM are notorious for their heterogeneity, and symptoms tend to evolve over time. Also, the pathophysiology of FM, and in particular the relative contributions of different pain mechanisms (e.g. increased facilitation and/or decreased inhibition) at different neural levels , remains a matter of debate , 32–34. With respect to the stimulation method, a recent magnetoencephalography (MEG) study used painful and non-painful mechanical pressure stimuli that were subjectively matched between patients with FM and HC subjects . Since pThe present study aimed to investigate the central augmentation of pain processing in patients FM using MEG and IES which can selectively stimulate cutaneous Aδ nociceptors . QuantitSubjects were right-handed (as confirmed by the Edinburgh Handedness Inventory) , femalesPatients were recruited from the outpatient clinics of the rheumatology departments of the Seoul National University Hospital and Hallym University Sacred Heart Hospital. Patients were eligible for participation if they were clinically diagnosed as having primary FM  and Hallym University Sacred Heart Hospital (2011-I048) and the study was conducted in compliance with the Declaration of Helsinki. All subjects received verbal information about the study protocol and signed the informed consent form prior to participation.For all subjects, age (years), marital status , education (years), employment status , and medication use were registered. For patients with FM, the disease duration (since onset of wide-spread pain) and number of tender points  were registered. The tender point count was (re-)assessed by a trained rheumatologist from Seoul National University Hospital (H.W.K) in both patients and HC subjects using a hand-held pressure algometer . In addition, subjects filled out the Fibromyalgia Impact Questionnaire  , Beck’s The intensity of average pain over the last week was assessed using a VAS. The qualitative aspects of clinical pain perception were assessed using the short-form McGill pain questionnaire (SF-MPQ) .All tests were performed on the right (dominant) upper extremity (hand and trapezius muscle). The test order was fixed. All tests were performed before MEG recordings.The tactile detection threshold (TDT) was determined using 5 Semmes Weinstein monofilaments . The filaments were applied at 2 locations over the hand dorsum and at 2 locations over the trapezius muscle. For each body region, the TDT was defined as the smallest filament that could be perceived at each location. In addition, subjects rated the perceived painfulness of a standardized pinprick stimulus .2 and a slope of 0.5 kg per second were used. Subjects were instructed to keep their arm in zero degrees of shoulder abduction and 90 degrees of elbow flexion. The PPT was then determined at 3 locations over the thenar eminence of the hand and at 3 locations over the trapezius muscle   and [Group] . For the stimulus-response curve, ratings for the series of fixed stimulus amplitudes at 25%, 100%, 175% and 250% of the EPT were compared between groups using a repeated measures ANOVA with factors [Intensity]  and [Group] . For temporal summation of pain, the ratings for the single pulse and pulse train stimulation at 100% of the EPT, were compared between groups using a repeated measures analysis with factors [Number of pulses]  and [Group] . Differential effects of temporal summation of pain were tested as interactions between the number of pulses and group as in a previous study [The peak latencies and amplitudes of the bilateral S2 sources were analysed using repeated measures ANOVA with a within-subjects factor [Source]  and between-subjects factor [Group] . Mauchly's test of sphericity was used to evaluate the assumption of sphericity. Significant between-subjects effects were further tested using independent t-tests. The between-group differences in peak latencies and amplitudes of the cS1 source were compared by independent t-tests with factor [Group] . Talairach coordinates of the cS1, cS2 and iS2 sources were compared separately by means of repeated measures ANOVA with coordinate  as a within-subject factor and group (FM and HC) as a between-subject factor. The relationship between the amplitude of cortical responses and FM pain intensity as reported for the last week (VAS) was assessed using Pearson’s correlation coefficient (r). The influence of potential confounders on bilateral S2 source amplitudes was assessed using a multivariate analysis with a dependent variables , factor [Group]  and covariate [potential confounder] . All factors were entered into the analyses separately. There were no significant effects for any of the covariates. The influence of potential confounders on cS1 source amplitudes was assessed using a multivariate analysis with dependent variable [cS1], factor [Group]  and covariate [potential confounder] . All factors were entered into the analyses separately. Although the covariate BAI was significant, the significant effect of [Group] remained. In summary, it is unlikely that the amplitudes of cortical sources were confounded by group differences in clinical variables relating to anxiety, depression or sleep quality.A total of 19 patients with FM and 21 HC subjects participated in the experiments.A summary of demographics and medical data is presented in A summary of the median and range of thresholds and ratings as obtained with QST is presented in The mean NRS scores corresponding to fixed levels of IES are presented for both groups in The mean stimulus intensity in patients with FM was 2.89 ± 0.89 mA (NRS6). The mean stimulus intensity in HC subjects was 5.60 ± 1.95 mA (NRS6 = HC-PE). Stimulus intensities for NRS 6 were significantly lower in patients with FM as compared to HC subjects . Fixed stimulus intensity of 2.66 mA in HC-IE was comparable to mean stimulus intensity in patients with FM .The spatial distribution of the somatosensory evoked fields in response to noxious IES of the right hand dorsum in representative FM (A) and HC (B) subjects is presented in The amplitude of the cS2 response was positively correlated to the clinical pain intensity over the last week  . In an eThe present study aimed to investigate the central augmentation of pain processing in patients with FM using MEG and IES. Dipole amplitudes in the cS1, cS2 and iS2, were found to be increased in patients with FM as compared to HC subjects, and the amplitude of the cS2 response in patients with FM was positively correlated to the clinical pain intensity reported over the last week. In addition, QST findings showed that patients with FM were more sensitive to painful IES as well as to mechanical stimulation, regardless of whether the stimulation site was the hand or the trapezius muscle. Interestingly, the slope of the stimulus-response relationship as well as temporal summation of pain in response to IES was not different between groups, suggesting that the observed pain augmentation in response to IES in patients with FM could be due to sensitization or disinhibition at the cortical level.Our findings showing no differences in tactile as well as electrical detection threshold between the groups suggest that tactile sensitivity in patients with FM is generally normal. This result is in line with several other studies that showed no differences between FM patients and HC subjects in terms of tactile perception threshold  and elecIn addition to sensory thresholds and ratings, we assessed temporal summation of pain in response to IES, which could be considered as the electrical equivalent of a noxious pinprick stimulus, as used in studies by the German Research Network on Neuropathic Pain . TemporaWhat is interesting about the findings in our study as compared to those in other studies is that we used the same type of stimulus (IES) for the assessment of temporal summation of pain, sensory thresholds and ratings, and cortical responses. The lack of differences between patients with FM and HC subjects with respect to temporal summation of pain in response to IES as observed in this study raises questions about the role of spinal sensitization in explaining the observed pain augmentation in response to IES in our patients with FM.After noxious stimulation of the skin, several cortical sources may be identified including the S1, S2, insular, and anterior cingulate cortex . These cAugmented cortical responses to nociceptive stimuli could be due to facilitation or disinhibition of nociceptive input at multiple levels in the cortical pain matrix. For example, it has been suggested that prolonged nociceptive input could lead to central sensitization and maladaptive neuroplasticity within the somatosensory and motor systems . In our In this study we used tools that have not been previously used (IES) or have been infrequently (MEG) applied in the study of FM. The advantage of MEG is that cortical responses can be measured in the time and space domain in great detail. However, only a subset of brain regions involved in pain processing can be reliably detected using this method. To obtain information about concomitant activation in other brain regions, other imaging methods as well as more complex analysis procedures , 85 may A particular strong point of our study was the assessment of cortical responses to IES in the context of behavioral responses to the same type of stimulus. Still, in order to do so, different levels of stimulation were used. Previous studies often used IES at or just above pain threshold levels (<2.5 mA) , 37, 85,Lastly, although the sample size in the present study was larger than that in previous clinical MEG studies, the sample size was still relatively small considering the heterogeneous presentation of FM. In addition, the unknown effects of medication (or rather the medication stoppage and limited washout period) limit the generalizability of the present results.The present study investigated the central augmentation of pain processing in patients with FM using MEG and IES. Increased responses were found in the cS1, cS2 and iS2 in patients with FM, and the amplitude of the cS2 response was found to be positively correlated with clinical FM pain intensity. These results corresponded with generalized hypersensitivity to both IES and mechanical stimuli as assessed using QST. Temporal summation of pain in response to IES was not different between patients with FM and HC subjects. Together, these results suggest that the observed pain augmentation in response to IES in patients with FM occurred relatively independent of peripheral and spinal sensitization to IES. The observed pain augmentation in response to IES in patients with FM could be due to sensitization or disinhibition of the cortical somatosensory system. The combination of MEG and IES could therefore be particularly useful to explore the role of bilateral somatosensory cortices in FM pathophysiology.S1 Dataset(ZIP)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Neck pain is associated with several alterations in neck motion and motor control. Previous studies have investigated single constructs of neck motor control, while few have applied a comprehensive set of tests to investigate cervical motor control. This comparative cross- sectional study aimed to investigate different motor control constructs in neck pain patients and healthy controls.A total of 166 subjects participated in the study, 91 healthy controls (HC) and 75 neck pain patients (NP) with long-lasting moderate to severe neck pain. Neck flexibility, proprioception, head steadiness, trajectory movement control, and postural sway were assessed using a 3D motion tracking system (Liberty). The different constructs of neck motion and motor control were based on tests used in previous studies.Neck flexibility was lower in NP compared to HC, indicated by reduced cervical ROM and conjunct motion. Movement velocity was slower in NP compared to HC. Tests of head steadiness showed a stiffer movement pattern in NP compared to HC, indicated by lower head angular velocity. NP patients departed less from a predictable trajectory movement pattern (figure of eight) compared to healthy controls, but there was no difference for unpredictable movement patterns (the Fly test). No differences were found for postural sway in standing with eyes open and eyes closed. However, NP patients had significantly larger postural sway when standing on a balance pad. Proprioception did not differ between the groups. Largest effect sizes (ES) were found for neck flexibility (ES range: 0.2- 0.8) and head steadiness (ES range: 1.3- 2.0). Neck flexibility was the only construct that showed a significant association with current neck pain, while peak velocity was the only variable that showed a significant association with kinesiophobia.NP patients showed an overall stiffer and more rigid neck motor control pattern compared to HC, indicated by lower neck flexibility, slower movement velocity, increased head steadiness and more rigid trajectory head motion patterns. Only neck flexibility showed a significant association with clinical features in NP patients.The online version of this article (doi:10.1186/s12891-015-0517-2) contains supplementary material, which is available to authorized users. Neck pain is common in the general population with one-year prevalence varying from 30% to 50% . GloballResearch over the last decade indicates several alterations in neck motor control and sensorimotor entities in subjects with neck pain compared to healthy subjects. Neck pain patients may have delayed onset of deep neck flexors , increasSurprisingly, few studies have utilized a comprehensive set of neck movement and motor control tests to contrast patients and healthy subjects. Such comparisons may help identifying specific underlying neck movement or motor control constructs that differentiate patients from healthy subjects. Based on the previous research we decided to group different neck motion and motor control parameters within different constructs of tentative underlying neck motor dysfunction. The aim of this study was thus to compare neck motion and motor control in neck pain patients with moderate to severe neck pain and healthy subjects with tests representing five different constructs: neck flexibility, proprioception, trajectory movement control, head steadiness, and postural sway. Secondary aim was to evaluate the association between clinical features such as pain, disability, and kinesiophobia and the constructs of motor control and neck motion.We conducted a comparative case–control study (n = 166) in the period August 2012 to February 2014. The data from healthy controls (n = 91) were collected by a nurse and a physiotherapist, while the neck pain patients (n = 75) data were collected by a second physiotherapist. The different examiners were equally and well trained in the test procedures. In addition the physiotherapist who performed the data collection for the NP group observed the data collection in the HC group to avoid discrepancies in the procedures. All subjects gave written and informed consent and the study was conducted in accordance with the Helsinki Declaration and approved by the Regional Committee for Medical and Health Research Ethics, REC Central .Men and women between 18–67 years with no neck pain were included in the HC group. The subjects were recruited by inviting friends and colleagues at the local university and university hospital. Exclusion criteria were episode of neck pain within the last 3 months, markedly reduced or uncorrected vision, history of neck trauma, diagnosed with neurological or orthopedic conditions that could affect motor control, positive Spurling’s test for neurological radiating arm pain, pregnancy, or insufficient comprehension of Norwegian.Neck pain patients were recruited from private physiotherapy clinics in primary health care (56 subjects) and from a specialized neck and back pain clinic at the university hospital (19 subjects). Patients were initially screened for eligibility by telephone. Upon later examination, inclusion criteria were non- traumatic neck pain as the main problem with a score of 3 or more on numerical rating scale  , where 0 represent no pain and 10 worst imaginable pain, at the day of testing and the current neck pain episode lasting >2 weeks. Exclusion criteria were the same as for the control group, except the criteria for neck pain.On the day of testing, both HC and NP patients first completed a questionnaire which consisted of biographical data , duration of current neck pain episode, neck pain intensity at the day of testing and average neck pain last month assessed by NRS. Further descriptive data were obtained by the Neck Disability Index  , Tampa SMotion data for the cervical and postural sway measurements were acquired with body worn sensors using the Liberty electromagnetic motion tracker system  with a sampling rate of 240 Hz. Sensor 1 (S1) was placed on the subject’s forehead 1 cm above arcus superciliaris, the second sensor (S2) was placed on the spinous process of Th2, and a third sensor (S3) was placed in the area of the spinous processes of L4-L5. Tight elastic bands were used to hold the sensors in position. The electromagnetic transmitter (TX) was positioned at a distance of 10–50 cm above the head during all the measurements. For S1 and S2 raw data were low pass filtered at 20 Hz using a 2nd order Butterworth filter, while raw data for S3 were low pass filtered at 5 Hz.A software tool based on Matlab  was developed  to record and analyze the motion data. Table The description of the tests of motor control and the calculated variables are summarized in Table 0 recumbent position and the shoulders fixed with nonflexible shoulder straps to avoid movement of the thorax. The subjects were asked to move as far as possible in all three primary movement planes  with a self- preferred velocity. Start and stop of the recording was manually set by the examiner before and after the movement. Maximal cervical ROM was calculated as the mean of three trials for each primary movement plane. During each primary plane ROM test neck flexibility was also assessed by the degree of motion in accessory planes, i.e., conjunct motion (CM), which was calculated as the maximum ROM in the two associated movement planes, adopted from Woodhouse et al. [Maximal cervical ROM was measured with the subjects seated on a wooden bench with backrest in 80e et al. . Peak vee et al. .Joint position error (JPE) was used to assess proprioception and was recorded as the difference in head orientation at neutral position before and after cervical left and right head rotation   and a “Two patterns of the Fly test Figure  were useIsometric neck flexion (INF) was used to investigate the ability to hold the head steady under two conditions, low load and high load. For the low load test the subjects were seated in a 60 ° recumbent position with footrest and without shoulder straps. They were asked to slightly lift their head (1-2 cm) from the backrest and hold their head as steady as possible in the same position for 1 minute. For the INF high load test the subjects were positioned in supine and were asked to do craniocervical flexion while their head was positioned on the bench, then to lift their head slightly from the bench and hold their head as steady as possible in the same position for 30 s. The test was ended if the subjects touched the table with the back of their head or if the subjects chose to end the test due to fatigue or neck pain. Angular velocity of the head was calculated to assess the ability to hold the head steady during the INF test. Holding time during the high load INF test was used as a descriptive variable. Angular velocity (deg/s) was calculated as the point to point change in orientation of the forehead sensor (S1) over time, relative to the sensor placed on the spinous process of T2 (S2). Holding time in the INF tests was registered with a stopwatch.2) was calculated.Postural sway in quiet standing was assessed during 60 s for each one of four conditions. The first condition was a dual task where the FOE test with low tracking velocity was performed during quiet standing. In the second condition eyes open (EO) the subjects were instructed to focus at a point on the wall 250 cm straight in front of them. For the third condition subjects were blindfolded (EC). The fourth and last condition was performed with eyes open standing on a balance pad (EOB). Unfortunately, postural sway during the FOE in standing was not recorded in 43 subjects in HC, leaving only 48 subjects in the HC group for this analysis. The same standing position was ensured for all conditions  and the order of presentation of conditions was the same for all subjects. The instructions given were to “stand still for one minute”. Sway was assessed from the antero-posterior and the mediolateral position data from the sensor (S3) placed on spinous process of L4-L5 and 95% confidence interval for sway area .z et al. : 95 % CIThe groups were similar in age and BMI, but there were a higher proportion of women in the HC group Table . The NP NP patients had significantly less maximal cervical ROM in flexion/extension and rotation compared to HC after adjusting for age and gender, while lateral flexion barely fell short of reaching significance Table A. SumminThere was no significant between group difference (p = 0.11) in relocation error in the JPE test Table .In the low load and high load tests NP patients had markedly lower head angular velocity compared to HC. In the low load test the mean group difference was −0.4 °/s  and in the high load test −1.7 °/s . Largest effect sizes were found for head steadiness and neck flexibility , CM , and peak velocity  during flexion/extension  months. We did a sensitivity analysis were we excluded the 17 subjects and found that the group results for the different tests did not change. Thus, we think that previous episodes of neck pain in the HC group did not bias the conclusions in this study. Other factors like work- load, education and physical fitness may have influenced neck motor control and neck pain and but were not measured in this study.NP patients had less cervical ROM, reduced conjunct motion, lower peak velocity during cervical ROM tests, less head motion in the isometric head steadiness tests, showed more “rigid” trajectory head motion patterns and more postural sway in standing on a balance pad. Overall the results clearly suggest altered motor control patterns in subjects with moderate to severe neck pain with long duration characterized by stiffening and rigidity Table . The rel