Bone pain in malignancy can be challenging to treat. Bisphosphonates have been found to be useful in adults with bone pain, but there are no reports of their use in children for this indication. In pediatric palliative medicine there are hurdles in translating knowledge gained primarily in adult studies into application in children. Obstacles exist in initially determining whether the evidence supports using a drug in children, and once a drug is chosen, then determining the optimal route of delivery. There is very little data to guide pediatric practitioners in this situation.A 9 year old boy with disseminated Ewing Sarcoma presented with extremity pain not responsive to a combination of opiates, gabapentin and non-steroidal anti-inflammatory drugs. Clodronate, a bisphosphonate, was added to the regimen to treat bone pain. It was given subcutaneously every 4 weeks with a good response and no side effects.This case report describes the use of a bisphosphonate, clodronate, given subcutaneously to a child with Ewing sarcoma with effective relief of bone pain. It describes how the care team encountered the challenges inherent in translating adult therapy into a pediatric regimen. Furthermore the report details how a regimen was developed to address this child's concerns regarding medication administration. Further effort needs to be made at finding solutions to address the lack of good evidence for pediatric palliative therapies. This report describes the use of subcutaneous clodronate to treat malignancy-related bone pain in a child. Pain is a significant problem in children with cancer, and treating it poses several challenges. One challenge for clinicians treating difficult pain in children is the lack of an evidence base and the frequent off-label use of medications. Treatment approaches and dose estimates are borrowed from adult medicine. A second challenge is to bridge to the child's developmental stage when devising an acceptable treatment. Developmentally appropriate behaviors and attitudes on the part of the child may be viewed by clinicians as difficult "issues". These may include taste preferences for medications, reluctance to swallow pills or refusal to have IV lines. Children may oppose particular treatment approaches even when "it is for their own good". This case report uses a simple example – the use of a previously unreported medication by a novel route – to illustrate the significant obstacles faced by clinicians providing pediatric palliative care, and to illustrate the processes often followed when devising treatment approaches.th birthday. He underwent peripheral blood stem cell transplant. One year later he presented with recurrent disseminated disease and restarted chemotherapy and received radiation. He was also referred to the pediatric hospice program.The patient was a 9 year old boy with Ewing Sarcoma initially diagnosed just before his 6His symptoms included lower extremity paralysis and significant weakness of the upper extremities. He developed a partial gastric outlet obstruction, which later resolved to the point that he was able to resume oral feeding, but had difficulty taking oral medications. At the time of treatment his weight was 23 kg.He had multiple pain complaints including headache, back pain and generalized arthralgia/myalgia. There was a particularly troubling bone pain involving his forearms, wrists and hands bilaterally. The arm pain was unpredictable, episodic and intense with aching and burning qualities. There were no shooting pains or electrical shock sensations, nor was there hyperalgesia or allodynia. Pain was assessed by verbal self-report as he did not want to use any of the standardized childhood pain scales, and by the nurse's assessment using the Canuck Place Comfort Assessment Tool.His pain was treated with continuous subcutaneous or transdermal fentanyl at 75 micrograms/hour. He had hydromorphone for breakthrough pain, 3 milligrams subcutaneously as needed every hour. Adjuvant analgesics included round-the-clock gabapentin and naproxen. He received lorazepam as needed and ondansetron and nabilone for nausea. PEG 3350 and docusate were used as laxatives. The above regimen achieved satisfactory analgesia for all his pains except for bone pain in the arms.The clinical team opted to try a bisphosphonate class drug for the bone pain. Selecting a medication route was a challenge; an indwelling vascular access device had been removed several weeks previously at the completion of chemotherapy. He refused to have a peripheral intravenous (IV) line placed because he found it uncomfortable and associated it with his previous unpleasant hospitalizations. Oral medications were considered, but with his recent history of gastric outlet obstruction, and his general reluctance  to take pills, this was not a reliable route. He refused rectal medications.We therefore opted for a subcutaneous route, which was acceptable to him. A dose of 300 milligram of clodronate (~15 mg/kg) was prepared in 40 ml of normal saline (7.5 mg/ml). It was infused subcutaneously over an 8 hour time period and vital signs were monitored. There were no side effects and the infusion did not cause localized pain. There was no subsequent bone pain exacerbation. Serum calcium levels 4 days post infusion were 2.3 mmol/L with an albumin level of 28 g/L. Four days after the infusion he reported the onset of relief of the bone pain in his arms. Functionally he was improved, for example being able to use a video game controller without pain and manipulate board game pieces. The Comfort Assessment Tool provided additional information that pain was improved. He required no increases in his other analgesics; because they were providing adequate relief for other pains he experienced we did not decrease them either. The analgesic effect lasted almost 4 1/2 weeks, when he again reported intense bone pain, and the 300 mg dose was repeated, with good results 4 days later. Thereafter he received regular infusions every 4 weeks, prior to the expected recurrence of pain.In order to minimize procedures in accordance with the emphasis on patient comfort, imaging studies were not obtained and laboratory studies were kept to a minimum. During this period he moved between home and hospice with readmissions for family care, respite and symptom management. He died peacefully at home 7 months after acceptance to the pediatric palliative program, and 19 days following his last clodronate infusion,When we decided to introduce a bisphosphonate because his extremity pain was not responsive to opiates or a series of adjuvant medications we were faced with the questions of which drug to use and by what route. Cancer-related bone pain is a particularly difficult symptom to treat. Bisphosphonates have gained acceptance as a standard approach to bone pain in adults. In the idealized scenario evidence exists to guide clinicians to the most effective drug with support for a dose and frequency. Similarly in the idealized scenario, the choice of medication route depends primarily on pharmacokinetic and pharmacy factors such as drug formulation. There is however a dearth of evidence regarding bisphosphonates in children, and controversy regarding dosing.The major effect of bisphosphonates is to decrease recruitment and function of osteoclasts and thereby reduce bone turnover. Bisphosphonates act via multiple mechanisms at the cellular and molecular level . The iniNoting the effectiveness in reducing bone turnover in a variety of adult conditions, bisphosphonates were then considered for use in children. Pamidronate is used routinely for children with Osteogenesis Imperfecta, given by IV. Since then bisphosphonate therapy has been trialed in a number of childhood diseases ,3. It shOur patient expressed a strong preference not to have an IV. The oral route was not considered to be reliable. He expressed no objection to a subcutaneous line, having already experienced subcutaneous infusions for chemotherapy and analgesia. We therefore explored this route of administration for bisphosphonates.We reviewed the literature on bisphosphonates [Medline 1966–2003] and engaged in email and telephone discussion with authors and expert clinicians in palliative medicine and pediatric endocrinology. . The evitcundy@auckland.ac.nz) 19 Jan 2004].The only published report of clodronate use in children was by Zacharin and Cundy who gave it by IV infusion to a child with a genetic bone disease, osteoporosis pseudoglioma syndrome . , to use in children. The recommendation to simply conduct more pediatric clinical trials is a laudable one. It raises, however, the many difficulties of conducting studies involving children with rare diseases. There are many hurdles involved in pediatric studies – recruitment, consent and achieving statistical power in small populations.One answer is for clinicians to develop the multi-centre networks required to answer questions regarding rare childhood conditions, especially at the end-of-life. A second is a reminder that when pediatric randomized trials are developed investigators should challenge themselves and ethical review boards to consider optimal designs, using randomized placebo-controlled trials where possible. A third suggestion is to consider the benefit of conducting and reporting n-of-1 trials. N-of-1 trials, which are single person, double-masked trials, can be combined to provide evidence of therapy. Lastly, when reporting new uses of old agents, authors should specifically demonstrate how they developed regimens even if based on weak evidence. This clarity will help other clinicians and researchers think more critically about developing further avenues for treatment and investigation.In conclusion this case report describes the use of subcutaneous clodronate for analgesia in a child with a bone tumour, with good results. It also describes the challenges and thought processes that clinicians frequently encounter in devising new empirical treatments for children.The author(s) declare that they have no competing interests.HS provided clinical care to the patient and wrote the manuscript.


The diagnosis of discogenic back pain often leads to spinal fusion surgery and may partly explain the recent rapid increase in lumbar fusion operations in the United States. Little is known about how patients undergoing lumbar fusion compare in preoperative physical and psychological function to patients who have degenerative discs, but receive only non-surgical care.Our group is implementing a multi-center prospective cohort study to compare patients with presumed discogenic pain who undergo lumbar fusion with those who have non-surgical care. We identify patients with predominant low back pain lasting at least six months, one or two-level disc degeneration confirmed by imaging, and a normal neurological exam. Patients are classified as surgical or non-surgical based on the treatment they receive during the six months following study enrollment.Three hundred patients discogenic low back pain will be followed in a prospective cohort study for two years. The primary outcome measure is the Modified Roland-Morris Disability Questionnaire at 24-months. We also evaluate several other dimensions of outcome, including pain, functional status, psychological distress, general well-being, and role disability.The primary aim of this prospective cohort study is to better define the outcomes of lumbar fusion for discogenic back pain as it is practiced in the United States. We additionally aim to identify characteristics that result in better patient selection for surgery. Potential predictors include demographics, work and disability compensation status, initial symptom severity and duration, imaging results, functional status, and psychological distress. Mechanical or chemical changes in degenerative intervertebral discs comprise a hypothesized cause of low back pain without sciatica or neurological deficits. This is commonly referred to as "discogenic" low back pain, and is distinct from a herniated disc causing sciatica. The diagnosis often leads to spinal fusion surgery and may partly explain the recent rapid increase in lumbar fusion operations in the United States (U.S.) ,2.A few randomized studies have examined outcomes of spinal fusion surgery compared to non-surgical treatment for discogenic pain; these suggest little or no advantage of surgery over carefully designed rehabilitation therapy -6. In onAlthough the concept of a painful disc causing back pain has merit on theoretical grounds, mechanical and chemical changes develop in all vertebral discs with aging. Clinical studies have not firmly established diagnostic criteria that distinguish patients with painful discs from others with normal aging. The distinction is often based on lumbar discography, itself a controversial procedure troubled with high rates of false positive results -12. ReseWe implemented a prospective cohort study to compare patients with presumed discogenic pain who undergo lumbar fusion with those who have non-surgical care. The study is intended to address several questions. First, are there differences in preoperative physical and psychological function between those having surgical versus non-surgical treatment? For example, do patients undergoing fusion for discogenic pain have greater preoperative psychological distress than patients not undergoing fusion? Secondly, how do treatment outcomes, including symptoms, functional status, return to work and subsequent surgery, differ between the two groups? Do the results support the conventional wisdom that outcomes improve more after fusion than after non-surgical care? A final study objective is to identify predictors of favorable outcomes of both surgical and non-surgical care for discogenic pain. Are there characteristics that predict a good response to surgical therapy, but not to non-surgical therapy? Such knowledge could result in better patient selection for surgery. Potential predictor characteristics include demographics, work and disability compensation status, initial symptom severity and duration, imaging results, functional status, and psychological distress.We designed a multi-center prospective cohort study of patients with presumed discogenic back pain. We will use follow-up assessments over two years to compare health outcomes between those who receive a spinal fusion versus those who receive other treatment. Important secondary analyses will include comparisons of those who have elective surgery and those who do not in terms of preoperative physical and psychological function and identification of patient characteristics that predict outcomes. The study protocol was approved by the University of Washington (U.W.) Human Subjects Division and all participants provide written informed consent.Patients are recruited from five orthopaedic clinics in the Puget Sound region of Washington State: the U.W. affiliated practice sites , Orthopaedics International , and Proliance Surgeons, Inc., P.S. . These practices include eleven surgeons who have referred patients to the study.We identify patients with predominant low back pain as a symptom, one or two-level disc degeneration confirmed by imaging, and a normal neurological exam. Because surgery for discogenic pain is rarely considered as initial therapy, we required patients to have pain lasting for at least six months. We did not require discography for diagnosis. Additional inclusion and exclusion criteria are listed in Table Patients are classified as surgical or non-surgical based on the treatment they receive during the six months following study enrollment. We use both patient interview and medical record information to determine whether patients have had surgery.Surgical details, including the type of procedure, levels operated, and surgical implants, are recorded from operative notes in the medical records. These details are important because there are several variations in surgical technique for spinal fusion for discogenic pain.Non-surgical treatment of patients with chronic low back pain and degenerative discs may include physical therapy, exercise, cognitive-behavioral therapy, medication, injection, transcutaneous electrical nerve stimulation, alternative treatments such as acupuncture and spinal manipulation, and intradiscal electrothermal therapy (IDET). The treatments patients receive are recorded both at baseline and at follow-up interviews.We conduct the baseline assessment in person and obtain the follow-up measures in telephone interviews at six, nine, twelve, and twenty-four months after enrollment. Also, after three months, we re-administer the baseline measures. For patients who have surgery late in the initial 6-month interval, this provides a more recent pre-surgical baseline for analysis.We evaluate several dimensions of outcome, including pain, functional status, general well-being, and role disability. The measures have been previously validated and have been recommended for standardized outcome assessment in back pain trials ,18. FurtThe Modified Roland Scale is the primary outcome measure. The original Roland-Morris Disability Questionnaire  was deriThe SF-36 Health Survey, Version 2  consistsStudy participants also complete the Symptom Check List-90 (SCL-90) 12-item somatization and 13-item depression scales . SubjectThe 13-item Pain Catastrophizing Scale  is used The baseline questionnaire also assesses demographics, pain , medical co-morbidity, back pain history, work status, and litigation/compensation issues. Problematic alcohol use is assessed by the first three items of the Alcohol Use Disorders Identification Test (AUDIT-C) . The AUDAlthough imaging is required for enrollment, not all imaging studies are accessible to the researchers . However, a majority of study participants have magnetic resonance imaging (MRI) scans that are available to the investigators. These images are interpreted by a neuroradiologist without knowledge of the patient's clinical history. The key imaging findings were defined as in the Longitudinal Assessment of Imaging and Disability for the Back and include T2 signal, spondylolisthesis, endplate Modic changes, disc height loss, disc morphology, annular tears, facet changes, and central and foraminal stenosis .All data are collected on paper forms, and then entered into a web-based data system requiring double entry to reduce transcription errors. Data checks to identify out-of-range answers, inconsistent responses, missing data, and response rates are performed on a monthly basis.In the primary analysis, the modified Roland Disability scale at 24 months will be compared between the surgical and non-surgical treatment arms using regression techniques to adjust for important baseline characteristics.Secondary analysis will include a comparison of pain, SF-36 scales, and psychological measures for the two treatment arms. To characterize time trends in the primary and secondary outcomes, we will use linear mixed models  to analyze the repeated measures obtained at all follow-up interviews. Finally, we will examine potential predictors of outcome, including baseline disability, psychological factors, and image findings. The goal will be to identify subgroups of patients who respond well to surgery but not to non-surgical therapy, or to non-surgical treatment but not surgery.The Maine cohort study  providedIn designing the study, we considered a randomized controlled trial (RCT), but chose an observational design for several reasons. First, the surgical treatments are already approved and in wide use, and physicians and patients often have strong preferences for either surgical or non-surgical care. Thus, genuine equipoise is rare among U.S. surgeons and patients. In fact, we attempted to enroll subjects in a pilot randomized trial and had no success. Second, randomized trials comparing surgery with non-surgical treatment have several features that are distinctly different from drug trials and result in serious limitations. If drugs cause side effects, they can be stopped and most ill effects will resolve. Surgery, however, has many irreversible features. Efforts to blind the treatment allocation require a sham surgical procedure, raising patient anxieties and ethical concerns. Without a sham surgical control, blinding is impossible. Unlike pills, which are essentially identical, no two surgical procedures are exactly the same. These features constrain the validity of surgical randomized trials in comparison to drug trials. Finally, we were interested in treatment outcomes as they occur in routine practice, rather than within the narrow constraints typically imposed in randomized trials. Thus, we chose to study treatment effectiveness in routine care, rather than efficacy under ideal circumstances. Though an RCT would provide the most valid data on efficacy, the prospective cohort design seemed substantially superior to uncontrolled case series, which remain the predominant study design in the surgical literature. Furthermore, when carefully designed, the results of cohort studies sometimes approximate the results of randomized trials ,33. The This study will contribute important new information on a highly controversial area of back pain treatment. Though it is not a randomized trial, we believe a rigorously designed and analyzed cohort study will improve our knowledge of both treatment effectiveness and safety in routine practice. The primary aim of this prospective cohort study is to better define the outcomes of lumbar fusion for discogenic back pain as it is practiced in the U.S. The results should help improve the selection criteria for surgical treatment, better define the prognosis after therapy, and improve our ability to match patients with optimal treatment approaches.The author(s) declare that they have no competing interests.RAD and SKM conceived of the study. RAD, BIM, SKM drafted the manuscript. PJH performed statistical analysis. All authors participated in the design of the study and coordination of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Mass-media campaigns have been known to modify the outcome of low back pain (LBP). We assessed the impact on outcome of standardized written information on LBP given to patients with acute LBP.Design: A 3-month pragmatic, multicenter controlled trial with geographic stratification. Setting: Primary care practice in France. Participants: 2752 patients with acute LBP. Intervention: An advice book on LBP (the “back book”). Main outcome measures: The main outcome measure was persistence of LBP three months after baseline evaluation.2337 (85%) patients were assessed at follow-up and 12.4% of participants reported persistent LBP. The absolute risk reduction of reporting persistent back pain in the intervention group was 3.6% lower than in the control group . Patients in the intervention group were more satisfied than those in the control group with the information they received about physical activities, when to consult their physician, and how to prevent a new episode of LBP. However, the number of patients who had taken sick leave was similar, as was the mean sick-leave duration, in both arms, and, among patients with persistent pain at follow-up, the intervention and control groups did not differ in disability or fear-avoidance beliefs.The level of improvement of an information booklet is modest, but the cost and complexity of the intervention is minimal. Therefore, the implications and generalizability of this intervention are substantial.NCT00343057ClinicalTrials.gov  About 60% of the population is concerned with low back pain (LBP) in Western industrialized countries Psychosocial factors have been shown to be associated with the development of disability with cLBP Several guidelines and reviews on the management of acute LBP and cLBP in primary care practice are available Information booklets, the lowest-cost information tools, have been developed to help health care providers inform and educate patients. Among these booklets The aim of this study was to assess the impact of the “back book” on outcome (persistence of pain at 3 months) in acute LBP in a French national sample of patients in a primary care setting.The protocol for this trial and supporting CONSORT checklist are available as supporting information; see We conducted a 3-month prospective, controlled study with a quasi-experimental design . Control and intervention areas were selected for their similarities in rural-to-urban distribution of the population and patients' access to GPs and to minimize risk of overlap between areas.A total of 60 GPs per geographic area were selected at random from a national database (Logimed) according to a computerized allocation Each GP had to enrol up to 4 consecutive patients with acute LBP. Patients were excluded if they (a) were less than 18 years old; (b) had pain for more than 4 weeks; (c) had pain intensity for the previous 24 hours less than 3 on a 11-point numeric scale ; (d) had sciatica; (e) had had a previous episode of acute LBP during the last 12 months; (f)did not work; (h) had consulted another practitioner for the same episode of back pain; (i) were pregnant; (j) had back pain related to infection, tumor, or inflammatory disease; or (k) had previously undergone back surgery.The study protocol was approved by the Commission Nationale Informatique et Liberté and the French National Medical Council . The study was conducted in compliance with the protocol Good Clinical Practices and Declaration of Helsinki principles. In accordance with the French national law, GPs and patients gave their written consent to participate after being informed about the study protocol.At baseline, all patients received medical care and oral information as usually provided by GPs. In the intervention group, all patients also received the “back book.”To assess persistence of LBP 3 months after baseline evaluation, patients were asked to answer Yes or No to the question “Has your low back pain persisted since the first visit to your GP 3 months ago?” Patients answering Yes were considered as having persistent back pain.Parts 1, 2, and 3 of the physician self-administered questionnaire completed at baseline concerned demographic data (age and sex), professional data (years of practice and exclusively private or public/private practice) and personal history of LBP , and self-limitation of physical activities for LBP , respectively. Part 4 dealt with GPs' formation of practice and practice for LBP: participation in an educational session on LBP in the last 3 years (yes/no); mean length of sick leave prescription for acute LBP if needed , advice about physical activities during sick leave for acute LBP . Part 5 assessed GPs' fears, avoidance attitudes and beliefs on the Fear-Avoidance Beliefs Questionnaire (FABQ)Baseline data were collected during the first visit to GPs. Patients were interviewed about pain intensity , physical demand of occupational activities , education level , presence of LBP in parents (yes/no), length of back pain (days), work-related back pain (yes/no), sport activities , medication intake for the previous week , pain intensity for the last 48 hours , and handicap level for activities of daily living . Self-rated disability was assessed on the Quebec questionnaire  At baseline, an appointment for a follow-up visit with the GP was established for the patient. Follow-up data were recorded during this visit to the GP (77% of patients) or by phone interviews (23% of patients), conducted by trained research assistants for patients who did not consult their physician. Patients were asked about persistence of LBP since the baseline evaluation (yes/no); whether radiography, computed tomography (CT), or magnetic resonance imaging had been performed (yes/no); sick leave since baseline evaluation (yes/no); sick leave duration (days); return to work (yes/no); and satisfaction with information received about physical activities, when to see a doctor, how to use medications, and how to prevent new episodes of LBP . For patients with persistent LBP, pain intensity, level of handicap, perceived disability, anxiety and depression, and LBP beliefs were recorded as during the baseline evaluation.Persistent LBP after an acute episode has previously been reported to occur in 7% of patients in France t-test. To take into account the cluster effect (patients are clustered within physician), the primary outcome (persistent pain) was also analysed in the framework of a generalized estimation equation (GEE) regression model, with the physician considered as a random effect. The same procedure was applied to assess the impact of the “back book” on the secondary outcomes.The impact of the “back book” intervention was assessed by comparing the proportions of patients with persistent LBP after 3 months who had been exposed to the “back book” and those who had not been exposed. Qualitative outcomes were compared by chi-square test and quantitative outcomes by The analysis was per protocol. We performed 2 intention-to-treat analyses. In the first analysis, we considered all patients lost to follow-up as having persistent pain at 3 months. In the second, we considered all patients lost to follow-up as having no persistent pain at 3 months.Data analyses involved use of SAS .The Logimed database contains information on 20 184 GPs. A total of 60 GPs per geographic area were selected at random from the database and asked to participate, with 1013 GPs agreeing to participate. Of these, 88% returned their questionnaires, and 709 (70%) included at least 1 patient . Among tA total of 2752 patients met the inclusion criteria, and 2337 (82.6%)  were assessed at follow-up. At baseline, patients lost to follow-up did not differ from those assessed at 3 months in terms of age, gender, pain and handicap levels, sport activities, education level, disability, and beliefs . The numPatients  and GPs At 3-month follow-up, 12.4% of participants reported persistent LBP. In the intervention group, the proportion of patients experiencing persistent back pain was lower than in the control group  . The outFor intention-to-treat analysis on the main outcome measure, we used sensitivity analysis on the primary outcome by considering two extreme scenarios . In the first scenario, we considered that all patients lost to follow-up had persistent back pain at 3 months. The proportion of patients reporting persistent back pain at 3 months was lower in the intervention than in the control group, but the difference was not significant . However, for this scenario, the power of the test to detect a statistically significant difference was only 25%. In the second scenario, we considered that all patients lost to follow-up had no persistent back pain at 3 months. The proportion of patients reporting persistent back pain was lower in the intervention than in the control group, but the difference was significant . For this scenario, the power of the test was 70%.Among patients with persistent pain at follow-up, the intervention and control groups did not differ in disability  or fear-avoidance beliefs .Our results suggest that providing the “back book” to patients consulting their GPs for acute LBP can reduce the proportion of patients reporting persistent pain at 3 months by 3.6% as compared with patients who did not receive the book. Previous studies have demonstrated a positive impact of such books for patients The “back book” may have several other positive effects. We observed a decrease of NSAID and myo-relaxant but not analgesic intake in the intervention group. This observation is not surprising, since advice about pain medications in this booklet recommends grade I analgesics, especially paracetamol. The other positive effect was patients' satisfaction with information. Most of patients' complaints and claims about medical procedures relate to lack of information However, overall the “back book” had no effect on the other main back-pain outcomes: the number of sick leaves taken or sick-leave duration and perceived disability in patients reporting persistent pain. This observation had already been observed after occupational low back injury The “back book” also had no effect on the rate of prescriptions to undergo spine imaging. Almost 29% of patients underwent plain radiography and 8% CT. Thus, GPs are not following guidelines Finally, the effects of the “back book” may be underestimated in this study, since GPs in the control group knew that the trial assessed the impact of information on patients with LBP and may have followed the guidelines more closely than under real-life conditions.Another important result is the high proportion of patients reporting persistent pain after 3 months in the control group. This proportion probably differs among countries Randomized controlled trials are widely accepted as the criterion standard in assessing the effectiveness of specific therapies The main analysis was conducted on a per protocol population. However, the proportion of patients lost to follow-up (15%) is acceptable and was similar in both arms. Moreover, patients lost to follow-up did not differ from those evaluated at 3 months in terms of baseline characteristics. Finally, to provide data on an intention-to-treat basis, we conducted a sensitivity analysis using two scenarios (worst and best-case imputation), which were highly unrealistic.Another possible limitation is that 2 procedures were used to record data at follow-up: visits to GPs and phone interviews. Phone interviews were used to decrease the number of patients lost to follow-up and were conducted by a trained research assistant. Outcome measures were easy to record by phone and the proportion of patients for whom data were collected by phone did not differ between the control and intervention groups. The difference in proportion of patients with persistent pain between phone and face-to-face interviews is probably a result of patient improvement. The patients without persistent pain were less likely to visit their doctors at 3 months than patients with persistent pain.Only patients reporting persistent pain were reassessed at 3-month follow-up, which limits the ability of this study to detect effects of the intervention on outcome measures that may influence back-pain recurrence such as disability and fear-avoidance beliefs.Finally, the sample size calculation did not take into account the cluster effect, which resulted in a lower power of our study, but which has no impact since the study results were positive.Low-tech and easy-to-disseminate interventions have enormous promise in LBP interventions. The level of improvement described in this study is modest, but the cost and complexity of the intervention is minimal. Therefore, the implications and generalizability of this intervention are substantial.Checklist S1CONSORT Checklist(0.04 MB DOC)Click here for additional data file.Protocol S1Trial protocol(2.15 MB PDF)Click here for additional data file.Alternate Language Abstract S1Translation of the abstract into French by Serge Poiraudeau(0.02 MB DOC)Click here for additional data file.


To describe the evaluation, treatment, management and referral of two patients with back pain with an eventual malignant etiology, who were first thought to have a non-organic biomechanical disorder.The study was a retrospective review of the clinical course of two patients seen by a chiropractor in a multi-disciplinary outpatient facility, who presented with what was thought to be non-organic biomechanical spine pain. Clinical examination by both medical and chiropractic physicians did not indicate the need for radiography in the early course of management of either patient. Upon subsequent re-evaluation, it was decided that certain clinical factors required investigation with advanced imaging.In one instance, the patient responded to conservative care of low back pain for nine weeks, after which she developed severe pain in the pelvis. In the second case, the patient presented with signs and symptoms consistent with uncomplicated musculoskeletal pain that failed to respond to a course of conservative care. He was referred for medical therapy which also failed to relieve his pain. In both patients, malignancy was eventually discovered with magnetic resonance imaging and both patients are now deceased, resulting in an inability to obtain informed consent for the publication of this manuscript.In these two cases, the prudent use of diagnostic plain film radiography did not significantly alter the appropriate long-term management of patients with neuromusculoskeletal signs and symptoms. The judicious use of magnetic resonance imaging was an effective procedure when investigating recalcitrant neuromusculoskeletal pain in these two patients. Neuromusculoskeletal (NMS) complaints are one of the most common reasons for physician visits around the world. In addition, nearly all patients who visit doctors of chiropractic present with neuromusculoskeletal complaints.  Most of Plain film radiography is a staple diagnostic test in the evaluation of spine pain, with patients often being x-rayed on the initial visit, and occasionally re-x-rayed as a follow up procedure. In particular, chiropractors often take radiographs for medico-legal reasons and for use as a screening tool.  The rateManaging low back pain (LBP) is a costly endeavor. An important contributor to the high cost is the use of radiography for assessing patients with acute LBP. In the United States, the annual cost of radiography of the low back was estimated at $500 million in 1991.  InterestPotential risks associated with spine radiography have also been identified. Because of the close proximity of the reproductive organs for example, lumbar spine radiography results in one of the highest cumulative doses of radiation to the gonads.  This expDespite these findings, the majority of doctors of chiropractic say that they would utilize radiography in patients with uncomplicated back pain without the presence of red flags such as high fever and the like. ,16 Some No diagnostic test should be ordered unless there is a strong likelihood that the results of that test, either positive or negative, will have an impact on the treatment or prognosis for a patient.For these varied reasons, diagnostic radiography in the management of spine pain should be used judiciously and it should be based on best practices information. Best practices is a process, which includes an oft-updated document, that reviews the current evidence regarding clinical procedures and helps the clinician provide the best care available to patients by accurately interpreting that evidence and making those interpretations available to clinicians in a readily useable format.This retrospective case review outlines two cases where best practices were used in the decision making process regarding radiography of the spine in patients presenting to a chiropractor in a multi-disciplinary practice setting. In both cases, the patients were eventually diagnosed with malignancy, but the initial decision to not perform radiography did not have a substantial negative impact on these patients' clinical outcomes.One author (RKP) retrospectively reviewed the charts, and both authors as well as a staff radiologist at the facility where the patient was seen, reviewed the diagnostic imaging studies, of two patients who were treated for spine pain in a multi-disciplinary outpatient clinic in Houston, Texas in 2003. There was no attempt at randomization. The patients were a 54-year old African American female and a 55-year old Caucasian male. Both patients were referred to the staff chiropractor at the facility by medical physicians for the management of back pain and related symptoms.Inclusion criteria for patients to be incorporated in this analysis were clinical signs and symptoms of pain that were initially thought to be biomechanical in origin, but where the patient was eventually found to have a malignancy in the general region of the initial complaints. The malignancy did not have to be responsible for the patient's initial complaints, however.The patients reported upon in this manuscript are now deceased and their consent to publish this report could therefore not be obtained.High-velocity low-amplitude (HVLA) manipulation along with along with various physical medicine procedures and therapeutic exercise was the management regimen used in these patients. The course of chiropractic care was nine weeks for the 54-year old female patient and four weeks for the 55-year old male. Each patient was seen 1–2 times per week during the course of care.The patients in this retrospective case series were treated with HVLA manipulation and other physical medicine interventions. The patients in this cohort were not subjected to any additional, non-routine clinical procedures as part of the chiropractic management protocol. The male patient did have trigger point injections into several intercostal muscles after failing to respond to the care provided by the chiropractor.Outcomes were based on improvement in clinical signs and symptoms, as well as the need for future intervention. Outcomes were classified into 3 categories: significant improvement, moderate improvement, and no change.Significant improvement was defined by at least a 90% resolution of the pain syndrome, based on pre and post treatment visual analog scale (VAS) (0–100) measures and with the ability to perform all normal activities of daily living (ADL) after care, as reported by the patient. Such patients would require no further conservative or surgical intervention. Moderate improvement was defined as between a 50–90% reduction of the pain syndrome, as measured by the difference between pre and post treatment VAS scores. In addition, such improvement would include only mild restriction in ADLs after care, as reported by the patient. The need for further conservative care was warranted, but no surgical intervention was required. A patient who did not exhibit at least a 50% improvement was placed in the no change category. The presence of any adverse side-effects resulting from the therapy prescribed in these cases was based on review of the patients' clinical records.Each patient was treated with HVLA manipulation, spray and stretch, massage and therapeutic exercise. The female patient was treated in the lumbar spine with lateral decubitus manipulation and the male patient was treated with prone manipulation of the thoracic spine.Each patient initially responded positively to therapy, including a decrease in VAS scores and increased subjective functionality as measured by increases in the ability to perform normal ADLs.The first patient was referred by her primary care physician for evaluation and management of non-organic biomechanical low back pain after a course of NSAIDs and pain medications. She had had moderate pain that was persistent for several months before admission. She demonstrated significant improvement with two weeks of chiropractic care as measured by progressively decreasing VAS scores. After the initial course of care which consisted of HVLA and continuous flexion distraction, she began having increasing low back and pelvic pain. The pain was different than at initial presentation and she appeared ill/gaunt. At this time, she also reported to the chiropractor managing her case that she had noted a 23 pound weight loss within the previous month.Plain film radiographs were obtained and read as normal. Figure In the second case, the male presented with mid-back pain in the peri-scapular area bilaterally and without any radiating symptoms. An initial 6-week course of treatment resulted in no change by measure of VAS scores and his ability to perform normal ADLs. He had previously been treated with HVLA for similar pain, which had resolved his complaints.However, he returned after two months with the similar mid-back pain and now, pain along the mid-right anterior-axillary line. The anterior-axillary pain was new, more severe as measured subjectively and with VAS, respectively. Based upon follow up examination he was referred for trigger point injections and was examined and treated by a physical medicine and rehabilitation (PMR) physician. His examination included chest film radiographs and treatment was focused in intercostals trigger point injections.His chest film was read as normal. Figure He returned after re-evaluation and treatment by the PMR physician. He now had posterior chest wall/rib pain at the 5–8 ribs on the right. A thoracic spine MRI was ordered to evaluate for the possible presence of soft tissue and/or disk injuries, whereupon high signal intensity lesions of the spine and ribs were discovered. Figure Current guidelines and best practices initiatives suggest that radiography in patients with apparently uncomplicated/non-organic biomechanical back pain without "red flags" is not indicated. The initial work-up of patients in these circumstances includes a complete history and physical examination. The Agency for Health Care Policy and Research(AHCPR), now called the Agency for Healthcare Research and Quality, published guidelines for the workup of patients with back pain.  They sugDeyo and Diehl suggested a number of indications for radiography in patients with low back pain, which differ from the AHCPR Guidelines.  Their suThe number, sequence and type of standard views for an examination should be problem-oriented and have clinical efficacy in terms of impact on treatment or prognosis. ,20 A patIn the first patient presenting with spine pain in this case series, her initial response was quite favorable. It was not until she began to demonstrate red flag signs  that radiographs were performed. Those radiographs were normal. It was decided that with the presence of such significant red flag signs that she should undergo advanced imaging, in this case an MRI, that revealed an underlying malignancy, which was likely not the primary cause of her initial back pain, which responded to conservative care as outlined above. A best practices approach was utilized in this patient and had no substantial negative effect on her outcome.In the second case, the gentleman presented with, what appeared to be to the medical and chiropractic doctors, non-organic biomechanical pain in the thoracic spine. Radiography was not initially performed. It was not until the patient failed to respond to conservative care that radiography was performed and, in this case was interpreted as normal. The patient again failed to respond to a different course of conservative care, whereupon MRI was performed. Once again, a best practices approach was utilized and did not adversely affect the outcome for this patient.Very often, apparently otherwise healthy patients present to doctors of chiropractic with neuromusculoskeletal symptoms that appear to be non-organic biomechanical or uncomplicated in etiology. Often, as a part of the initial workup of these patients, plain film radiography is performed and many times, as was the case in the two patients in this case series, the plain films are interpreted as being normal.In a study designed to assess the use of radiography, Harger, et.al. discovered that 74% of the chiropractors have radiographic facilities in their offices. The most common reasons listed for performing radiography included contraindication to manipulation screening (71%), pathological diagnosis 63%), biomechanics and posture 51%) and medicolegal protection (27%). [%, biomec1% and mePhysicians often suggest that screening for serious pathology is an acceptable reason for performing radiographs on most all, if not all patients, who present with spine pain. Finding an occult malignancy is an oft cited reason for this practice. Deyo and Diehl evaluated 1,975 walk-in patients with back pain. Of those patients, 13 (0.66%) eventually were diagnosed with malignancy as the cause of their back pain. Age of 50 years or greater, previous history of cancer, failure to improve within one month and anemia were some of the primary findings that were associated with malignancy in their patient cohort. They developed a diagnostic algorithm that combined history and physical examination findings with erythrocyte sedimentation rate that would have reduced the percentage of patients who were radiographed to 22%, while still uncovering all of the malignancies in their patients. In some patients, as was the case in this investigation, plain film radiographs are normal when there may be an underlying aggressive pathology. Deyo and Diehl suggest that in patients who have negative radiographs, but in whom the findings noted above are seen, further workup, including advanced imaging, would be worthwhile.  In our tEven in light of rising health care costs, some providers suggest that patients who have back pain expect radiography as a part of the clinical services provided by physicians. Deyo, et. al. examined the psychological, functional, and financial consequences of omitting spine films for patients with back pain where the patients had only minimal risk of having underlying aggressive disease. Their patients were divided into two groups. One group received immediate radiography of the area of chief complaint upon admission and the other group received a brief educational intervention about back pain and radiography. Radiography would only be performed on patients in the second group for failure to improve. Initially, 73% of the group who had immediate radiography believed that people with back pain should have an x-ray, while only 44% of the education group had the same thoughts. After three months, only 31% of those patients in the education group had received radiography. Radiology charges in the second group were still far less than those of the group with immediate radiography. Of particular importance is the fact that no aggressive spinal disease was missed, and outcomes for the two groups were the same. They conclude that, "eliminating or delaying spine films need not cause anxiety, dissatisfaction, or dysfunction. This strategy may modify future expectations of roentgenography use and reduce health care costs."  KendrickIn these two cases, standard evidence-based medicine guidelines and best practices were utilized in making clinical decisions about the care for these patients, without any unwanted or adverse side effects. Although both patients were eventually diagnosed with malignancy, this approach did not significantly alter the appropriate long-term management of these patients who presented to a chiropractor with neuromusculoskeletal signs and symptoms. Interestingly, manipulation provided some positive outcomes in these patients, suggesting that these patients had both uncomplicated/non-organic biomechanical spine pain along with malignancies. In both cases, plain film radiographs were initially thought to be of little help, as there was a low index of suspicion for cancer. Plain film radiographs were eventually obtained and were essentially normal without indication of malignancy in either case.The judicious use of MRI was an effective procedure when investigating recalcitrant neuromusculoskeletal pain in the patients in our series.The author(s) declare that they have no competing interests.RKP conceived of the study, and participated in its design and coordination and helped to draft the manuscript. LHW participated in the study design and records review, helped to draft the manuscript, and was the corresponding author. Both authors read and approved the final manuscript.


People are using the Internet as a method of getting medical advice. Some Web sites include the email addresses of physicians, and some people are contacting these physicians for advice. As many patients undergo surgery on a "day surgery" basis, they often have no opportunity to ask anesthesiologists for advice before surgery; these patients may be more likely than other groups to use Internet email to ask questions. It seemed that it would be useful to find out what, if any, advice anesthesiologists would give in response to email from an unknown patient.To determine how anesthesiologists would respond to an email requesting advice about an anesthetic problem from an unknown patient.In February 1998, an email message was sent from a fictitious patient, using an email address created for this study, to 115 anesthesiologists whose email addresses were found on publicly accessible web sites. The message described the patient's problem with a previously administered anesthetic and requested advice about anesthesia for upcoming surgery. Responses were entered in a database and analyzed to determine the percentage of anesthesiologists who responded, and how helpful, accurate, and complete their advice was.Fifty-eight responses were obtained from 108 valid email addresses (54% response rate). Of these, 78% were received within 48 hours. Eighty-three percent (83%) of respondents suggested contacting a local physician, 62% mentioned reviewing the old chart, and 41% suggested a specific diagnosis. None of the initial replies contained inaccurate advice, but only five responses were considered to be comprehensive. Ten percent (10%) included a disclaimer with the response. Eighty-three percent (83%) of replies were subjectively assessed as being friendly in tone.At present, patients who email an unknown anesthesiologist can expect to get a reply from over half. The advice is likely to be prompt, friendly, and to provide accurate and appropriate - but probably incomplete - advice. Kuszler, MD, JD, has been published in this issue.Note: An accompanying editorial,                             Many patients are using the Internet as a source of medical information. Mainstream publications, such as "Consumers Reports" are teaching the public how to use the Web, Internet mailing lists, and email to get medical information and advice from the Internet .New methods of communication between doctors and the public give rise to new practical, ethical, moral, and legal issues . There aOne study published in the lay press  investigThis study involved sending email to physicians who have published an email address on a web site, but have not specifically requested email from patients. In a similar study, it was found that 18 out of 56 dermatologists were willing to offer a diagnosis for an unknown patient via email , it seemHotMail. An email message asking for advice about an anesthetic problem was created, based on an actual email the author had received from a patient. In this message [see To determine the response a patient would get from sending an email request for advice to an anesthesiologist, a fictitious patient email address was set up using sage see  the patiGASNet, the Anesthesiology section of The Mining Company(now About.com), and Anesthesia and Critical Care Resources on the Internet. Pages were searched for the "@" sign. Where the context made it clear that this was an anesthesiologist's email address, the address was used. Responses were read and analyzed for the presence or absence of certain types of statements, such as a disclaimer of responsibility, a diagnosis, specific points of advice, or suggested course of action. Data was entered into an EpiInfo 6.0 database [The message was sent in February 1998 to 115 anesthesiologists whose email addresses were published on publicly accessible web sites. The addresses were found by searching English-language web pages listed at major anesthesia sites such as A follow up message was sent to each responding anesthesiologist eight to ten days later, stating that the patient had been diagnosed with pseudocholinesterase deficiency and had had a successful anesthetic avoiding the use of succinylcholine see .Dear Doctor:I would appreciate your advice about an anesthesia problem.When I had my appendix out, I had to be put on a breathing machine after surgery. I was told this was because of a problem with the way my body handles anesthetic drugs.Now I need surgery on my gall bladder and I am worried about the anesthetic. Can you give me any advice?Thank you,John WilkinsonDear Doctor:Thanks for your reply to my request for anesthetic advice.I thought you would like to know that a blood test showed I lacked an enzyme called "pseudocholinesterase" which makes me sensitive to "succinylcholine".My anesthetist used a different drug and everything went fine.Thanks again,John WilkinsonThe results are summarized in Six respondents declined to give an opinion without more information. Ten asked "Who are you?", and six asked "Where are you?". Ten asked specific clinical questions, and seven invited further correspondence, including one who gave a fax number to which the patient's physician could forward the old medical record.Forty-eight respondents (83% of replies) suggested the need to consult a physician. Forty-seven suggested an anesthetic consult, and five suggested contacting the family doctor. Fifteen responses stressed the need to arrange an early preoperative consultation. Thirty-six responses (62% of replies) mentioned the need to review the old chart.Twenty-four responses (41% of replies) suggested a specific diagnosis. Of these, 88% mentioned succinylcholine, 67% specifically suggested avoiding succinylcholine, 58% suggested a blood test, 50% suggested other possible diagnoses, and 33% suggested that this could be a genetic problem.Ten percent of respondents prefaced their remarks with a disclaimer, and one said that it was inappropriate to seek medical advice by email. None referred the patient to another resource, such as a web page or a journal article. Twenty-six (45%) of respondents offered reassurance that the problem could be dealt with safely. None of the initial replies contained inaccurate or inappropriate medical advice.Only five of the responses were comprehensive, including the probable diagnosis, a mention of familial involvement, the possibility of a blood test, the need for an anesthetic consult, and the recommendation to avoid succinylcholine. The overall tone of the messages was subjectively assessed as being unfriendly in 3%, neutral in 14%, friendly in 78% and very friendly in 5% of replies.A second email was sent to the 58 respondents, reporting the successful outcome of the surgery. This generated 26 responses (45%). Responses included: "Glad to hear all went well" (15 responses); "Document problem/tell others" (9); "Consider a MedicAlert bracelet" (7); "Thanks for letting me know" (5); "Beware of Mivacurium as well as succinylcholine" (4); "Have family members tested" (4); "It is not a problem now that it is diagnosed" (4); and "Avoid Atracurium" (1). This last was the only false piece of advice in any response to the survey.As the public becomes more aware of medical resources on the Internet, some patients are emailing unknown physicians to request medical advice. This produces an ethical and legal dilemma, as the recipient of the message has to balance a natural and desirable human response to offer help to someone who has a problem against the medical, legal, and ethical pitfalls of providing advice to an unknown person, without access to the past medical history, a physical examination, or laboratory data . UsuallyA recent survey of dermatology web sites revealed that 24% attempted to answer patients' questions individually, 27% did not usually respond and 24% usually sent a form letter . As partIn the current study, just over half (54%) of anesthesiologists responded to the email request, and of these 41% suggested a specific diagnosis. Only a minority were concerned enough to add a disclaimer to their comments. They provided advice which was timely and appropriate, in a friendly manner, but which was rarely complete. From a patient's perspective, emailing an unknown anesthesiologist for advice about an anesthetic problem appears to be a useful way of acquiring information, even if the majority of responses included the suggestion of consulting a local anesthesiologist and having him/her review the old chart.It is estimated that 28 million people undergo surgery each year in the USA alone . Many ofIdeally, patients seeking advice about anesthesia should be able to contact a local anesthesiologist in person, so that the situation can be reviewed in conjunction with medical records and laboratory data. Email may be appropriate for follow up, for example for the patient to provide extra details, or for the anesthesiologist to forward laboratory results. However, some patients are likely to want second opinions, or to ask advice of someone assumed to be an expert in a specific field (such as the author of a relevant web page). This survey suggests that if they do so, they stand a reasonable chance of getting a prompt, friendly reply, which is likely to be valid, but may be incomplete.


Shoulder pain is common in primary care, and has an unfavourable outcome in many patients. Information on the costs associated with health care use and loss of productivity in patients with shoulder pain is very scarce. The objective of this study was to determine shoulder pain related costs during the 6 months after first consultation in general practiceA prospective cohort study consisting of 587 patients with a new episode of shoulder pain was conducted with a follow-up period of 6 months. Data on costs were collected by means of a cost diary during 6 months.84% of the patients completed all cost diaries. The mean consumption of direct health care and non-health related care was low. During 6 months after first consultation for shoulder pain, the mean total costs a patient generated were €689. Almost 50% of this total concerned indirect costs, caused by sick leave from paid work. A small proportion (12%) of the population generated 74% of the total costs.The total costs in the 6 months after first consultation for shoulder pain in primary care, mostly generated by a small part of the population, are not alarmingly high. Shoulder pain is common with a one-year prevalence ranging between 5% and 47%-6. The pMusculoskeletal disorders are the second most expensive disease group for health care costs in the Netherlands, and represent 6% of the total healthcare costs . InformaWe performed a cohort study among patients who presented shoulder pain to their general practitioner, and followed them for 6 months. Our objective was to determine the shoulder pain related costs during the 6 months following first consultation for their complaints in general practice.Between January 2001 and June 2003, 103 general practitioners (GPs) recruited patients at first consultation for a new episode of shoulder complaints in three geographic areas in the Netherlands .In this study shoulder pain was defined according to the 1999 version of the Dutch guidelines for shoulder complaints, issued by the Dutch College of General Practitioners ,15. ShouPatients were selected if they were older than 18 years of age, and had not consulted their GP or received any form of treatment for the afflicted shoulder in the preceding three months. Sufficient knowledge of the Dutch language was required to complete written questionnaires. Exclusion criteria were severe physical or psychological conditions .The participating GPs were educated and trained to apply treatment according to the 1999 version of the Dutch guidelines for shoulder disorders issued by the Dutch College of General Practitioners,15. The Cost data were collected from a societal perspective, using a cost diary that has been shown to be valid and feasible for patient completion . The diaWe compared the baseline characteristics of patients who completed all cost diaries with those who did not and analysed possible differences using multiple logistic regression analysis. Health care consumption for shoulder pain and associated costs are presented in tables, for three time periods separately: short-term (1–6 weeks), intermediate term (7–12 weeks), and long-term follow-up (13–26 weeks). The arithmetic mean, standard deviations, maximum value (only for consumption) were computed for direct , and indirect costs. Despite the skewness in the distribution of costs, it is the arithmetic mean that is the most informative measure for health care policy makers ,21. MeasThe study was approved by the Medical Ethics Committee of the VU University Medical Center, Amsterdam, the Netherlands.A total of 587 patients were included in the cohort study. A total of 95 patients did not return one or more of their cost diaries. A multiple logistic regression analysis showed that patients with incomplete cost data were significantly (p < 0.10) younger (46 years versus 52 years) and had more concomitant neck pain (38% versus 35%). The results of this study were based on the 492 patients (84%) who completed all five cost diaries. Table Health care consumption and sick leave are presented in Table The mean costs and standard deviations are presented in Table Figure The present study is the first to evaluate the overall costs generated by patients presenting with shoulder pain in primary care. Healthcare consumption and sick leave did not seem to be alarmingly high in this primary care population with mean total costs of €689 per patient during the 6 months after first consultation. A small part (12%) of the population accounted for 74% of the total costs.The response rate was high (84%) and differences at baseline between completers  and non-completers (<5 cost diaries) were small. We expect that the differences in age and concomitant neck pain between completers and non-completers will not have substantially influenced our cost estimates.There was a high percentage of patients who reported persistent symptoms after 6 weeks (70%) and 6 months (46%) in this population . These rAn explanation for the modest health care costs could be that general practitioners stick to the interventions recommended in the Dutch guidelines for shoulder disorders ,15  -9 in genThe author(s) declare that they have no competing interests.TK carried out the analysis and drafted the manuscript. MWT participated in the design and drafting of the study. GJH participated in the design and drafting of the study. LMB participated in the design and drafting of the study. DAW participated in the design and drafting of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Opioid misuse can complicate chronic pain management, and the non-medical use of opioids is a growing public health problem. The incidence and risk factors for opioid misuse in patients with chronic pain, however, have not been well characterized. We conducted a prospective cohort study to determine the one-year incidence and predictors of opioid misuse among patients enrolled in a chronic pain disease management program within an academic internal medicine practice.One-hundred and ninety-six opioid-treated patients with chronic, non-cancer pain of at least three months duration were monitored for opioid misuse at pre-defined intervals. Opioid misuse was defined as: 1. Negative urine toxicological screen (UTS) for prescribed opioids; 2. UTS positive for opioids or controlled substances not prescribed by our practice; 3. Evidence of procurement of opioids from multiple providers; 4. Diversion of opioids; 5. Prescription forgery; or 6. Stimulants (cocaine or amphetamines) on UTS.The mean patient age was 52 years, 55% were male, and 75% were white. Sixty-two of 196 (32%) patients committed opioid misuse. Detection of cocaine or amphetamines on UTS was the most common form of misuse (40.3% of misusers). In bivariate analysis, misusers were more likely than non-misusers to be younger , male , have past alcohol abuse , past cocaine abuse , or have a previous drug or DUI conviction . In multivariate analyses, age, past cocaine abuse , drug or DUI conviction , and a past alcohol abuse  persisted as predictors of misuse. Race, income, education, depression score, disability score, pain score, and literacy were not associated with misuse. No relationship between pain scores and misuse emerged.Opioid misuse occurred frequently in chronic pain patients in a pain management program within an academic primary care practice. Patients with a history of alcohol or cocaine abuse and alcohol or drug related convictions should be carefully evaluated and followed for signs of misuse if opioids are prescribed. Structured monitoring for opioid misuse can potentially ensure the appropriate use of opioids in chronic pain management and mitigate adverse public health effects of diversion. The past decade and a half has witnessed an expansion of opioid analgesic use for patients who have chronic non-cancer pain -5. The mChronic pain is recognized as another important public health problem that is often undertreated ,15,16. EThe incidence and prevalence of opioid misuse in patients treated for chronic pain is unclear and remains a topic of debate. Little is known about the factors predisposing patients to opioid misuse in the outpatient setting. Although histories of drug or alcohol abuse are commonly accepted proxies for patients at risk for opioid abuse , few epiWe sought to determine the one-year incidence and predictors of opioid misuse in a cohort of patients enrolled in a chronic pain disease management program within an academic general internal medicine practice.This study was conducted in patients with chronic pain who were referred to a chronic pain disease management program within an academic internal medicine practice . PatientAt enrollment, patients signed a medication agreement at enrollment , specify• To receive O/CS only from this practice.• To use a single pharmacy.• Not to sell or share medication.• Not to abuse alcohol or illicit drugs (e.g. cocaine).• That lost, stolen, or misplaced medication would generally not be replaced and that consideration of replacement would only occur at a clinic visit.• That requests for medication renewals would occur only during regular clinic business hours, and not by telephone request.• That regular urine toxicological screens would be performed, and• That background checks for criminal drug and alcohol convictions would be performed.As stipulated in the medication agreement, we prospectively monitored for misuse through clinical history, review of medications, review of outside medical records, communication with pharmacies and providers, and urine toxicological screening (UTS) ,34. PresWe defined opioid misuse prospectively as any of the following:1. Negative UTS: Defined as UTS negative on at least two occasions for prescribed O/CS in the context of a reported history that the patient was taking the medication as prescribed (Repeatedly "negative" urines were considered an indicator of possible diversion)2. Inconsistent UTS: Defined as UTS positive on at least two occasions for O/CS medications not prescribed by our practice3. Doctor collecting: Evidence of concurrent procurement of O/CS from multiple providers4. Diversion of O/CS5. Prescription forgery6. Stimulant positive (cocaine or amphetamine) UTS: Evidence of cocaine or amphetamines in the urine while being prescribed opioids was considered opioid misuse because it was in violation of the patient's medication agreement and because concurrent use of cocaine and amphetamines was felt to increase the risk of diversion in order to procure additional stimulants.opiate assay has greater sensitivity and specificity for morphine and codeine, the presence or absence  of other opiates  were also confirmed by GC/MS. All positive results for amphetamines were confirmed with GC/MS to exclude the possibility of assay interference from other medications [Urine toxicology screening included immunoassays for opiates, amphetamines, cannabinoids, benzodiazepines, methadone, propoxyphene, cocaine metabolite, and barbiturates. Testing was conducted at each visit and was correlated with the patient's reported history of O/CS use. In collaboration with our institution's toxicologist, results of the UTS were verified using gas chromatography/mass spectrophotometry (GC/MS) confirmatory assays. Because the UTS ications . Urine sA single positive cannabinoid finding on UTS was not defined as misuse, but patients with multiple chronic positive results were strongly counseled to refrain from use of marijuana. Continued positive UTS for cannabinoids were tracked, however, to examine this variable as a potential predictor of opioid misuse as defined above. Neither past drug or alcohol abuse, nor past drug or alcohol criminal convictions disqualified patients from participating in our program, or receiving opioids within it.Patients were advised at entry into the program that that the aforementioned violations would result in discontinuation of O/CS. A formal committee was constituted to evaluate and respond to instances of opioid misuse. It consisted of the practice medical director, two other attending physicians, the program clinical pharmacist practitioner, two resident physicians, and a nurse. The committee deliberated through secure e-mail. Patients committing opioid misuse were offered referral to substance abuse experts at our institution, or in their respective communities. Practice policy stipulated that the reinstitution of O/CS therapy could occur if the patient completed 6 months of substance abuse counseling. Patients who forged prescriptions were subject to dismissal from the practice.Patients provided informed consent and underwent a comprehensive baseline medical assessment that included collection of socio-demographic data, assessment of pain, disability, mood, and literacy, using validated scales. Using the 11-point Brief Pain Inventory (BPI), patients rated their current pain and their pain at its worst, least, and average over the past month ,36. The Opioid misuse, as defined above, was the primary outcome of interest. The misuse categories described are presented individually as counts and proportions and are combined as a composite outcome in logistic regression analysis. Predictors of both opioid and other drug misuse were examined in bivariate and multivariate analyses. Bivariate analyses are reported as proportions and relative risks, with p-values and 95% confidence intervals (CI) for dichotomous variables and t-tests for continuous variables. All exposure variables with a p-value of <0.1 were analyzed in multivariate modeling. Models were reduced using the Maximum Likelihood Ratio Test. Statistical analyses were performed using Stata 7.0 . The research protocol was approved by the Committee on the Protection of the Rights of Human Subjects, School of Medicine, University of North Carolina at Chapel Hill and patients provided informed consent.Between December 2002 and December 2003, 199 consecutive patients were referred. Of that number, 196 agreed to participate, and were enrolled  patients  or history of drug misuse [The limited clinical trials in the literature examining the use of opioids in the treatment of chronic pain do not identify factors that put chronic pain patients at risk for opioid misuse. They do not provide concrete guidance about how to select appropriate candidates for opioid therapy in a primary care setting. Although the incidence of misuse that we report is higher than that reported in other studies, many studies have not clearly defined their monitoring procedures to detect opioid misuse, have excluded patients g misuse , and havg misuse ,47-49.addiction at approximately 4 in 10,000 treated patients [misuse of opioid medications at 24% and 31%, respectively [Diagnostic and Statistical Manual of Mental Disorders, Third Edition. Twenty-three percent of patients were found to have active drug abuse disorders [Some authorities have asserted that substance abuse and dependence are uncommon or rare consequences of opioid use for pain; however, the heterogeneity of the available evidence does permit accurate estimates of the prevalence or incidence of abuse in opioid-treated patients. One widely cited reference estimates opioid patients . Such a patients . Pain sppatients . In primectively . A studyisorders . In genemisuse in our study because misuse encompasses behaviors with both medical and non-medical dimensions, whereas abuse more properly denotes the medical substance abuse or dependence disorders. The standard psychiatric definitions of abuse and dependence focus on tolerance and withdrawal which cannot be used to identify aberrant behavior in patients who are prescribed and regularly taking the medication that they may or may not be abusing as well. We adhered to published guidelines and literature that discourage opioid prescribing to patients with a history of previous or ongoing substance abuse. Stimulant-positive urines were considered evidence of, or proxy for, ongoing substance abuse and hence a contraindication to prescribing opioids. Evidence of stimulant abuse thus constituted opioid misuse as defined by our medication agreement but not opioid abuse or dependence per se. Also, we suspected that another subset of patients was procuring and diverting opioids for monetary gain as evidenced by the frequent finding of negative UTS in patients who reported they were using their medication as directed. These misusers might not receive substance abuse diagnoses. Based on consistently negative UTS, diversion of O/CS medications appears to be a common form of misuse encountered in our study. While the reasons for different forms of misuse were not qualitatively examined, the high street value of prescription opioids may have led to a temptation to sell them [We chose the term ell them . AlternaWe chose not to define a single positive cannabinoid test on UTS while receiving O/CS pharmacotherapy as an act of misuse that would result in sanction. We did, however, advise patients against marijuana use. Research in twins suggests that marijuana use is a risk factor for developing more severe and pervasive drug misuse disorders . Our datCurrently, most primary care settings have not organized care in a way that allows systematic evaluation of patients with chronic pain for either response to pharmacotherapy or misuse ,30,57. WStriking a balance between appropriate use of opioids and prevention of misuse is important for successful management of chronic pain. This study and others have found that the multidisciplinary disease management for chronic pain, can produce significant reductions in pain, improvements in depression and health-related quality of life through the establishment of a pain diagnosis and management plan ,59. ReceThis study has several limitations. As noted above, the study population was drawn from referrals within a single, academic general internal medicine practice. As such, the sample may not be representative of all opioid-treated patients in primary care settings. Because we sought referrals of patients that were difficult to manage, the incidence of opioid or other drug misuse in this investigation may be higher than in other primary care or community-based populations of opioid-treated patients. Public information on drug offenses and DUI, while easily obtained online in North Carolina, is less accessible in other states. The initial assessment of prior or current drug misuse was based on self-report and clinical assessment rather than a structured diagnostic interview; better measurement may have allowed more accurate classification and assessment of risk. In addition, we did not inquire about histories of substance abuse other than alcohol and cocaine. Finally, we have limited data about the patients' outcomes after completing the study. Patients who were identified as committing misuse usually dropped out of the program, and we were unable to assess outcomes of pain, functional status, and mental health status once contact was lost.Identifying chronic pain patients at risk for opioid misuse remains a challenge. This study and other studies of chronic pain patients -54, suggAdditional prospective studies in primary care settings are needed to confirm these findings and to examine other potential predictors of opioid misuse. Also, better studies of interventions to reduce misuse of opioids and programs designed to effectively treat pain in patients with active substance abuse disorders are needed . At the The author(s) declare that they have no financial or non-financial competing interests.TJI developed the study design and intervention, administered surveys, directed pain management and drug misuse monitoring, assisted in the drafting, editing, and revision of the manuscript. PRC developed the study design and intervention, performed statistical analyses and drafted, edited, and revised the manuscript. CAH-S developed drug misuse monitoring protocols, provided expert consultation on clinical protocols using urine toxicological testing and edited the manuscript. RMM developed the study design, oversaw data management, and edited and revised the manuscript. JSP developed opioid misuse monitoring protocols, administered surveys, performed data management, edited the manuscript. NMP developed opioid misuse monitoring protocols, administered surveys, performed data management, edited the manuscript. BBS developed the study design, participated in data management, edited the manuscript. DAD provided statistical analytical support, and assisted in the drafting, editing, and revising the manuscript. MPP developed the study design, supervised overall conduction of the study, participated in data analysis, and assisted in the drafting, editing, and revision of the manuscript.The pre-publication history for this paper can be accessed here:


The number of patients suffering from unexplained chest pain (UCP) is increasing. Intervention programmes are needed to reduce the chest pain and suffering experienced by these patients and effective preventive strategies are also required to reduce the incidence of these symptoms. The aim of this study was to describe general coping strategies in patients with UCP and examine the relationships between coping strategies, negative life events, sleep problems, physical activity, stress and chest pain intensity.The sample consisted of 179 patients younger than 70 years of age, who were evaluated for chest pain at the emergency department daytime Monday through Friday and judged by a physician to have no organic cause for their chest pain. The study had a cross-sectional design.p = 0.02). Women used emotive coping to a greater extent than did men (p = 0.05). In the multivariate analysis was shown that physical activity decreased emotive coping  while sex, age, sleep, mental strain at work and negative life events increased emotive coping. Twenty-seven percent of the patients had sleep problems 8 to14 nights per month or more. Permanent stress at work during the last year was reported by 18% of the patients and stress at home by 7%. Thirty-five percent of the patients were worried often or almost all the time about being rushed at work and 23% were worried about being unable to keep up with their workload. Concerning total life events, 20% reported that a close relative had had a serious illness and 27% had reasons to be worried about a close relative.Emotive coping was related to chest pain intensity (r = 0.17, Our results indicated that patients with more intense UCP more often apply emotive coping in dealing with their pain. Given that emotive coping was also found to be related to disturbed sleep, negative life events, mental strain at work and physical activity, it may be of value to help these patients to both verbalise their emotions and to become cognizant of the influence of such factors on their pain experience. Chest pain is one of the most common symptoms prompting individuals to seek acute care; however, more than half of the patients will not be judged to have chest pain of a cardiac origin ,2. In SwThe unexplained chest pain (UCP) is often experienced for more than three months as was shown in two qualitative studies ,5 that iUnexplained chest pain is complex and gives rise to feelings of fear and anxiety, uncertainty, stress and loss of strength. The chest pain often persists, resulting in long term physical limitations and impairment of daily activities ,5. PatieBradley et al  comparedSleep problems are a frequent complaint in patients with chronic pain. Sleep is important for health and is related to physical and emotional well-being. Hack and Mullington  investigSince psychosocial factors are related to chest pain there is a need for treatments that complement customary medical care for UCP patients -18. To dThe aim of this study was to describe general coping strategies in patients with UCP and examine the relationships between coping strategies, negative life events, sleep problems, physical activity, stress and chest pain intensity.Present study had a cross-sectional design and was carried out at Sahlgrenska University Hospital in Göteborg, Sweden from December 2002 to September 2003, with a five-week break in June–July. The study was approved by The Ethics Committee of Göteborg University, Sweden (Study code 169-02) and carried out in accordance with the Declaration of Helsinki.Patients younger than 70 years of age who were evaluated for chest pain at the emergency department (ED) daytime Monday through Friday and judged by a physician to have no organic cause for the chest pain were included . In total, 285 patients were eligible during the study period. Patients were excluded who 1) were identified for transfer to intensive care or were too ill to take part in the pain assessment or 2) had language difficulties. In total, 179 patients (73.4%) participated in the study  has been reported for intensity ratings of the POM-VAS [The Pain-O-Meter (POM) is based on the gate control theory  and is d POM-VAS .According to Lazarus and co-workers , coping Jalowiec Coping Scale (JCS)  was usedSleep problems were assessed using Jenkins Sleep Scale . This quPsychological stress was assessed with two questions related to stress at work and home. Stress was defined as feeling irritable, filled with anxiety or having sleep problems. The participants were asked to report how often they had felt stress on a 6-step scale: never experienced stress (0), experienced some period of stress (1), some period of stress in the last five years (2), several periods of stress in the last five years (3), permanent stress in the last year (4) and permanent stress in the last five years (5). A summary score is obtained by averaging the ratings from the two questions . These two questions are based on one single question combining stress at work and home used in numerous studies in Göteborg, Sweden, e.g. in a case-control study in 52 countries on psychosocial risk factors and acute myocardial infarction .Mental strain at work was assessed with two questions: "How often do you worry about being rushed at work?" and "How often do you worry about keeping up with your workload" Ratings are made on 5-step response scale: never (1), seldom (2), sometimes (3), very often (4) and almost all the time (5). A summary score is obtained by summing the ratings of the two questions (range = 2–10). These two questions have been used in a case-control study in patients with acute myocardial infarction  and CronPhysical activity in leisure time was assessed on a 4-step scale: sedentary (1) moderate physical (2) regular physical activity (3) and hard training or competitive sports (4) .Negative life events were assessed in relation to the following 10 events: serious illness in a close relative; death of a close relative; worry about a close relative; divorce; forced to move to a new home: forced to change jobs; unemployment; insecurity at work; serious financial worries; an event leading to legal consequences. The response alternatives were: no (0); yes, earlier (1); yes, during the last year (2); yes, both during the last year and earlier (3) . The instrument has been used in patients with acute myocardial infarction .All statistical analyses were performed in SAS  version 8.2 . Standard descriptive statistics were used. Spearman's correlation coefficient was used to evaluate relationships between selected psychosocial factors and chest pain intensity. P-value < 0.05 was accepted as statistically significant. To test the internal consistency of the scales, Crohnbach's alpha was computed. Odds ratios were calculated by a logistic regression model in order to determine the relationship between coping strategies and demographics, sleep problems, life events, physical activity and mental strain at work.Of the 179 participating patients, 56.4% were men. The mean age for men was 44.2  and 46.6  for women. There was no significant age difference between men and women. Thirty-four percent of the patients were immigrants; the average length of residence in Sweden was 23 years (SD ± 13) for men and 25 years (SD ± 14) for women. Patient characteristics are presented in table The patients were asked to indicate the intensity of their worst pain during the last 24 hours. The median value for chest pain intensity was 60 (range 5–100) in men and 70 (range 1–100) in women.p = 0.05). Table There were no significant gender differences in the use of confrontive (COS) or palliative (POS) coping strategies, but women used emotive (ECS) coping strategies to a greater extent than did men , 20% (n = 35) of the patients reported that a close relative had had a serious illness, 27% (n = 49) had had reasons to be worried about a close relative and 11% (n = 19) reported that a close relative had died.Permanent stress at work during the last year was reported by 18% of the patients (n = 31) and during the last five years by 11% (n = 20). Permanent stress at home during the last year was reported by 7% (n = 13) and during the last five years by 8% (n = 14).Concerning mental strain at work, 35% (n = 63) of the patients were worried often or almost all the time about being rushed at work and 23% (n = 41) were worried about being unable to keep up with their workload.Twenty-seven percent (n = 47) of the patients had sleep problems more than 14 nights per month . Twelve percent (n = 22) of the patients slept 5 hours or less, 26% (n = 47) slept 6 hours and 61% (n = 109) slept 7 hours or more.Table p = 0.02).Spearman's correlation coefficient was used to evaluate univariate relationships between worst chest pain intensity in the last 24 hours, demographics and psychosocial factors. The only significant relationship was found between increased chest pain and emotive coping with a correlation of r = 0.17 (p < 0.0001) and positively to sex, age, sleep, mental strain at work and negative life events  and Wilhelmsen et al.  have shoTyni-Lenne  investigSleep was also found to be related to emotive coping. In a study by Welin et al, 7% of mSedentary in leisure time and sleep problems were related to emotive coping and may therefore be important factors to pay attention to in efforts to alleviate chest pain. Studies have shown that regular exercise, such as walking, improves sleep ,35. In tet al. [Many UCP patients suffer from their symptoms for a long time ,5. In diet al.  conducteThe number of patients suffering from UCP is increasing and, correspondingly, the costs for caring for these patients are escalating, since many of them are admitted to the emergency ward overnight to rule out cardiac causes to the pain. It is therefore important to develop not only effective treatment strategies to reduce the suffering experienced by these patients, but also preventive strategies to reduce the costs for society.The main limitation of the present study is its cross-sectional design which only assesses the use of coping strategies at only one point in time. The data were also collected at a single hospital at daytime, which means that our results are not generalisable to patients who seek care at night. In order to further explore the influence of psychosocial factors on UCP, we plan to conduct a case-control study comparing patients with UCP with a referent group to determine if patients with UCP differ from a healthy population regarding psychosocial factors.There is a lack of intervention studies concerning UCP patients which can be explained by a gap in the knowledge about this patient group, but also by difficulties to find robust methods to reduce biasis and to enhance the generalizability of the findings. Esler and Bock  describeBased on the results from this study, an intervention programme with a bio-psychosocial model could be appropriate in order to enhancing the patients coping ability since the emotive coping style seems to increase the chest pain intensity. A programme, containing education about chest pain, improved awareness about own coping strategies and reactions on stress situations, and the importance of physical activity could be valuable to decrease pain and improve the quality of life for these patients.Intervention programmes should be designed to be applicable to the entire UCP patient group, but implemented in such a way that the needs of the individual patient are met. This means that the nurse must listen to how the patient describes and manages everyday life and promote communication conducive to learning .Our results indicate that the intensity of unexplained chest pain is related to emotive coping, where patients with more intense UCP more often apply emotive coping in dealing with their pain. Given that emotive coping was also found to be related to negative life events, mental strain at work, disturbed sleep and physical activity, it may be of value to help these patients to both verbalise their emotions and to become cognizant of the influence of such factors on their pain experience.The author(s) declare that they have no competing interests.MJ contributed in all stages of the research: planning, data collection and analyses, and in writing the bulk of the paper. FG-J initiated the research project. KK contributed in the analyses and writing. CW contributed in all stages of the research project. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here: