Chronic back pain is a significant problem worldwide and may be especially prevalent among patients receiving care in the U.S. Department of Veterans Affairs healthcare system. Back pain affects adults at all ages and is associated with disability, lost workplace productivity, functional limitations and social isolation. Exercise is one of the most effective strategies for managing chronic back pain. Yet, there are few clinical programs that use low cost approaches to help patients with chronic back pain initiate and maintain an exercise program.We describe the design and rationale of a randomized controlled trial to assess the efficacy of a pedometer-based Internet mediated intervention for patients with chronic back pain. The intervention uses an enhanced pedometer, website and e-community to assist these patients with initiating and maintaining a regular walking program with the primary aim of reducing pain-related disability and functional interference. The study specific aims are: 1) To determine whether a pedometer-based Internet-mediated intervention reduces pain-related functional interference among patients with chronic back pain in the short term and over a 12-month timeframe. 2) To assess the effect of the intervention on walking (measured by step counts), quality of life, pain intensity, pain related fear and self-efficacy for exercise. 3) To identify factors associated with a sustained increase in walking over a 12-month timeframe among patients randomized to the intervention.Exercise is an integral part of managing chronic back pain but to be effective requires that patients actively participate in the management process. This intervention is designed to increase activity levels, improve functional status and make exercise programs more accessible for a broad range of patients with chronic back pain.NCT00694018 Chronic pain, especially low back pain, is a significant problem worldwide, with one fourth of adults in the U.S. reporting low back pain in the past three months and about one-half reporting back pain during a given year -3. Low bPain affects many patients using the U.S. Department of Veterans Affairs (VA) health care system -12, and The high prevalence, high cost and negative consequences of chronic back pain underscore the significant need for effective and efficient approaches for managing this condition. Strategies for managing chronic back pain range from traditional medical management approaches  and self-management programs to interventional pain management techniques and complementary and alternative medicine -22. TherStaying active and exercise therapy can prevent recurrence, reduce pain, improve functional status, and decrease disability for patients with chronic back pain ,21,26-28Research also shows that a variety of exercise programs including yoga as well as aerobic and strengthening exercises result in both clinically and statistically significant improvements in outcomes for patients with chronic back pain ,21,26-28A recent review article found only low to moderate evidence supporting walking as an effective intervention for low back pain . Yet, thenhanced pedometer to promote walking directly through feedback, goal setting and monitoring. Walking is considered an ideal exercise since it is something that most anyone can do regardless of their health condition and does not involve the use of specialized equipment. Second, this intervention promotes walking through the use of a website that includestargeted content to enhance exercise self-efficacy. The website also contains materials to reinforce other important activities for managing chronic back pain, such as the use of strengthening and stretching exercises. The third component of the intervention is an e-community to provide social support, both peer and professional, that encourages patients to initiate and adhere to a walking program. We believe that more walking will contribute to improvements in function among patients with chronic back pain through multiple mechanisms, including improvements in mood, weight loss and by combating pain-related fear and self-protective behaviors, which can lead to reduced muscle tone, increased pain perceptions and functional disability.Given the challenges just described, we have developed an intervention that uses generally available tools and a relatively low cost approach to help patients with chronic back pain initiate and maintain an exercise program. The conceptual framework shown in Figure Others have previously demonstrated the feasibility and safety of home-based walking programs for individuals with chronic health conditions, including chronic pain conditions -38. AddiInternet based programs are an increasingly popular option for delivering behavior change interventions ,47-49. TOne of the challenges of Internet-based behavior change programs is keeping participants interested and engaged for a sufficient duration, which can be important to ensure a therapeutic benefit . An e-coThis randomized controlled trial includes outcomes measured at baseline, 6 and 12 months , quality of life, pain intensity, pain related fear, and self-efficacy for exercise.Aim 3 To identify factors associated with a sustained increase in walking over a 12-month timeframe among patients randomized to the intervention.Patients with chronic back pain receiving care at a VA health care system are being recruited to participate in the study and are randomized to either enhanced usual care (control) or the pedometer-based Internet-mediated intervention. All participants are required to attend a general educational program ("back class") for individuals with chronic back pain. This ensures that all participants have a basic understanding of back mechanics and general strategies for managing back pain. Ethical approval for this study has been granted by the VA Ann Arbor Healthcare System human studies sub-committee.Potential participants are identified both through provider referral to back class and through data obtained from the VA electronic medical record system. Specifically, these data are used to identify patients who had two or more outpatient encounters in the prior 12 months with a diagnosis of back pain with no neurologic findings . To be eligible for the study participants must: 1) have back pain that has persisted for more than 3 months; 2) have a sedentary lifestyle ; 3) have access to a computer on at least a weekly basis with an available USB port and Internet access; 4) be able to provide written informed consent; 5) be able to communicate in English; 6) be non-institutionalized; 7) be able to walk at least one block; and 8) report they are not pregnant. Prior to participation, eligible patients must attend back class and obtain medical clearance from a physician, which may be their primary care provider, cardiologist, physical medicine and rehabilitation or pain management physician.During back class, a physical therapist provides general education about back problems and strategies for managing back pain, with an emphasis on the importance of exercise  [materials available upon request]. During the class, patients practice strengthening and stretching exercises under the guidance of a physical therapist who adapts the exercises based on a patient's medical conditions. Up to 20 patients are scheduled per class, and each class takes approximately two hours.During the enrollment process, written informed consent is obtained and patients complete a six-minute walk test. All participants then receive an enhanced pedometer and USB cable to allow them to upload their step counts to a secure study website. Participants receive general guidance about how to use the pedometer and specific instructions for uploading data. The pedometer used for this study is the Omron HJ-720ITC, which contains a dual axial accelerometer, an internal clock, enough memory to store 42 days of detailed time stamped step count data, and an embedded USB port. The Omron pedometer is accurate within 1 to 4% compared to directly observed step-counts . PedometFollowing enrollment, participants are instructed to wear their pedometer for seven days with the read out on the pedometer covered. At the end of the seven days they are asked to upload their pedometer data for the first time so we can establish a baseline measurement. After completing a baseline survey, uploading seven days of useable pedometer data and receiving medical clearance the participant is flagged as active in the system, and the computer randomly assigns them to the intervention or control group. The participant then receives an e-mail message with their group assignment, instructions to upload on either a weekly (intervention) or monthly (control) basis, and is instructed to remove the sticker covering the pedometer face.sustained increase in walking among generally sedentary individuals [Participants randomized to the control group, receive monthly e-mails asking them to upload their pedometer data. Those data are stored but not used for any further feedback to patients. Although the pedometer is an enhancement to what patients receive in standard practice, past studies suggest that pedometers in isolation are unlikely to result in a ividuals . While cThe study intervention is based on the Stepping Up to Health program developed by Richardson and colleagues . The intThe participant website is tailored according to gender and includes information and messages  to promote walking and a healthy lifestyle. New motivational or informational messages addressing potential barriers to physical activity  or issues related to diet or other health conditions  appear every other day. Brief updates about topics in the news or new research findings related to back pain or physical activity are generally posted on a weekly basis so the website content does not get stagnant. The website also includes the materials and hand-outs that participants received at back class as well as a video demonstrating the proper technique for the strengthening and stretching exercises taught during the class.The e-community component of the intervention consists of a thread-based forum that allows participants to conduct asynchronous text-based discussions. Each participant selects a pseudonym in order to establish an on-line identity while maintaining privacy. Following work by Lorig et al. , the e-cThe study includes several mechanisms for monitoring, troubleshooting and identifying the minority of patients for whom a relatively low intensity walking program is considered unsafe. Medical clearance is required and patients for whom walking is not a recommended activity, due to for example balance problems or cognitive impairment, are not eligible to participate. However, since we are trying to use relatively few exclusion criteria it is possible that some patients will be eligible but later develop signs or symptoms that suggest walking may no longer be a safe activity. Both intervention and control participants are encouraged to report adverse events including any health problems they experience whether or not they are thought to be study related. Participants can report adverse events by using a link on the website, by e-mail and over the phone. All email messages contain a link to the adverse events reporting form and the study's toll-free number for reporting adverse events. After completing four weeks of the study and every eight weeks thereafter, participants are prompted to complete a survey on the website that asks about specific adverse events and symptoms. This information is closely monitored by project staff so that any patients who appear to be experiencing a potentially serious health-related problem can be contacted for further assessment and follow-up.Measures have been selected to assess our principal hypothesis that the proposed intervention will increase walking, as measured by step counts, among intervention patients relative to controls and reduce pain-related functional interference. Potential mediating factors, such as self-efficacy, and the benefits of a walking program, such as improvements in mood and quality of life, are also of significant interest. Data collection includes a computer-based survey completed at baseline, 6 months and 12 months, a six-minute walk test conducted at baseline and 12 months, and the step counts collected when participants upload their pedometer data. We are also collecting quantitative information about patients' use of the system via computerized records that the system maintains of all contacts. Health services use is assessed by patient report and by data obtained from the VA computerized medical record system.The primary outcome for this study is pain-related disability and functional interference. Following the recommendations made through the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) , we are ® Health Survey [Secondary outcomes include average daily steps, functional status, general health-related quality of life and pain intensity. Walking, which is a key aspect of the intervention, is measured as the number of average daily steps using the Omron HJ-720ITC pedometer. Rather than having to rely on self-reported step counts, the Omron allows us to upload the objectively recorded pedometer data directly to a database through the use of an embedded USB port. All data are time stamped by the pedometer. As an objective measure of function and to help validate the step count data obtained using the study pedometers we are conducting a six minute walk test at baseline and 12 months ,71. Parth Survey . PatientOther secondary outcomes and potential moderators include pain-related fear or kinesiophobia, which is being measured using a revised version of the Tampa Scale of Kinesiophobia (TSK-R) ; self-efThe patient is the primary unit of analysis for this study. Our sample size calculation was based on the RDQ index as the primary endpoint with a minimally detectable effect size determined as a difference of 0.4 standard deviations (SD) based on published data ,77,78. TTo determine whether the intervention reduces pain-related functional interference we will compare the difference in the RDQ index at 12 months between the two groups using a linear mixed-effects model. Similarly, mixed-effects models will be used to assess the effect of the intervention on step counts, quality of life, pain intensity, pain related fear and self-efficacy for exercise. Identifying factors associated with a sustained increase in walking over a 12-month timeframe is an exploratory analysis within the intervention group.In addition, to understand features of successful versus less successful intervention experiences, we will analyze data collected through our monitoring of participant system use and semi-structured interviews conducted with a purposeful sample of intervention participants . Using standard qualitative methods , we willThe two major limitations of the study design are: (1) we will be unable to directly compare the effect of this intervention to the effects of other types of exercise programs that have demonstrated promise in randomized trials ; and (2) usual care patients will receive some intervention elements . Nevertheless, we believe that the design represents the optimal compromise between scientific rigor and real-world practicality. Further, we expect that neither the pedometer nor the extra education will have a substantial influence on our primary outcome. If they do have any impact, the effect would be to reduce the likelihood of finding treatment differences between the control and intervention groups. Thus, the design for this study will provide rigorous evidence about the effectiveness of the proposed intervention, which is novel and has yet to be evaluated and determined to be effective in isolation, as well as information about possible implementation in other settings.Current evidence suggests that physical activity is one of the most effective strategies for managing chronic back pain and improving function ,19,25. NThe authors declare that they have no competing interests.SLK, JDP, EAK, HMK and CRR were involved in the conception and design of the study. TM, RK and MH are involved in study data collection. All authors were involved in drafting the manuscript and revising it for critically important content. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/11/205/prepub


Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches.Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient.An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention.The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed. Low back pain (LBP) is a substantial health problem. It affects up to 80% of the adult population  and accoThe prognosis for acute NSLBP (ANSLBP) is relatively favourable. A significant percentage of sufferers, probably over 50%, do not consult a health care professional for the problem . Among tIn a small group of acute patients, the problem fails to resolve as it should. Perhaps 10% will go on to develop chronic, disabling LBP -14. It iRecent systematic reviews of the most commonly applied treatments reach remarkably similar conclusions. Most treatments provide small, short-term benefits when compared to no treatment or sham treatment, but offer little benefit when compared to other forms of intervention . No treaRecent work evaluating the clinical importance of outcome in CNSLBP reinforces this perspective. Keller et al  calculatvan Tulder et al.  evaluateThe disappointing results from clinical trials may be interpreted in two ways. Firstly, it is possible that the clinical trials are wrong. That is, for various reasons, the clinical trial process fails to capture the reality of the clinical setting and underestimates the true effectiveness of current practice. Alternatively, the clinical trials are right and current approaches to the management of CNSLBP are of limited value.The former perspective is one commonly taken by clinicians who feel the results of clinical trials are at odds with their clinical experience. Numerous explanations have been proffered, including insufficient treatment dose , inapproThe alternative interpretation, that the clinical trials are correct and current practice offers little benefit, is often neglected, and along with it the research agenda that would have as its priority the development of new and novel models of care for CNSLBP. The purpose of this paper is to encourage clinicians to consider this alternative. Particularly, that for management to move forward clinicians may need to regard CNSLBP in a very different way. We will attempt to do this in two ways. Firstly, we feel that the sub-grouping paradigm potentially stifles engagement with this view and believe it is important that clinicians and researchers more closely scrutinise the sub-grouping approach. Accordingly, the first section of the discussion attempts to do this by considering possible weaknesses in the sub-grouping perspective. Secondly, an alternative model for understanding CNSLBP will be presented, which offers potential for very different ways of managing the problemWhat clinicians and researchers mean by a sub-group is not always clear. Sometimes it may refer to clustering of effect modifiers within a distinct diagnostic group, what may be referred to as a 'clinical sub-group'. Other times the term is used to indicate groups with a unique mechanism or cause underlying the disorder, the terms 'aetiological' or 'mechanistic sub-group' probably best capture this perspective. Both are seen in the LBP literature, for example the three major categories in the McKenzie approach  can be tThe statistical problems and pitfalls of sub-grouping have been reviewed extensively in the literature -38. HoweThere is no doubt that CNSLBP represents a complex, multi-dimensional problem. The chronic LBP experience is characterised by a vast array of physical -42 and pThe multi-dimensional nature of CNSLBP may also be interpreted in this way. While complexity in behaviour can be explained by distinct mechanistic sub-groups, it can equally be interpreted as the individualisation of response to a single underlying problem, and while the complexity of the presentation requires that intervention be broad and personalised it may still have as its basis a single idea.Not only is CNSLBP complex, it is also possible to observe clustering of various characteristics in this population ,33,53,54Another consideration is the variability seen in clinical trials of treatment for CNSLBP. Most commonly applied interventions have been subject to numerous studies, and for any given intervention it is possible to identify some studies in which there is a demonstrated effect and others in which there is no effect. Failure to account for sub-groups within the LBP population has again been cited as a potential explanation for these findings ,32.There are several alternative explanations that are worthwhile contemplating. Firstly, statistical power may underpin some of the variability seen. The inconsistency does not necessarily reflect variability in treatment efficacy, just variation in the statistical efficiency of studies to detect treatment effects. Secondly, there is likely to be some random error associated with a large number of studies. One would expect to see most studies yield results representative of the average effect of that intervention. Likewise, there would be some variability in the response, with a few studies showing effects greater than the average and a few studies showing effects lower than the average. The variation may simply be noise, rather than variability induced by "innovative trial design" . FinallyA further commonly applied argument for the pursuit of mechanistic sub-groups is that NSLBP is too broad a category. Researchers suggest that since the majority of low back pain patients fall into this category, it's value in characterising a patient's presentation is only marginally more helpful than simply stating that they have pain in the back ,40. NSLBThis section concludes that a number of the features of CNSLBP can be explained by mechanisms other than the inculcation of mechanistic sub-groups. This does not invalidate sub-grouping, it merely recognises that it is one of several alternatives. A more robust critique of the sub-grouping perspective requires consideration of the predictions that a sub-grouping model makes, and investigation of data related to these predictions. This is the aim of the next section.Supporters of the sub-grouping model contend that the small effect sizes seen in clinical trials result from the large positive effects seen in some patients being 'washed out' by the smaller or negative effects seen in others . The solSeveral different protocols have been used that compare tailored to non-tailored treatment programmes, and all reach similar conclusions. Comparisons between treatment programmes based on individual patient assessment and more general and generic treatment programmes demonstrate equivalence in outcome -68. ProvKent and colleagues  systematHayden et al  comparedIf the CNSLBP population contains distinct mechanistic sub-groups requiring different intervention strategies, then a reasonable prediction would be that multimodal interventions demonstrate superior outcomes to unimodal care, particularly when the unimodal components have been shown to impart some benefit to patients. The sub-grouping model would predict that subjects in multimodal care have a greater likelihood of receiving their appropriate intervention, thus decreasing the chance of 'washout'. While there is a possibility that treatments may interact negatively, or in other complex ways, we consider this a reasonable prediction. While some papers show small differences with the addition of treatments -74, the Hayden et al  again prOne approach to investigating sub-grouping in LBP is to consider which cluster of patient factors identify those most likely to benefit from a particular treatment. Research on ALBP, for example, has identified distinct and theoretically plausible clinical profiles that predict success from manipulation  and stabIf CNSLBP is similarly made up of different mechanistic subgroups, and a particular intervention is applied to the whole group, those patients that are matched to that treatment should obtain benefit and their clinical profile ought to emerge from analyses of treatment moderators. There have been many attempts to elucidate the features that influence outcome in CNSLBP patients receiving care. These data are difficult to interpret. The results are influenced by the type of outcome investigated and the follow-up interval . In addiWhile acknowledging these problems, there is little evidence from clinical studies of a patient profile that responds uniquely to a given intervention. Pain intensity, duration of the problem and distress appear repeatedly as important predictors of outcome regardless of the type of treatment ,90,92-96In the previous sections we saw that the features of CNSLBP that have prompted clinicians and researchers to consider sub-grouping may have alternate explanations and that clinical data on CNSLBP does not strongly support the presence of sub-groups. Despite its popularity, sub-grouping may not be an important explanation for the disappointing results seen in clinical trials. An alternative perspective is that treatment has been ineffective because it has been misdirected. One possible scenario is that the problem of CNSLBP does not lie within the back, but within the brain. Thinking of CNSLBP as a problem of cortical reorganisation and degeneration may increase our understanding of the problem and more appropriately direct intervention.There is growing evidence that the brains of patients with CNSLBP are different to those of normal subjects -102 and Recently investigators have looked more widely at brain structure and function, and a consistent pattern of brain changes has begun to emerge. Siddall et al.  used magBrain morphometry has been used to investigate both general and regional gray matter density changes in CLBP patients. Apkarian et al.  reportedAlteration in brain function may be the mechanism that underpins the problem of CNSLBP. The patterns of central changes are consistent across a number of studies and methodologies and the extent of the central nervous systems changes are proportional to the duration and severity of the condition ,99,102. A cortical model of CNSLBP must be able to explain the complex clinical presentation of the problem. Critical challenges include accounting for the innumerable physical and psychological manifestations of CNSLBP and offering an explanation for the equivalence in outcome of very disparate treatments. Though speculative, alteration in brain function may offer some interesting perspectives and insights into these issues.There is now strong evidence that structural changes within the spine have little meaning in the context of CNSLBP ,116,117.Sensitization of the nociceptive system is one suggested explanation for this problem. Enhanced synaptic efficiency of nociceptive networks may facilitate the perception of pain with little or no peripheral nociceptive input. Evidence indicates that there is some degree of sensitisation in CNSLBP patients ,120,121.Studies of inflammatory and neuropathic pain models in animals demonstrate extensive structural and functional alterations in the dorsal horn of the spinal cord that represent a relatively specific degeneration of the inhibitory interneurone system, leading to central sensitization and increases in pain-related behaviours (for review see ). SimilaMethodological barriers to studying cord structure and function in humans make it difficult to ascertain the contribution of such changes to CNSLBP. Furthermore, in rodents, the spinal cord represents a far greater proportion of the CNS than in humans, and animal models demonstrate that while cord changes are prevalent in younger animals, brain changes dominate in older animals . NeverthThe work on brain changes in CLBP patients provides speculative support for this view. Schmidt-Wilke et al.  demonstrA second proposition for the perception of pain in the absence of spinal pathology is the presence of central pain memories. Flor  has suggAn alternative mechanism has been proposed by which cortical reorganisation may lead to the generation of ongoing, movement related pain from within the brain. Harris  suggestsMcCabe et al.  providedLack of visual input of the moving part is a critical component of the incongruence hypothesis . Vision Interestingly, conditions that generate sensory-motor conflict are associated with increased activation in the right dorsolateral prefrontal cortex (DLPFC) . As mentIn summary, there are numerous ways whereby reorganisation within the brain may generate persistent pain in the absence of ongoing peripheral pathology. These include, reduced cortico-cortical and descending inhibition producing an abnormally sensitised state, the reactivation of implicit pain memories, and centrally generated pain in response to sensori-motor incongruence when the patient moves the back. It is plausible that these mechanisms coexist. It is currently unknown to what extent that these brain changes are reversible. Similar but distinct brain changes are noted in phantom limb pain and CRPS I, and both these conditions appear amenable to treatment directed towards the brain -114. If The biomechanical aspects of LBP have been widely investigated , and theThe congruence seen within these data is surprising. The overwhelming sense is a loss of confidence, control and coordination within the back. While Moseley and Hodges  contend Support for this view can be seen in a number of areas. There appears to be little association between changes in patient centred outcome and changes in any aspect of low back related physical performance . Lumbar Psychological factors are an important part of the chronic LBP experience. They contribute to the progression to chronicity, explain a significant amount of the variance among CLBP patients and have been identified as important barriers to resolution ,175,176.Pincus et al. ,176 citePsychological variables also account for a significant amount of the variance in the CNSLBP condition . DespiteThe fear-avoidance model is seen as a central psychological mechanism in the maintenance of CNSLBP ,185. FunOne possible candidate for the genesis of these beliefs is alteration in cortical representation of the back and resultant distorted body schema. Keefe et al  state thIt is also possible that degeneration within the DLPFC may contribute directly to greater catastrophic interpretation of pain. The DLPFC seems to be important in emotional disengagement from pain ,129 and Individuals' coping strategies are also considered to be important contributors to the disability associated with CNSLBP. Active coping strategies, characterised by efforts to function in spite of pain or to distract oneself from pain are thought to be important in adaptive functioning . PsycholFigure In summary, CNSLBP patients have back pain yet no conservative or surgical pain relieving measures directed at the back appear effective. They display a number of biomechanical abnormalities, however treatment directed at normalising lumbar biomechanics has little effect and there is no relationship between changes in outcome and changes in spinal mechanics. Finally, these patients demonstrate some psychological problems but psychologically based treatments offer only partial solution to the problem. A possible explanation for these findings is that they are epiphenomena, features that are incidental to a problem of neurological reorganisation and degeneration.As discussed, the response of CNSLBP patients is very similar across a broad range of treatment options. A simple explanation would be to conclude that current interventions are ineffective or demonstrate only non-specific or placebo effects. However, the evidence does not support either of these perspectives. Most commonly applied conservative treatments demonstrate some level of effectiveness, albeit small, and this seems to be above what is produced by sham treatment . AlternaThis perspective may also explain the disappointing effect sizes seen with conservative care. A possible reason for the small effects seen is that none of these interventions are currently delivered in a way that focuses on central processing. Mobilisation of the lumbar spine might be made more cortically directed by having the patient respond verbally to the stimulus, trying to localise the level or determine direction of pressure, akin to the sensory discrimination task employed by Flor et al.  in managSimilar thinking can be applied to most commonly applied conservative interventions, and whilst changing the emphasis of existing treatments may be a viable option for enhancing clinical efficacy, it may also be useful to consider other possibilities. There is mounting evidence for the effectiveness of alternative and innovative strategies for "re-training" cortical function in other complex, long standing, pain problems -114,193 In conclusion there is little evidence to endorse current treatment for CNSLBP. Most treatments provide only small short-term changes and there is currently scant evidence that one form of treatment is superior to another. Sub-grouping of CNSLBP is a common response to these disappointing results. The sub-grouping perspective is not consistently supported by the available data and it is important that other research agendas are entertained. An alternative perspective is that treatment has been ineffective because it has been misdirected. CNSLBP may be a problem of abnormal cortical function. There is growing evidence of supraspinal abnormalities in CNSLBP, these mechanisms can potentially explain the complexity of the LBP experience and the outcomes of clinical trials on CNSLBP. Various research groups have demonstrated the potential value of 'training the brain' in other conditions characterised by abnormal cortical processing. Given the growing body of evidence indicating similar neural mechanisms in CNSLBP, the development of clinical strategies targeted at normalising neurological processing represents a challenging new direction for musculoskeletal clinicians and researchers involved in the management of CNSLBP.• Clinical trials offer little support for current management of chronic non specific low back pain• Sub-grouping has been commonly offered as an explanation for the disappointing results of clinical trials• Much of the literature on CNSLBP do not strongly support a sub-grouping model• Evidence is emerging of significant cortical alterations in CNSLBP patientsThese changes may offer an explanation for the complex problem of CLBP and a potential focus for effective treatment.The author(s) declare that they have no competing interests.Both authors contributed to the development of the ideas and arguments within this manuscript. Both authors have read and approved the manuscriptThe pre-publication history for this paper can be accessed here:


Eighty ASA physical status I and II patients undergoing general anaesthesia for elective surgery were enrolled. The patients were randomised to receive 100% oxygen (O2), or 50% N2O in O2 for 3 minutes followed by a subparalysing dose of rocuronium 0.06 mg/kg. After induction of anaesthesia with thiopentone 5 mg/kg, an intubating dose of rocuronium 0.6 mg/kg was given. The patients were observed after injection of rocuronium 0.06 mg/kg, and asked to rate pain in the arm on a 4-point (0–3) verbal rating scale . After the intubating dose of rocuronium, withdrawal reactions were recorded. Thirty-six patients (90%) in the group N2O and 15 patients (37.5%) in the group O2 reported no pain (P < 0.001). The pain was mild in 1 (2.5%) and 9 (22.5%) patients in N2O and O2 groups, respectively (P = 0.006). Moderate pain occurred in 2 (5%) patients in group N2O and 15 (37.5%) patients in group O2 (P = 0.001). Severe pain was reported by one patient in each group (P = 0.47). Withdrawal response after an intubating dose of rocuronium was observed in 6 (15%) and 18 (45%) patients in the N2O and O2 groups, respectively (P < 0.05). Inhalation of 50% N2O in O2 reduces the incidence and severity of pain and the withdrawal reactions associated with rocuronium injection.A prospective, randomised, double-blind, placebo-controlled study was carried out to determine the effect of nitrous oxide (N Pain during induction of anaesthesia is distressing and it increases the stress and anxiety among patients just before surgery. Rocuronium is a widely used steroidal neuromuscular blocking agent with an intermediate duration and a rapid onset of action. The major disadvantage of rocuronium is the pain associated with its injection, the cause of which is not clear. With a subparalysing dose, 50–100% of patients report discomfort. A number32O is an analgesic gas that has been used for more than 100 years. It has been used effectively to reduce the pain associated with propofol injection but its effect on reducing pain on rocuronium injection has never been studied. We hypothesised that inhalation of 50% N2O reduces the incidence and severity of pain and the withdrawal reactions after injection of rocuronium. Hence, the primary aim of this prospective, randomised, double-blind, controlled trial was to determine the effect of N2O on the incidence and severity of pain during injection of a subparalysing dose (0.06 mg/kg) of rocuronium. Our secondary aim was to determine its effect on incidence of withdrawal reactions after administration of an intubating dose (0.6 mg/kg) of rocuronium after induction of anaesthesia.N2O, and patients receiving analgesics or sedatives were excluded from the study. Patients were informed that they would be receiving a drug at the start of their anaesthesia that may make their arm "sting." They were told that they would be asked to score their pain on a 4-point scale (0-3), if any, after the drug had been given. They were, however, informed that they would be blinded to their group assignment.After obtaining approval from the institutional ethics committee and written informed consent, 80 unpremedicated ASA physical status I or II patients, aged 18–55 years, undergoing general anaesthesia for elective surgery were enrolled. Patients with chronic pain, anticipated difficult airway, pregnancy, contraindication to N2O in oxygen (O2) for 3 minutes (Group N2O) or inhalation of 100% O2 (control) for 3 minutes. During this time, a screen was placed in front of the flow meters in such a fashion that the investigator collecting the data  was blinded to the group assigned. Once the patient had inhaled 50% N2O-O2 mixture or pure O2 for 3 minutes, a subparalysing dose of rocuronium 0.06 mg/kg, diluted with saline to an injection volume of 5 ml was injected over 10 seconds. The patients were observed and asked immediately if they had pain in the arm, and their response was assessed according to the verbal rating scale[µg/kg before intubation. Further anaesthesia was continued using drugs and techniques at the discretion of the attending anaesthesiologist.A 20-G intravenous cannula was placed preoperatively in the largest vein on the dorsum of the hand and an intravenous infusion of sodium chloride 0.9% was started. On arrival at the operating room, all the patients were monitored with an electrocardiograph, pulse oximeter and an automatic noninvasive arterial pressure monitor. The patients were randomly assigned to one of the two groups by drawing of lots . They received either inhalation of 50% Ning scale. AnaesthP value of less than 0.05 was considered significant.To detect a 50% reduction at a significant level of 5% and a probability of 80%, this study required at least 40 patients per group, estimating the frequency of 80% of patients who experience pain or withdrawal movement on injection of rocuronium. Data are expressed as mean ± SD or numbers (percentages). Statistical analyses were performed using SPSS Windows based version 15.0 . Patient characteristics were analysed using one-way analysis of variance. Chi-square test was used for other statistical analysis (gender and injection related pain or movement). A 2 or 50% N2O in O2. The overall incidence of pain was 62.5% in the O2 group and 10% in the N2O group (P < 0.001). Although the incidence of severe pain was similar among the two groups (P = 0.47), 15 (37.5%) patients in the O2 group had moderate pain and 9 (22.5%) had mild pain. The inhalation of 50% N2O in O2 significantly reduced the pain and discomfort reported by patients. One (2.5%) out of 40 subjects in the N2O group had mild pain (P = 0.006) and two (5 %) had moderate pain (P = 0.001 vs. control) [All the 80 patients completed the study. Demographic data were comparable among the two groups . Figure control) .2O group than in the O2 group (P < 0.01) [The intubating dose of rocuronium caused fewer withdrawal reactions in the N < 0.01) . None ofet al.[et al.[Pain associated with administration of rocuronium is common and distressing for patients‐5 and haet al. althoughThe mechanism of rocuronium-induced pain remains unclear although various theories have been proposed to explain the aetiology of this pain. These include direct activation of C-nociceptors by the osmolality or pH of the solution, or activation by the release of endogenous mediators such as histamine, kinin and other substances mediating inflammation.278 Altho2744949et al. reported a child who developed pulmonary aspiration secondary to gastric regurgitation caused by spontaneous movements after the injection of rocuronium.[Rocuronium can also cause pain even after induction of anaesthesia resulting in withdrawal movements. These withdrawal movements may negatively affect the patient outcome. Lui et acuronium. Pain, emcuronium.2O in O2 could alleviate pain on rocuronium injection and reduce the withdrawal response to injection because its analgesic efficacy is well known and it has previously been used successfully to alleviate pain associated with injection of propofol. Sinha et al. have reported the use of N2O in reducing pain on propofol injection in adult patients.[2O (with or without premixed lignocaine in propofol) for the prevention of propofol-induced pain and found a significant decrease in the incidence of pain from 36.7% (in patients who received 50% O2 in air with lignocaine mixed in propofol) to 3.3% with use of 50% N2O in O2 along with the above mentioned regime. While Harmon et al. reported inhalation of N2O in oxygen O2 to decrease pain on propofol injection with similar efficacy to the admixture of 20 mg lidocaine in propofol,[et al. found that combination of intravenous lidocaine and N2O in O2 inhalation pretreatment was more effective than either treatment alone in decreasing pain on propofol injection.[The present study was conducted to evaluate if the inhalation of 50% Npatients. They compropofol, Niazi et2O in O2 (P < 0.001). These results are comparable to the results obtained with the use of other agents by different investigators. Yavascaoglu et al. found that esmolol and lidocaine reduced the frequency of pain associated with rocuronium injection, the incidence of no pain being 77.5% in the esmolol group and 80% in the lidocaine group .[et al. compared the addition of fentanyl 100 µg, lidocaine 2% and sodium bicarbonate 8.4% to 10 mg of rocuronium and found that addition of fentanyl or lidocaine reduced the complaint of pain reported by patients by 1.9 times (P < 0.049) and 3.6 times (P < 0.0001), respectively.[P < 0.0001).[et al. in their study using sodium bicarbonate.[2O to 15% that is comparable to the results obtained by Yavascaoglu et al. in their study using lidocaine .[In the present study we found that the incidence of pain on injection of rocuronium was significantly reduced if the patients inhaled 50% N< 0.001). Chiarell2O is a centrally acting sedative and an analgesic agent, commonly used in anaesthetic practice. It is widely available and easy to administer. It is inexpensive and relatively free from side effects and has been used for many years to provide analgesia for various day care procedures.[2O in limiting pain on rocuronium injection is in patients with anticipated difficult airway who need preoxygenation with 100% O2. Moreover, N2O has its own well-known contraindications. However, since N2O is known to alleviate pain on propofol injection and we have shown that it reduces the pain associated with rocuronium injection, N2O may be particularly useful in cases where a combination of propofol and rocuronium is used for induction.Nocedures. It has bocedures.23 While 2O is a simple and effective method to reduce pain and withdrawal response on rocuronium injection. Further studies are required to compare its efficacy with other drugs and methods in reducing pain.In conclusion, inhalation of 50% N


This qualitative systematic review of the clinical methodology used in randomised, controlled trials of oral opioids  for cancer pain underlines the difficulties of good pain research in palliative care. The current literature lacks placebo-controlled superiority trials. Recommendations for future research are discussed. Conducting randomised controlled trials in the palliative-care patient population is a challenge. It is difficult to recruit patients and to conduct trials successfully due to the serious nature of the illness and the inevitability of symptom progression.Pain trials are especially prone to error. Pain is a subjective experience and as such is influenced by a number of variables that are difficult to control, both in the clinical situation, and in the context of a controlled trial. Psychological factors such as anxiety and depression may influence the perception of pain and even the effect of opioids . The autevaluate the general methodological quality of randomised, controlled trials of opioids in cancer painidentify factors related to poor methodological qualityinvestigate whether psychological factors are routinely addressed in opioid trialsmake recommendations for future clinical research on pain treatment in palliative careThe objective of this review was to conduct a systematic investigation of specific oral opioid  pain trials in adult cancer patients in order toIt was decided to restrict the review to oral opioids in order to have consistency and to minimise variation in the studies, concentrating on study drugs that behave in a similar manner.Search terms were oxycodone, morphine, hydromorphone, cancer, using the Boolean operators ‘OR’ and ‘AND’. The search was performed in the Cochrane Central Register of controlled trials (CENTRAL) (current issue), The Cochrane Database of Systematic Reviews (current issue), MEDLINE (1966 – January 2005) and EMBASE (1980 – January 2005). Abstracts and unpublished reports were not considered. There was no language restriction. The date of the most recent search (CENTRAL) was 9 November 2005.All identified records from each of the databases were examined. Studies in adult patients 18 years and above involving treatment of chronic cancer pain with specific oral opioid  were considered. The titles and abstracts of studies were examined independently by two reviewers  and potentially relevant studies were retrieved for assessment for inclusion in the review. Each trial report that appeared to meet the criteria was independently assessed for inclusion by three reviewers .Study quality  were evaluated using the three item (1–5) Oxford Quality scale  , in seven using verbal rating scale (VRS) and in four trials using a numerical rating scale (NRS). Thirteen trials used VAS in addition to VRS. One trial used a nonvalid assessment, nurse-rated VRS that was later converted to a numerical score. Five trials rated pain relief in addition to pain intensity. In three of these trials, pain relief was assessed using VAS and in two trials using VRS.The criteria for adequate/inadequate pain relief was clearly defined in only eight of the 34 trials. The criteria differed for each of these trials and for adequate pain relief included: ‘maximum 3 on a 7 point VRS, and not more than two daily requests for rescue analgesia’  financial support , manufacture of placebo double-dummy medication  morphine assays . Twenty-three of these 24 trials were equivalency studies.This review has identified several factors/areas that could improve the methodological quality of studies on cancer pain. The findings of the review also suggest that specific validity scores should be developed to focus more on factors that are relevant in cancer pain.The most commonly asked research question in these trials is whether one opioid is as good as another, or whether two forms of administration of the same opioid are equally effective. However, what we really need to know is more about factors which influence the cancer patient's experience of pain, and which factors influence treatment outcome. In order to do this, we need to define good and bad responders and to identify factors that influence treatment outcome. It is important to understand why some patients do not achieve pain relief, for example with opioids, and why some patients respond to one opioid but not to another.Thirty-three of the 34 trials in this review are equivalency (or non-inferiority) studies comparing two opioids or two or more formulations of the same opioid.vs drug B), the focus is a comparison of the test drug with standard therapy (active control), not efficacy of the test drug per se. Equivalency trials are potentially problematic since they do not measure efficacy directly. In such a trial, the same result is consistent with three possible conclusions  opioids. In these studies, it would have been possible to include a placebo-arm, provided the patients had free access to normal-release opioid as rescue medication, and using consumption of rescue medication as the primary outcome measure. This type of study should have a limited duration, for example 14 days, and should not present ethical problems since the treatment is similar to the clinical treatment of breakthrough pain, and would be expected to give satisfactory pain relief. Indeed, the ethics of using a placebo control in this kind of design should be compared to the potential ethical dilemma of exposing seriously ill patients to trials which do not produce reliable results due to lack of power, sensitivity or other methodological problems.Crossover or parallel group?: A crossover design may be useful as it increases the power of the study and uses the patient as his/her own control. Crossover trials are important since they can identify clear patient preferences for one drug over another and suggest ideas for future research for the mechanisms behind these differences. Crossover trials should have as short a duration as possible in order to reduce number of withdrawals, while parallel group trials allow longer follow-up with regular assessment of outcomes.Since trial size is a general problem, efforts should be made to enable combination of data from different trials . Data should be given as means±s.d., or medians+range together with responder status. The latter will help those who perform meta-analysis and also enable the researchers to further analyse the reasons why some patients respond to analgesic drugs and others do not. Adverse effects should be reported as dichotomous data. Patient treatment preference is valuable information and should be recorded. For example, some adverse effects may be more acceptable than others.Cancer pain may be constant, intermittent or both. It may be nociceptive, neuropathic or mixed. It may be cancer-related or treatment-related. If we are to investigate opioid efficacy, we at least need to know what kind of pain is being treated. In a parallel group study, if there are more patients in one group having neuropathic pain, then this would be expected to influence opioid treatment outcome.As a minimum requirement, each patient included in a pain trial should be assessed specifically for pain and given a simple pain diagnosis. A common agreement on what constitutes treatment effect is important. The fact that the criteria for adequate/inadequate pain relief were clearly defined in only eight of 34 trials, and differed for each of the trials, indicates a need for standardisation.No trial specifically addressed psychological variables and the importance of these in the perception of pain. We need to know whether levels of anxiety and/or depression are similar in treatment groups, since this may affect outcome. There is a commonly held belief that the anxiety-reducing and euphoria-producing components of opioid actions account in large part for their analgesic efficacy. This would be interesting to explore in the context of a randomised trial. For example, do psychological factors such as anxiety and depression improve when pain scores improve? Is it possible that patients with specific psychological coping profiles, in particular those who cope anxiously, may have a poor response to opioid therapy? Studies of specific variables such as catastrophic thinking about pain (Patients recently or currently receiving radiotherapy and/or chemotherapy were excluded in 20 of 34 trials. Whether patients receiving oncological treatment which may influence pain should be excluded from drug trials on cancer pain depends on the trial design. In studies of long duration, that is, several days or longer, including these patients is a confounding factor. In short studies, for example those examining the effect of short-acting rescue medication for breakthrough pain, including such patients should not be a problem.A number of other factors, including gender, diurnal variation, pharmacogenetics and opioid pharmacokinetics, may influence the cancer patient's experience of pain and the outcome of opioid therapy. While it is not possible to control for all these variables, some simple measures are available and useful, such as matching groups for gender and controlling plasma opioid concentration at steady state.The majority of studies were funded by the pharmaceutical industry. This may represent a source of bias, since research questions of interest for the industry, for example comparing two formulations of the same opioid, may not necessarily coincide with questions of importance for the clinician.Pain is a subjective experience that is affected by many different factors. This makes pain difficult to measure and clinical pain research a challenge. The challenge is even greater in a palliative-care setting where there are special standards of care to maintain, and numerous potential confounding factors.The data support the clinical experience that it is difficult to perform high-quality scientific trials in palliative-care pain patients. However, it is important to maintain scientific rigour and to ensure that research questions that are relevant to clinical practice are asked.A number of methodological problems have been identified, including low trial sensitivity, too small trial size and lack of standardised measures of efficacy. Placebo-controlled efficacy trials of oral opioids for cancer pain are lacking. A placebo control is feasible in selected trials. It is important to know which type of pain is being treated and there should be a common definition of opioid efficacy. Psychological factors can influence the experience of pain and should be assessed and reported. A number of other factors have the potential for influencing opioid response, and future research should involve identifying and controlling for such factors.Having analysed the literature we conclude that there is a need for standardisation and uniformity of design and reporting of trials. Trials must be designed to produce reliable results. This cannot be accomplished by a single researcher, but requires the collaboration of experts in several fields.We propose a consensus meeting where pain researchers, systematic reviewers in pain relief, palliative-care physicians, oncologists, epidemiologists/statisticians and pain psychologists are represented. The objective of such a meeting would be to produce a standard trial design, or set of trials, for opioids in cancer pain. In addition, a checklist for the performance of trials, based on tailor-made validity scores for cancer pain . The doc


Chest pain is a common complaint and reason for consultation in primary care. Research related to gender differences in regard to Coronary Heart Disease (CHD) has been mainly conducted in hospital but not in primary care settings. We aimed to analyse gender differences in aetiology and clinical characteristics of chest pain and to provide gender related symptoms and signs associated with CHD.We included 1212 consecutive patients with chest pain aged 35 years and older attending 74 general practitioners (GPs). GPs recorded symptoms and findings of each patient and provided follow up information. An independent interdisciplinary reference panel reviewed clinical data of every patient and decided about the aetiology of chest pain at the time of patient recruitment. Multivariable regression analysis was performed to identify clinical predictors that help to rule in or out CHD in women and men.Women showed more psychogenic disorders , men suffered more from CHD , trauma  and pneumonia/pleurisy  Men showed significantly more often chest pain localised on the right side of the chest . For both genders known clinical vascular disease, pain worse with exercise and age were associated positively with CHD. In women pain duration above one hour was associated positively with CHD, while shorter pain durations showed an association with CHD in men. In women negative associations were found for stinging pain and in men for pain depending on inspiration and localised muscle tension.We found gender differences in regard to aetiology, selected clinical characteristics and association of symptoms and signs with CHD in patients presenting with chest pain in a primary care setting. Further research is necessary to elucidate whether these differences would support recommendations for different diagnostic approaches for CHD according to a patient's gender. Chest pain is a common complaint and reason for consultation in primary care and incidence varies according to setting, country and inclusion criteria -3 Chest To our knowledge this is the first prospective primary care study investigating the epidemiology of chest pain where the large sample size allows a statistical analysis for gender differences. We aimed to analyse gender differences in aetiology, clinical characteristics, risk factors and comorbidities of chest pain in a primary care setting. In addition we wanted to provide gender related symptoms and signs that could support rational diagnosis of CHD.We conducted a cross-sectional diagnostic study with a delayed-type reference standard in a primary care setting The finaWe used an existing network of collaborating research practices to approach 209 GPs in the State of Hesse of whom 35.4% agreed to participate in the study. Only GPs being prepared to undergo random recruitment audits could take part. The 74 participating doctors (58 practices) had to recruit consecutively every attending patient with chest pain, both as presenting complaint or on questioning. The recruitment period lasted 12 weeks for each practice and was staggered in four waves between October 2005 and July 2006. Informed consent was obtained from all patients and documented accordingly.Every patient above 35 years with pain localized in the area between clavicles and lower costal margins and anterior to the posterior axillary lines had to be included. Doctors were also asked to recruit during home visits and emergency calls. Patients were eligible irrespective of the acute or chronic nature of their complaints, of previously known conditions including CHD or related risk factors. Patients whose chest pain had subsided for more than one month, whose chest pain had been investigated already and/or who came for follow-up for previously diagnosed chest pain were excluded. Like the whole study protocol, this procedure was approved by the Ethics Committee of the Faculty of Medicine, University of Marburg. The study complies with the declaration of Helsinki.GPs took a standardized history and performed a physical examination according to a case report form (CRF) that was piloted and modified accordingly. The CRF covered information on basic patient and pain characteristics, accompanying symptoms and risk factors for CHD. GPs also recorded their preliminary diagnoses, investigations and management related to the patients' chest pains.Patients were contacted by phone six weeks and six months after the index consultation. Study assistants, who were blinded to clinical data previously recorded, asked about the course of the patients' chest pain, treatments including hospitalisations and drugs. Discharge letters from specialists and hospitals were requested by GPs.A reference panel consisting of one cardiologist, one GP and one research associate  of the department of Family Medicine reviewed baseline and follow up data of each patient. They decided on the most likely medical condition having caused the individual patient's chest pain at the time of the index test (delayed type reference standard). The GP's initial diagnosis contributed to the decision made by the panel.The analyses for gender differences in regard to the final diagnoses and the probabilities for any CHD are based on the sample of all patients with chest pain where diagnostic classification was possible. Clinical characteristics, risk factors and comorbidities were analysed for patients with CHD as final diagnosis.For univariate analyses we calculated proportions and diagnostic odds ratios (OR) for all clinical items covered by the CRF. The Chi-Square test was used for univariate comparisons of categorical data. Fisher's exact test was used when the nominator was equal or below five. We calculated the z-ratio and associated two-tail probabilities for the difference between proportions. As this is an explorative study including many comparisons between different variables, p < 0.01 was considered to provide evidence of an association, while p < 0.05 was considered to indicate a possible association Index teThe majority of the participating 74 GPs were male (67%), mean age of GPs was 49 years. Two thirds of the practices were located in urban areas (63.5%). The participating GPs' demographic characteristics are similar to the population of GPs in the State of Hesse. According to our estimate participating GPs encountered around 190.000 patients during the study period and approached 1355 patients with chest pain. 7 patients did not meet the inclusion criteria and 99 refused to participate in the study. GPs returned valid CRFs (T0) for 1249 patients (548 men and 701 women). 60 cases were consequently lost to follow up and 11 died but provided enough information to be judged by the reference committee; 3 cases were early drop outs (2 women and 1 man) and were therefore not included. For 34 cases (22 women and 12 men) follow up information was lacking, incomplete or ambiguous so that no final diagnosis could be made . At T1 (6 months) we thus analysed 1212 patients (534 men and 678 women) for the aetiology of their chest pain; of those 180 patients (92 men and 88 women) were diagnosed as having CHD , CHD, psychogenic disorders and upper respiratory infections constituted the main diagnostic groups for both genders making up 80.2% of all diagnoses in women and 77.5% in men. Women showed significantly more psychogenic disorders, men suffered more from CHD, trauma and pneumonia and/or pleurisy  there were no gender related differences in other risk factors  for chest pain patients with any CHD (acute or chronic).No significant gender differences were observed for cerebrovascular disease, heart failure, peripheral occlusive arterial disease, diabetes mellitus and hypertension as comorbidities in chest pain patients with CHD.33 items for women and 29 items for men . For pain character and other accompanying symptoms we found only possible associations. This is in contrast to several other publications where women reported more nausea, burning pain and shortness of breath,11,22-24Our data add as a second interesting finding that in more men than women pain localisation was on the right side of the chest. This finding is only partly supported by studies conducted in high prevalence settings which report gender differences for jaw pain,23 but nExcept for smoking which showed a possible association with male gender we did not find gender related differences in risk factors for CHD and in related comorbidities. This is supported by data from Western countries where smoking prevalence was partly still higher among men, partly In women pain duration above one hour was associated positively with CHD while shorter pain durations showed an association with CHD in men. Chun et al. found in a systematic review about the accuracy of bedside findings for diagnosing CHD a pain duration of over 30 minutes to be a strong negative predictor. In men Most of the corresponding LRs are in a range that goes along with a small to moderate change in disease likelihood, insufficient to rule in or out disease However,In summary we found gender differences in regard to aetiology, selected clinical characteristics and association of symptoms and signs with CHD in patients presenting with chest pain in a primary care setting. Further research is necessary to elucidate whether these differences would support recommendations for different diagnostic approaches for CHD according to a patient's gender.Conflict of Interests: JRS acts as scientific advisor for MSD and ESSEX.All other authors do not declare any competing interests.NDB formulated the research question, designed the study and supervised its conduct together with ACS. NDB, EB, JH, ACS, MAH, HK, JRS, KK and SB were involved in acquisition, analysis and interpretation of data. SB drafted the article; NDB, EB, JH, ACS, MAH, HK, JRS and KK revised it critically. All authors approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/10/79/prepub


During first stage of labour, many women suffer from lower back pain. Since cutaneous afferents from the lower back converge to the dorsal horns in the same segments there is anatomical support for the lower back pain being a referred pain. Intracutaneous injections of sterile water in the skin over the sacrum have been shown to relieve the pain of labour and it is free from negative side effects associated with use of other methods.The study was conducted after approval of institutional ethical committee on 100 pregnant patients admitted to the labour room of Lok Nayak hospital, New Delhi. Patients received 4 intracutaneous injections of sterile water or normal saline 0.5ml in the lumbo-sacral region. Pain scores, progress of labour and fetal outcome were studied. There was significant reduction of pain scores in the sterile water group but not in the normal saline group at 10, 45 and 90 minutes after injection. There was no difference in the progress of labour and fetal outcome between the two groups. To conclude intracutoneous sterile water injections over the sacrum is a simple and effective method to control pain during labour. Labour pain is a unique visceral pain associated with a wonderful and meaningful life event – the birth of a baby. From many years many methods have been used to make labour smooth and pain free. Many are effective but none proved to be free from side effects. Our aim was to discover a method which will be not only effective but also free from side effects.During first stage of labour, many women suffer from lower back pain. The cervix and corpus uteri are supplied by afferent neurons ending in the dorsal horns of spinal segments T10-L1Intracutaneous injections of sterile water in the skin over the sacrum have been shown to relieve the pain of labour in open studies and in controlled prospective studies4The aim of the present study was to discover whether intracutaneous sterile water injections are effective to relieve back pain during labour and free from side effects in Indian parturients. The study was carried out by randomized, double-blinded trial including a placebo treated patient group with normal saline and comparing with sterile water injections treated patients group.The study was conducted after approval of institutional ethical committee comprising of 100 pregnant patients admitted to the labour room of Lok Nayak hospital, New Delhi. To qualify for entry into the trial they had to be in the first stage of labor  and require pain relief of lower back pain on admission or during their stay in the labour room. Written informed consent was taken by all the patients.Selection criteria- All patients in first stage of labourExclusion criteria-1. Infection in the area of injection2. Patients not willing for the procedure3. Patients who have received any analgesic following onset of labourThe women were randomized into 2 groups by computer generated numbers.Sterile water injection group patients received 4 intracutaneous injections of 0.5 ml sterile water in the lumbar- sacral region in the sitting position. One injection was given at the posterior superior iliac spine(Point.1) on both sides and second injection at 1 cm medial, and 1-2 cm inferior to the first point on both the sides (Point.2) using an insulin needle. These points overlie the area called Michaelis' rhomboid Normal saline injection group patients received injections of 0.5 ml isotonic saline in the same region using an insulin needle.All the solutions were prepared by the first author while the second anaesthesiologist and the obstetrician were blinded to solution used. All the injections were given by the two anaesthesiologists simultaneously on each side to coincide with the pain of labour contractions. All the patients had a brief stinging pain when the injection was given. The pain lasted longer in the serile water group but subsided within a few seconds.The following parameters were recordedPain assessment with the help of verbal numerical rating scale, 0-100 at 10min, 45min and 90min after giving the injections was carried out by the second anaesthesiologist who was blinded to the solution injectedPhysician assessment of pain (performed by obstetric senior resident on duty at that time in labour room), at 10min, 45min and 90min after giving the injections. The pain relief was graded as none, mild, moderate and excellent. The obstetrician was blinded to the solution injected for pain reliefProgress and duration of labour as assessed by the obstetricianOperative interventionApgar score of the neonateTotal number of women investigated was 100, 50 in each group. The sample size calculated to achieve a significant end point of pain score of 100 to pain relief pain score of 30 was 6 in each group to achieve a power of 80%. The sample size of 6 was derived from the hypothesis that pain would be reduced from 100 to 30 on the VAS scale. Statistical analysis was done by using T- test for equality of means of patient age and gestational age and also for Apgar score, Chi-square tests for parity, cervical dilatation, physician assessment of pain. Mann-Whitney U and Wilcoxon W tests respectively were done for VAS at 0, 10, 45, 90minutes (between groups) and duration of labour and for statistical significance of change of VAS from 0 to 10 min, 0 to 45 min and 0 to 90 min in each group.The women in the 2 groups were similar with regard to age, parity and gestational age . CompariThe mean VAS score at start of treatment was 75.3 in sterile water group and 74.7 in normal saline group with statistical insignificance between both groups. The mean VAS pain score 10 minutes after treatment when compared to the pretreatment score was found to be reduced  in sterile water group but not in normal saline group. Mean VAS pain score at 45min and 90min was also found to be reduced  considerNo other method of pain relief was used in both the groups other than using sterile water or placebo with normal saline. As per the labour room protocol of our hospital, uncomplicated parturients are not given labour analgesia unless they demand it. In 8 out of 50 sterile water group, crowning of the baby's head was detected in early stage by physician with absence of complaint of pain by the patient.The mean period between injections and delivery was 4.01±2.15 hrs in sterile water group and 4.17±2.30 hrs in normal saline group. The difference was not significant. Only two patients in sterile water group underwent operative delivery i, e. lower segment caesarean section(LSCS) the indications being cephalopelvic disproportion and previous LSCS.Mean Apgar score of the newborns in both the groups was 8.7±0.5 and 8.58±0.15 respectively. There was no difference between the two groups.Uterine contractions are felt as back pain because rami of T10 – L1 supplying the uterus also supply the skin over the lumbo-sacral areaInjecting solutions of osmolality other than blood irritates biological tissues. Sterile water injection evokes intense pain, probably due to the difference in osmolality10Epidural analgesia using opioids is the most potent method for women in labour in need of effective analgesia6This study is limited by the fact that the duration of the study of pain was restricted to 90 minutes only and the maximum duration of pain relief could not be studied. However, we had aimed only to study whether this method was actually as effective as quoted in various studies or not.In summary, sterile water given intracutaneously seem to be an efficient and simple method for antagonizing parturition low back pain. It provides a powerful effect lasting from 45-90 minutes, and may be repeated during labour. It may be a very useful treatment for low back pain during the initial part of the first stage of labour even for those women that may require epidural analgesia when labour proceeds. It can easily be administered by the patient's midwife and no side effects have been observed other than a burning pain lasting for a few seconds


Inguinal hernia repair is one of the most frequently performed procedures in Switzerland (15'000/year). The most common complication postoperatively is development of chronic pain in up to 30% of all patients irrespective of the operative technique.® 0.25% at the end of the operation according to a standardised procedure. Group II patients get a 20 ml placebo  injection. We use pre-filled identically looking syringes for blinded injection, i.e. the patient, the surgeon and the examinator who performs the postoperative clinical follow-ups remain unaware of group allocation. The primary outcome of the study is the occurrence of developing chronic pain (defined as persistent pain at 3 months FU) measured by VAS and Pain Matcher® device .264 patients scheduled for an inguinal hernia repair using one of three procedures  are being randomly allocated intra-operatively into two groups. Group I patients receive a local injection of 20 ml CarbostesinThe study started on July 2006. In addition to a sample size re-evaluation three interim analyses are planned after 120, 180 and 240 patients had finished their 3-months follow-up to allow for early study termination.Using a group sequential study design the minimum number of patients are enrolled to reach a valid conclusion before the end of the study.® device are used for the evaluation of pain. This allows us also to compare these two methods and further assess the use of Pain Matcher® in clinical routine.To limit subjectivity, both a VAS and the Pain MatcherThe occurrence of chronic pain after inguinal hernia repair has been in focus of several clinical studies but the reduction of it has been rarely investigated. We hope to significantly reduce the occurrence of this complication with our investigated intervention.Our trial has been registered at ClinicalTrials.gov. The trial registration number is: [NCT00484731]. Inguinal hernia repair is one of the most frequently performed procedures in Switzerland (about 15'000 cases per year) -7. CalleIn addition to the problems caused by hernia surgery the objective evaluation of the postoperative pain is limited. The Visual Analogue Scale (VAS) is often used in similar study settings and is well known as "gold standard" for eliciting pain. However Lundeberg et al.  reported® by Cefar Medical AB, Lund, Sweden. This perceptual matching device uses electrical stimulation against which the patient has to match the perceived pain with nonvisualized endpoints. It seems to be more objective and reduces recording bias. The device has been tested for safety and reliability in several clinical trials [An alternative option for measuring pain is the recently developed Pain Matcherl trials -16 and hThe use of local compared to general anaesthesia in hernia surgery has only been described by O'Dwyer et al.  not inveWe designed a randomized placebo controlled triple blinded trial to investigate the effect of an additional intra-operative infiltration with local anaesthesia on the development of chronic postoperative pain. Because of incertainty of data used for sample size estimation, a sequential design data analysis for early study stopping along with revision of sample size is applied. As Aasvang and Kehlet  pointed Patients are recruited in the outpatients and the emergency department. If they meet the inclusion criteria (see next section), informed consent is obtained and the operation is planned. According to our randomization process the patient is automatically either allocated to the verum or control group by the sequence of the consecutive numbered and block randomized syringes. An overview of the patient recruitment and follow-up is presented in Figure Adult patients (≥ 18 years) with primary or recurrent single or double sided symptomatic but not incarcerated inguinal hernias with an elective hernia repair are included. No other interventions  are allowed. Written informed consent needs to be obtained.® and vice versa patients with pacemakers or other implanted electrical devices were also excluded.Patients with legal incompetence, pregnant and nursing women, patients with presence or history of active malignancy or systemic diseases, under immunosuppressive treatment, with systemic or severe local inflammation or infection, with wound healing disorders and with physical or mental incapacity, which makes it impossible to obtain informed consent are excluded. As pacemakers interfere with the electrical stimulation of the Pain MatcherAllowed standardized surgical procedures for the hernia repair are Lichtenstein ,23, BarwBupivacain (Carbostesin® 0.25%) or the placebo Saline (0.9 %) is injected close to the nerves of the groin region following a standardized procedure  in the operated groin region for our primary outcome.According to Courtney et al.  who conc®- Pain Matcher- VAS- Areas of hyperalgesia, hypaesthesia- Length of stay (days)- ASA-Classification- Beginning of mobilisation (days)- Removal of drainage (days)- Return to work or normal activity (days and %)- Quality of life (SF36)Amounts of follow-up and recorded parameters are summarized in Table We hypothesise a 50% reduction of the occurrence of postoperative chronic pain after 3 months in the intervention group receiving intra-operative infiltration with local anaesthetic after an inguinal hernia repair compared with patients in the control group receive placebo infiltration.® Version 4 . Sample size estimation was based on a risk of occurrence of chronic pain without local anaesthetic infiltration of 30% in patient having inguinal hernia surgery  are going to be enrolled.Assuming a dropout rate of 10%  in the study, To allow for early stopping of the trial, a group sequential analysis is performed. The first of three interim analyses will be performed as soon as 120 patients (60 per group) have had their 3-month follow-up. Further interim analyses are planned after 180 and 240 patients .2-test to test the null-hypotheses. The analysis will be performed on the 'intention-to-treat' basis, i.e. patients will be analyzed in the groups to which they were randomized.We will use a χThe randomization code will not be broken for the interim analyses, unless a stopping rule is met. At each interim analysis, the following stopping rules will apply:2-test demonstrates that one treatment is superior over the other (i.e. rejection of the null-hypothesis) OR,1. A χ2. If statistical significance cannot be likely reached with the maximum allowable number of patients for the study, which is set to 200 per arm (i.e. acceptance of the null-hypothesis).2-test at each interim analysis. Boundaries for the interim analyses are calculated on the model developed by O'Brien & Fleming [Table  Fleming -32 .The study was approved by the local ethical committee of the Kanton Luzern on the 1Chronic pain after inguinal hernia repair is a common complication that needs to be addressed. This randomized placebo controlled triple blinded designed trial should provide conclusive results regarding the effectiveness of intra-operative use of local anaesthesia in mitigating this problem.Using a group sequential study design, a minimum number of patients will be recruited until interim results suggest continuing the study became unethical. This approach has been described first by Pocock ,34 who p® for the evaluation of pain which allows us to compare these two methods and confirm the good results of the recently published studies [® in clinical routine.We are using the VAS and Pain Matcher studies -16 usingPublishing this study protocol we contribute to good, honest and ethically correct clinical research already called for in 1999 by Chalmers and Altman . This stASA american society of anaestesiologistsCONSORT Consolidated Standards of Reporting TrialsFU follow upRCT randomised controlled trialSF36 short form 36TEP total extraperitoneal hernioplastyVAS visual analog scaleThe authors declare that they have no competing interests especially not with the companies mentioned in this publication.PH was responsible for the methodological background, the final design of the trial, drafted the clinical investigation plan and the manuscript. HF conceived of the main study idea, drafted the manuscript as well and was responsible for the coordination. AK participated in the design and coordination. GS conceived of the anaesiological method section. LA is responsible for the sequential design and helped to draft the CIP and the manuscript. JM is the principal clinical investigator and responsible for the whole project especially the surgical background. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Bone marrow edema (BME) is a common cause of hip pain. The aim of the study was to assess the efficacy of the vasoactive drug iloprost in the treatment of BME of femoral head.We reviewed 27 patients  with BME of the femoral head. Their mean age was 53.7 ± 10.8 years. All patients were treated with iloprost, a vasoactive drug that dilates arterioles and venules, reduces capillary permeability and suppresses platelet aggregation. The therapy comprised a series of five infusions with 20 to 50 μg iloprost over 6 h on 5 consecutive days each. Weight bearing was reduced for up to 3 weeks, depending on the severity of symptoms. Pain at rest as well as under stress was assessed with a semi quantitative scale from before and 4 months after therapy. MRI investigations were done before and repeated 4 months after therapy.P < 0.0001). Pain under stress decreased by a mean of 41.9% (P < 0.0001). On MRI, 20 patients had a significant reduction of BME size or complete normalization and 4 showed no change. Worsening of the MRI pattern was found in 3 patients.At the clinical follow up of four months after therapy, the pain level at rest had diminished by a mean of 58.3% (The authors conclude that the use of parenteral iloprost might be a viable method in the treatment of BME of femoral head. Bone marrow edema syndrome (BMES) of the hip is being discussed as a possible early reversible stage of avascular necrosis,57911When waiting for spontaneous remission, the natural time for improvement of clinical symptoms and normalization in magnetic resonance imaging (MRI) takes from 3 to 18 months.91441Since 1998, parenterally administered iloprost has been used to treat BMES and early stages of osteonecrosis in our institution.The aim of this retrospective study is to assess the efficacy of iloprost concerning reduction of pain and size of BME in the treatment of BME of different etiologies, located in the hip joint.The study was approved by the appropriate ethics committee and was therefore performed in accordance with the ethical standards laid down in the Declaration of Helsinki. The patients between 16-80years with pain in the hip joint and MRI verified BME were included in the study. For all patients, trauma or corticosteroid medication constituted exclusion criteria because of the enhanced risk of osteonecrosis.We reviewed 27 Caucasian patients  with MRI-verified BME of the femoral head treated between January 2001 and January 2002. Their mean age was 53.7 ± 10.8 years. The mean duration of time from first symptoms to treatment with iloprost was 14.6 weeks. Bone marrow edema was classified as idiopathic in 16 patients and as secondary to osteoarthritis in 11 patients. Standard serological parameters showed hepatopathy in three patients and mild hypercholesterolemia and hypertriglyceridemia in eight patients. Two patients suffered from hypothyroidism, in one patient a nodular goiter had been diagnosed, two patients needed medication because of hypertension and one treatment due to diabetes.Plain radiographs  were obtained before therapy. MRI were performed before and four months after therapy. For all patients except four, the same 1.0 Tesla MR scanner was used. Coronal turbo SE (spin echo) STIR and T1-weighted MR images of the affected hips were acquired. The STIR sequence, parameters were: repetition time (TR), 2500 ms; echo time (TE), 10 ms; and inversion time (TI), 100 ms. For the T1- weighted sequence, parameters were: TR, 498-750 ms; and TE, 10 ms. A 256 × 256 matrix and a slice thickness of 4 mm were used for both sequences. Both MR examinations (baseline and follow-up) of a particular patient were always performed with the same MR scanner.μg iloprost on 5 consecutive days each. The drug was administered in 500 ml of sodium chloride solution over 6 h using a drop counter. The daily overall dose of 50 μg was reduced to 20 μg, when we observed frequent side effect. It achieves a dramatic reduction in the frequency and severity of side effects. In cases of major subjective side effects , the drugs were discontinued but patient was not excluded from the study. Flow rate was adjusted to side effects, but there was no adjustment for body mass. Symptoms were treated with antiemetic or analgesic drugs.Two independent orthopedic surgeons reviewed the MRI pictures and evaluated visually the size and intensity of the BME located in the femoral head. The therapeutic scheme was adjusted to that used for Raynaud's disease in accordance with the pathophysiological hypothesis that BME reflects a disturbance of microcirculation. The therapy comprised a series of five infusions with 20 to 50 Weight bearing was reduced by crutches for up to 3 weeks, depending on the severity of symptoms. There was no other special mobilization protocol provided. Pain at rest as well as under stress was assessed with a semi quantitative scale from 0 (no pain) to 5 (unbearable pain) before and 4 months after therapy. Pain categories were calculated as mean values (mean ± SD), and their changes at follow-up were analyzed with the Wilcoxon test. MRI investigations were done before and repeated 4 months after therapy. All patients suffered from severe pain during mechanical loading, and 21 of them also had pain at rest or at night for a mean of 14 weeks (range: 6 to 40 weeks).Two independent orthopedic surgeons reviewed the MRI pictures and evaluated the size and intensity of the BME located in the femoral head. Changes in BME size were recorded semiquantitatively on a scale from −3 (severe deterioration) to +3 (complete recovery).μg iloprost, and 18 patients 20 μg. Side effects during infusion therapy were seen in 9 patients, i.e., 6 cases of mild headache, 2 cases of mild nausea, and 1 case of flushes. These side effects disappeared within 15 min after the end of infusion.The patients were divided into two dosage subgroups: 9 patients received 50 P < 0.0001): 81% of patients reported a reduction in pain, 15% no change and 4% an increase in pain at rest. Pain under stress decreased from 3.19 ± 0.86 to 1.85 ± 1.43 : 63% of patients had less pain during activity, 37% no change from baseline and no patient had an increase of pain level.At the clinical follow up, of 4 months after iloprost therapy, pain at rest had diminished from 1.78 ± 1.29 to 0.74 ± 1.07 (58.3%, On MRI, 20 patients had a significant reduction of BME size or complete normalization and 4 showed no change. Worsening of the MRI pattern was found in 3 patients. These seven patients were estimated as nonresponders to the treatment with iloprost.μg, the incidence of side effects could be reduced from 75.0% to 15.8%. Despite lowering the daily iloprost dose from 50 μg to 20 μg, there was no significant difference of reduction of pain and improvement of MRI patterns between dosage subgroups.With the reduction of daily dose from 50 to 20 The therapeutic options for BMES are limited. Nonoperative management, consisting of symptomatic therapy and reduction of weight bearing until the clinical and radiological findings normalize has been recommended.49261In contrast to these symptomatic treatment options, we wanted to address the causative pathogenetic vascular abnormalities using the vasoactive compound iloprost. During treatment with iloprost intravenously, most patients showed immediate improvement of symptoms, which was maintained throughout the observation period. Although the clinical outcome was excellent, the occurrence of temporary side effects, such as nausea, vomiting and headache, was also noted. These beneficial effects of treatment with iloprost in BMES of the femoral head are comparable to those that have been published for the treatment of BMES of the talus,The validity of our study is limited by the small number of patients involved and the lacking of a control group. A randomized multicenter study will be necessary in order to reach a final conclusion. Nevertheless, our experience with iloprost shows that parenteral use might be a viable method in the treatment of BMES of different origins. Both the natural course of the disease and the normalization of the signal pattern of the MRI seem to be accelerated. Based on the findings of this study, we can recommend iloprost for the nonoperative treatment BME of the femoral head.