Impingement syndrome and shoulder pain have been reported to occur in a proportion of patients following whiplash injuries to the neck. In this study we aim to examine these findings to establish the association between subacromial impingement and whiplash injuries to the cervical spine.We examined 220 patients who had presented to the senior author for a medico-legal report following a whiplash injury to the neck. All patients were assessed for clinical evidence of subacromial impingement. 56/220 patients (26%) had developed shoulder pain following the injury; of these, 11/220 (5%) had clinical evidence of impingement syndrome. Only 3/11 patients (27%) had the diagnosis made prior to evaluation for their medico-legal report. In the majority, other clinicians had overlooked the diagnosis. The seatbelt shoulder was involved in 83% of cases (p < 0.03).After a neck injury a significant proportion of patients present with shoulder pain, some of whom have treatable shoulder pathology such as impingement syndrome. The diagnosis is, however, frequently overlooked and shoulder pain is attributed to pain radiating from the neck resulting in long delays before treatment. It is important that this is appreciated and patients are specifically examined for signs of subacromial impingement after whiplash injuries to the neck. Direct seatbelt trauma to the shoulder is one possible explanation for its aetiology. Whiplash injuries of the cervical spine are common. Additionally these injuries have a high incidence of legal action and employment loss. There are a number of well documented symptoms associated with whiplash injuries. These may include neck pain, occipital headaches, thoraco-lumbar back pain, parasthesia, weakness, visual disturbances, vertigo and even dysphagia -4. Pain Impingement syndrome, as a separate entity, however, has less established links with neck injuries. Chauhan and colleagues examined 524 patients who presented to the Accident and Emergency department and reported a 9% incidence of impingement type pain . It has In this paper we review the incidence of impingement syndrome in association with whiplash injuries in a group of patients presenting for medicolegal claims and review the relevant literature.Individuals presenting to the senior author in a 10-year period for a medico-legal report who had suffered a whiplash injury, were assessed prospectively for evidence of subacromial impingement. Whiplash was considered when the individual was complaining of pain and aching to the neck in the presence or absence of restriction of neck movements secondary to a hyper flexion/extension injury caused by their recent accident. Those with neck or shoulder symptoms prior to the index injury were excluded from the study.Anyone with shoulder pain was evaluated for clinical evidence of impingement syndrome. This involved a full examination of the neck and shoulder and assessing for evidence of subacromial impingement. The diagnosis was made on the basis of the following clinical tests: the Neer impingement sign , HawkinsThe inclusion criteria were therefore anyone with a new onset shoulder pain following their neck injury as well as having four positive clinical tests as described above.If the injury was sustained in a Motor Vehicle Accident (MVA) the position of the patient in the car, site of impact and the use of headrests and seatbelts were documented.220 medico-legal reports were reviewed retrospectively. Patients had been examined an average of 13.4 months (range 1–59 months) following their accident. Male to female ratio was 1:1.3 with an average age of 38 years (range 10–83 years).202/220 of the patients (92%) were involved in an MVA. 129/220 (64%) were as a result of rear impact. The remaining 18 patients were riding motorbikes or bicycles, or were pedestrians. 161/202 of the car accident victims (80%) were drivers and 36/202 (18%) front seat passengers. Only 3/202 (1.5%) individuals were not wearing a seatbelt and 5/202 (2.5%) did not have a headrest in position at the time of the accident.Although none had an associated cervical spine fracture, 9/220 patients (4%) had sustained fractures of the limbs or the skull. 133/220 patients (60%) had a concomitant soft tissue injury to their thoracic or lumbar spine and had complained of back pain after the incident. 21/220 patients (9.5%) had also sustained a minor head injury at the time of the accident.2, P = 0.021). In the 2 shoulders that the non-seatbelt side was involved there had been documentation of direct injury to the non-seatbelt side of the body in the patients' medical notes at presentation. All of the patients had noticed pain in their affected shoulder within the first week after the injury and none had pre-existing shoulder symptoms.A total of 56/220 patients (26%) had shoulder pain following the injury, of these 11/220 (5%) had signs and symptoms consistent with subacromial impingement  patients had had their subacromial impingement diagnosed prior to the medicolegal report .The incidence of shoulder pain following soft-tissue injuries to the neck is variable. In a prospective study of 93 car-accident victims, 16 (18%) were found to have shoulder symptoms at follow-up . Others All our patients were involved in litigation and may therefore have different characteristics. It has been shown that long-term disability following neck injury is unrelated to the physical insult and those pursuing compensation have the highest physical disability in terms of neck pain . AlthougIn our review of the literature we identified two other studies that reported shoulder pain and subacromial impingement following whiplash injuries to the neck ,12. GorsIn our study clinical examination was the main tool for diagnosing subacromial impingement although some of our patients table  did havePain radiating from the neck to the shoulder after whiplash injuries is common and difficult to treat. In contrast impingement syndrome can be helped with physiotherapy, injection of corticosteroids and even surgery. It is therefore important for clinicians to suspect and correctly diagnose subacromial impingement in patients complaining of shoulder pain following neck injuries instead of merely blaming radicular neck pain as the cause. In fact careful assessment can even identify and successfully treat a group of patients who may present with 'asymptomatic impingement' with pain outside the neck and at the medial aspect of the scapula but not in the shoulder itself .In our series all the patients with subacromial impingement had consulted their family doctor but only 9% had been referred to a specialist and less than a third had had their diagnosis made prior to our medicolegal report. None were diagnosed by their general practitioners. This study highlights the fact that a potentially treatable condition in a small group of patients is diagnosed late or not at all due to lack of awareness of the association between neck injury and subacromial impingement.2, P = 0.021) suggesting direct trauma from the seatbelt as a possible cause. Moreover all 11 patients had developed their symptoms early and between 1 and 7 days after the injury further supporting direct trauma as an underlying cause. Only two (17%) patients had symptoms in the non-seatbelt shoulder. But even these patients were found to have evidence of direct trauma to the non-seatbelt side of their body. 'Patient 4' who was a driver with left subacromial impingement was noted to have 'bruising' around the left elbow and forearm on the day of the accident. 'Patient 9' who was a driver with bilateral impingement (left worse than right) also had severe bruising and tenderness on the left chest wall and axilla after the accident and was admitted to hospital for analgesia and observation. In our study therefore, all of the shoulders that had developed subacromial impingement had been subject to direct trauma, by the seatbelt or otherwise.The exact cause of impingement syndrome associated with whiplash injuries is subject to debate. In our study the seatbelt shoulder was involved in 83% of cases . This suggests that age or pre-existing degenerative change leading to a decrease in the subacromial space may be a risk factor for developing subacromial impingement following direct trauma to the shoulder.This study has several limitations. It is based on patients in legal proceedings and may not truly reflect the general population. The diagnosis of subacromial impingement was made on clinical grounds only and although imaging was available in a number of cases table  it was nAlthough a significant number of seat-belted shoulders were identified, the numbers involved were small and a larger study needs to be conducted to confidently link seatbelt trauma to the development of impingement syndrome.Recent studies have suggested an association between whiplash injuries to the neck and shoulder pathology ,12. It hFollowing a neck injury therefore, patients who present with pain outside the neck and radiating to the shoulder should be carefully assessed for evidence of subacromial impingement to avoid delay in the diagnosis of a potentially treatable condition.AA performed the data collection, the literature review and wrote the manuscript, GEG performed the medico-legal reporting, oversaw the data collection and helped in manuscript preparation.


There was a greater majority of women in the DD group  compared with the remaining 34 patients . Toxicity was often severe, leading to patient death in two cases (both women). The toxicity score  was twice as high in patients with marked DD  compared with patients with moderate DD , P = 0.008. In the DD group, there was a high frequency of neurotoxic syndromes . The two deceased patients both had severe neurotoxicity. The occurrence of cardiac toxicity was relatively rare . These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile. © 1999 Cancer Research CampaignDihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. We report lymphocytic DPD data concerning a group of 53 patients , treated by 5-FU-based chemotherapy in different French institutions and who developed unanticipated 5-FU-related toxicity. Lymphocyte samples (standard collection procedure) were sent to us for DPD determination . Among the whole group of 53 patients, 19 had a significant DPD deficiency (DD; below 150 fmol min


To assess the efficacy and safety of steroid injections for patients with tendonitis of the shoulder or elbow.A systematic review of the literature using PubMed, EMBASE, the Cochrane library and manual searches was performed until April 2008. All randomised controlled trials (RCTs) reporting the efficacy on pain or functional disability, and/or the safety of steroid injections, versus placebo, non-steroidal anti-inflammatory drugs (NSAIDs) or physiotherapy in patients with tendonitis were selected. Pooled effect size (ES) was calculated by meta-analysis using the Mantel–Haenszel method.In all, 20 RCTs were analysed . The pooled analysis indicated only short-term effectiveness of steroids versus the pooled controls for pain and function , pain at week 4–8 ES = 1.30 (95% CI 0.55 to 2.04), pain at week 12–24 ES = −0.38 (95% CI −0.85 to 0.08) and pain at week 48 ES = 0.07 (95% CI −0.60 to 0.75)). Sensitivity analyses indicated similar results whatever the localisation, type of steroid and type of comparator except for NSAIDs: steroid injections were not significantly better than NSAIDs in the short-term. Steroid injections appeared more effective than pooled other treatments in acute or subacute tendonitis. The main side effects were transient pain after injection (10.7% of corticosteroid injections) and skin modification (4.0%).Steroid injections are well tolerated and more effective for tendonitis in the short-term than pooled other treatments, though similar to NSAIDs. No long-term benefit was shown. The clinical question considered was whether or not steroid injections are effective compared with other commonly used treatments  or placebo in terms of improvement of pain and functional ability in tendinosis .This meta-analysis was conducted according to the Cochrane Collaboration guidelines.10A systematic literature search was performed in PubMed Medline, EMBASE and Cochrane library databases up to April 2008 without limitation of years of publication or journal, using the following keywords: ((“shoulder pain”[MeSH] OR “shoulder pain”[All Fields]) OR (“shoulder joint”[MeSH Terms] OR “shoulder joint”[All Fields]) OR (“rotator cuff”[MeSH Terms] OR “rotator cuff”[All Fields]) OR  OR (epicondylitis [All Fields] OR “tennis elbow”[MeSH Terms] OR “tennis elbow”[All Fields]) OR (“tendon injuries”[MeSH Terms] OR “tendon injuries”[All Fields])) AND ((“steroids”[MeSH Terms] OR “steroids”[All Fields] OR “steroid”[All Fields]) OR ). The limits were English or French language and clinical trial or RCT. In addition, reference lists of the papers initially detected were manually searched to identify additional relevant reports.The trials were initially selected on the basis of their titles and abstract, then on the full texts. The inclusion criteria were all RCTs reporting the efficacy on pain and/or function, and/or the safety of steroid injections versus placebo, “wait and see”, NSAIDs or physiotherapy in patients with epicondylitis, rotator cuff tendonitis or subacromial impingement. Articles reporting no interpretable results (data required included mean (SD)) for any of the three outcome measures  were not analysed.One investigator (CGV) selected the articles and collected the data using a predetermined form. The following methodological features were collected: blinding, intention to treat analysis or not and number of participants who completed follow-up. The Jadad scale was applied,In order to evaluate safety, data were extracted from each study in active and control groups regarding the number and the type of all adverse events reported.2).23In each trial the effect size (ES) or the standardised response mean (SRM) were determined to assess the magnitude of treatment effect. The ES is calculated as the ratio of the treatment effect (mean differences in treatment group minus differences in control group) to the pooled standard deviation of these differences.Initially, 218 potentially relevant articles were screened. From them, 199 were excluded. Finally, after manually searching the reference lists, 20 randomised trials were included: 16 for efficacy and 19 for safety . Thus, this systematic review included 1731 patients; 744 (43.0%) patients treated by injection and 987 (57.0%) patients treated by other treatments (n = 570) or placebo (n = 417). A total of 618 (35.7%) presented with a shoulder lesion and 1113 (64.3%) with an elbow lesion. The mean (SD) age of these patients was 47.6 (4.8) years and 694 (38%) were women. Patient characteristics are detailed in The methodological quality was correct: the mean (SD) Jadad score was 3.1 (0.9) (range 1–5). In all, 13 (65%) trials performed intention to treat (ITT) analyses . Of the 16 trials for efficacy, 9 included a flowchart or described precisely the patient selection process and outcome, 14 used a concealed random allocation and 11 presented differences in change with confidence intervals, 2 with interquartile range and 2 with standard error of the mean.Of the 20 RCTs analysed, 16 provided the required data to calculate the efficacy on pain intensity for 511 participants who received steroid injections and for 763 who received a comparator. Eight studies concerned shoulder tendinosis and eight epicondylitis. The data on function were extracted from 7 RCTs: 4 concerning the shoulder and 3 concerning the elbow . The characteristics of these trials are summarised in the Supplementary material and the ES or SRM for pain intensity and physical function at different end points  are detailed in The pooled analysis is shown The heterogeneity was substantial for pain, and to a lesser extent for function, at week 1–3 and at week 4–8 . The other results were homogeneous.In the assessment of heterogeneity, sensitivity analyses showed no changes in the conclusions according to the localisation, or the type of steroid (data not shown).Steroid injections were more efficient in the short-term (week 1 to 3 and week 4 to 8) than different comparators . HoweverThis meta-analysis suggested that steroid injections are more effective in acute or subacute tendonitis (duration of symptoms below 12 weeks) than in chronic disease: pain at week 1–3 SRM = 3.35 (95% CI 1.63 to 5.08) versus 0.37 (95% CI −0.17 to 0.92) (p<0.001).In all, 19 studies (no. of patients = 1754) provided suitable data to assess corticosteroid injection safety. The main side effects were transient pain after injection (10.7% of corticosteroid injection) and skin atrophy or depigmentation (4.0%). There were no treatment discontinuations for toxicity. The NNH for steroid injection versus other commonly used treatments was 26  compared to all the comparators, and versus placebo it was 9; however, the confidence intervals were not significant. The NNH values versus each comparator and calculated for each adverse event are provided in This meta-analysis indicated short-term effectiveness (1–3 weeks and 4–8 weeks) of steroid injections in shoulder and elbow tendinosis on pain and functional disability, but at longer-term follow-up no difference for pain could be detected and steroid injections appeared less effective for function than pooled other treatments. Compared to NSAIDs however, steroid injections did not appear statistically more efficacious in the short term.There is little consensus on the optimum timing of corticosteroid injections in tendonitis, relative to the symptom duration. Some experts advocate injections when the patient does not respond to a certain period of rest (2 or 3 months),Despite the high level of interest in the aetiologies, diagnosis and treatment of tendonitis in the literature, there are relatively few randomised controlled trials and the outcomes used are heterogeneous. Physical function was rarely assessed by the same score in different studies. In some studies the ES or the SRM could not be extrapolated either due to lack of data or to inappropriate outcomes . Another limitation of this review is possible publication bias .et alet alet alSeveral reviews on the utility of steroid injections in shoulder pain have been performed and conflicting results found, but the studies analysed assessed a wide variety of conditions and disorders (including frozen shoulder) and there was often no pooling of results.However, this review differs from these earlier works in several important respects. Firstly, it included diagnostic considerations and attempted to differentiate studies based upon the nature of the populations being studied, recognising that the benefits of treatment may vary for different underlying causes of shoulder or elbow pain. This analysis was thus centred on tendinosis. Secondly, steroid injections were compared to placebo but also to other commonly used treatments  and this heterogeneity in comparators was taken into account, leading to sensitivity analyses. Thirdly, effect sizes were calculated for the different reported outcome measures in different trials. This enabled a direct comparison between studies using the same scale, whatever the outcome measure. If the ES could not be calculated, another pooled measure of effect, the SRM, was calculated when available in order not to lose information. Fourthly, time since injections was taken into account, as efficacy was assessed by the change in overall pain intensity and/or physical functional status between baseline and week 1 to 3, week 4 to 8, week 12 to 24 and week 48. In spite of these measures, statistical testing revealed heterogeneity during the first weeks. The a priori defined sensitivity analyses showed no changes in the main conclusions with the localisation, duration of pain, or type of corticoid. Some other possible reasons for this heterogeneity are variation in study quality (but only three Jadad scores were lower than 3), differences in the type of patients included or the composition of the various injection fluids, variation in the number and interval of injections  and different methods of outcome measurement. In addition, diagnostic accuracy is always a difficulty in particular for shoulder disorders: selection may have influenced the results, as patients who were heterogeneous may have been included in the original RCTs.et al indicated that, even in the hands of musculoskeletal specialists, only a minority of injections for shoulder pain are performed accurately  and that outcome significantly correlates with accuracy of injection.et al.13Accuracy of placement of the needle for injections may also be an issue. Eustace Although steroid injections were more efficacious in the first weeks than pooled comparators, importantly, steroid injections did not demonstrate superiority in the first weeks either for pain or for functional disability compared to NSAIDs. This is an important finding since NSAIDs are a widely used and relatively safe therapeutic option in tendonitis, leading to questions regarding the role of steroid injections in these pathologies. In usual care, steroid injections are in fact most often performed after NSAIDs have been prescribed but without sufficient efficacy. It should be noted that none of the studies included in this meta-analysis did in fact test this treatment strategy.et al assumed that postinjection pain is caused by the volume effect of the injection and the corticosteroid itself.et al reported a much lower percentage of postinjection pain for local anaesthetics (11%) than for corticosteroids (50%) for the same volume, indicating a possibly specific irritation caused by steroids.Adverse clinical effects of steroid injections were systematically investigated in this meta-analysis. This study indicates steroid injections are well tolerated, with infrequent and minor side effects. The main side effect was transient pain after injection (10.7% of corticosteroid injections). Haker In summary, these findings suggest that injections of corticosteroids are well tolerated and effective compared with other commonly used treatments  or placebo in terms of improvement of pain and function in tendinosis  in the short term, however no long-term benefit was shown by this meta-analysis. Moreover there appears to be no benefit of steroid injections compared to NSAIDs. This study may lead the doctor to systematically prescribe a course of NSAIDs (if there are no contraindications) before potentially performing a steroid injection. Moreover it may lead the doctor to perform steroid injections mostly in acute or subacute tendonitis, where the potential benefit appears clearer than in chronic disease.


Chikungunya virus (CHIKV) is responsible for major epidemics worldwide. Autochthonous cases were recently reported in several European countries. Acute infection is thought to be monophasic. However reports on chronic pain related to CHIKV infection have been made. In particular, the fact that many of these patients do not respond well to usual analgesics suggests that the nature of chronic pain may be not only nociceptive but also neuropathic. Neuropathic pain syndromes require specific treatment and the identification of neuropathic characteristics (NC) in a pain syndrome is a major step towards pain control.We carried out a cross-sectional study at the end of the major two-wave outbreak lasting 17 months in Réunion Island. We assessed pain in 106 patients seeking general practitioners with confirmed infection with the CHIK virus, and evaluated its impact on quality of life (QoL).The mean intensity of pain on the visual-analogical scale (VAS) was 5.8 ± 2.1, and its mean duration was 89 ± 2 days. Fifty-six patients fulfilled the definition of chronic pain. Pain had NC in 18.9% according to the DN4 questionnaire. Conversely, about two thirds (65%) of patients with NC had chronic pain. The average pain intensity was similar between patients with or without NC (6.0 ± 1.7 vs 6.1 ± 2.0). However, the total score of the Short Form-McGill Pain Questionnaire (SF-MPQ) and both the affective  and sensory subscores  were significantly higher in patients with NC. The mean pain interference in life activities calculated from the Brief Pain Inventory (BPI) was significantly higher in patients with chronic pain than in patients without it . This score was also significantly higher in patients with NC than in those without such a feature .There exists a specific chronic pain condition associated to CHIKV. Pain with NC seems to be associated with more aggressive clinical picture, more intense impact in QoL and more challenging pharmacological treatment. Togaviridae family. It is transmitted to humans by the Aedes ssp mosquitoes. The virus was first isolated in 1953, in Uganda, during an epidemic in the province of Newala in Tanganyika (now Tanzania)[département (French administrative unit), with 266,000 people infected, constituting 34% of the island's total population [Chikungunya fever is a viral disease caused by the arthropod-borne Chikungunya virus, from the Tanzania). EpidemiAedes mosquitoes) are widely distributed throughout the world; thus many countries not initially hit by previous epidemics present a potential risk of outbreaks [Interest in this viral infection has grown in recent years. Competent vectors .This study was approved by our institutions ethics review board in compliance to the Helsinki declaration. It was carried out from June to July 2006 in 13 general practices located throughout Réunion Island. All subjects received written information on the study and gave written informed consent prior to participation. All patients spontaneously seeking medical attention were directly asked whether they were on pain. Patients were included if they presented with any type of pain and previous serologic confirmation of CHIKV infection based on CHIKV IgG and IgM detected by direct ELISA and ELISA following immunocapture, respectively, as originally established at the Centre National de Référence pour les Arbovirus  . The stuThe intensity, location and effect of pain on quality of life were assessed with the Brief Pain Inventory (BPI) . In thisIn addition, patients were asked to provide details of current pain treatment  and their efficacy: low = < 30% pain reduction, moderate = 30-70% pain reduction and good = > 70% pain reduction. Pain relief after analgesics was considered a >30% pain reduction from baseline .2 test was used to compare proportions. P < 0.05 was considered significant in all instances.Quantitative variables were expressed as means and standard deviations (SD). Qualitative variables expressed as proportions and percentages. We used analyses of variance (ANOVA), with Fisher's PLSD test, to compare pain intensity and duration and questionnaire scores between patients with or without chronic pain and between patients with or without neuropathic characteristics. Multiple regression was used to analyze the association between the effect of pain on QoL (i.e. mean interference score) and clinical characteristics . The ChiOne hundred and six consecutive painful patients (79 women) were included in this study 47.3 ± 11.9 years). All reported pain at multiple sites. All patients reported pain in at least one joint  had suffered pain for less than one month, 33 patients (31%) between one and three months and 56 (53%) patients suffered chronic pain .Pain had neuropathic characteristics (NC) in 20 patients (18.9%) of patients. Pain with NC was located mostly in the upper (37%) or lower (48%) limbs and more rarely in the back (7%) or head/neck (7%).About half (53%) of patients with NC had chronic pain. The average pain intensity was similar between patients with or without NC (6.0 ± 1.7 vs 6.1 ± 2.0). However, the total score of the SF-MPQ  and both the affective  and sensory subscores  were significantly higher in patients with NC.The mean pain interference score calculated from the BPI was significantly higher in patients with chronic pain than in patients without . This score was also significantly higher in patients with NC than in those without NC .Multiple regression analysis showed that the interference of pain with quality of life was significantly associated with average pain intensity, the DN4 score and SF-MPQ affective score, but not with age or duration of pain Table . The iteEighty-eight 83%) patients had received analgesic treatment for their pain. The most frequently used drugs included: corticoids (40%), non-steroid anti-inflammatory drugs (NSAID) (22%) and acetaminophen (8%)  of these patients suffered from chronic pain. Consistent with previous reports, all of our patients presented with arthralgia. Joint involvement has been increasingly recognized in CHIKV infections and its relationship with certain predisposing genetic profiles, such as HLA B27, has been proposed -20. HoweThe association between chronic pain and CHIKV has been assessed in only a few studies ,10. The Nevertheless, this subgroup of patients deserves particular attention. Indeed, the presence of NC was associated with a less favorable outcome, in terms of a greater impact on quality of life and lower efficacy of treatment. In particular, the poorer outcome of treatment may be explained by the fact that neuropathic pain syndromes, which do not respond to conventional analgesics, respond better to antiepileptics and tricyclic antidepressants , which wWhether our findings could be extrapolated to CHIKV infections in other geographic areas remains uncertain, since a series of findings suggest that CHIKV infection during the Réunion outbreak was particularly aggressive. Thus, more cases with severe neurological complications, such as meningoencephalitis, requiring intensive-care units, and the first cases of vertical maternal fetal transmission were reported during this outbreak -4,23,24.Another limitation is that our study was based on the evaluation of patients in a primary care setting. Although this allowed a broad assessment of the study population, more severe cases, treated in secondary and tertiary centers, may have been missed. We also only evaluated patients with painful syndromes seeking medical attention and therefore could not estimate the actual prevalence of chronic pain in CHIKV infections. Future prospective studies including long-term follow-up are warranted to estimate the prevalence of chronic pain related to CHIKV infections.This study suggests that chronic pain is a frequent long-term complication of CHIKV and that the presence of neuropathic features is associated with a more severe condition. Thus, although its mechanisms remain to be determined, improved characterization of pain, including the identification of neuropathic features with an easy-to-use clinical tool, could help to significantly improve treatment outcome.The authors declare that they have no competing interests.DCA and DB have made substantial contributions to conception of the study, data analyses, and writing the draft of the manuscript. SJ, PC, and RD contributed to data acquisition, analysis and interpretation. DB was involved in revising the manuscript critically for important intellectual content. All authors contributed to the writing of the manuscript, and all approved its final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/10/31/prepub


Motilin, a peptide hormone has a direct excitatory effect on circular smooth muscle strips derived from the human colon. Reduced plasma motilin concentration has been reported in adults with chronic constipation. Erythromycin, a non-peptide motilin receptor agonist, induces phase 3 of the migrating motor complex (MMC) in the antro-duodenum and also reduces oro-cecal transit time. A pediatric study has reported an improvement in clinical symptoms of constipation following erythromycin administration, but the effect on colon motility in children has not been formally evaluated. We used colon manometry to study the effect of intravenous erythromycin lactobionate at 1 mg/kg on colon motiltiy in ten children.We selected patients with normal antroduodenal and colon manometry studies that were performed simultaneously. All studies were performed for clinically indicated reasons. We quantified the effect of erythromycin on colon contraction by calculating the area under the curve (AUC).The mean (SE of mean) AUC in the colon during the fasting, post-erythromycin and postprandial phases of the study was 2.1 mmHg/sec (0.35), 0.99 mmHg/sec (0.17) and 3.05 mmHg/sec (0.70) respectively. The AUC following erythromycin was significantly less compared to the fasting phase of the study (p < 0.01).Erythromycin lacks colon prokinetic effect in children with chronic constipation evaluated by colon manometry. Constipation accounts for 3% of general pediatric and 10–20% of pediatric gastroenterology outpatient visits [Motilin is a 22-amino acid peptide hormone secreted by the enterochromaffin cells of the small intestine ,5. It exConflicting results exists regarding the erythromycin effect on circular smooth muscle strips derived from the human colon. Few studies have reported the stimulatory effect of erythromycin in human smooth muscle contractions ,11 and NErythromycin is a non-peptide motilin receptor agonist which induces phase 3 of the migrating motor complex in the antro-duodenum. Several studies have reported that erythromycin is safe and effective in improving feeding intolerance in preterm infants and children -19. The The aim of our study was to evaluate the effect of intravenous erythromycin lactobionate (1 mg/kg) on colon motility in children with chronic constipation and fecal incontinence using colon manometry.We retrospectively evaluated 10 simultaneously performed antro-duodenal manometry (ADM) and colon manometry (CM) studies performed at the Children's Hospital of Wisconsin between June 2000 and June 2005. These studies were performed to exclude an underlying small bowel and/or colon motility disorder. Only patients with normal antro-duodenal and colon motility studies were included. The presenting symptoms were chronic constipation in 8 patients, abdominal pain and fecal incontinence in 1 and abdominal distension and pain in 1 patient. Hirschsprung's disease was excluded either by anorectal manometry or rectal biopsies in all subjects. This retrospective chart review study was approved by the Children's Hospital of Wisconsin Human Research Review Board . Informed consent was not obtained from the patients as this was a retrospective chart review study.All drugs known to affect the gastrointestinal motility were discontinued at least 72 hours before the motility studies. Patients fasted for at least 8 hours before the study. All children were anesthetized without a muscle relaxant. We waited for the child to recover completely from the effects of the drug before starting the motility tests . ColonosAntro-duodenal manometry was considered normal if i) phase 3 of the MMC, as defined by repetitive antral contractions occurring at a rate of 2–3 per minute and 10–12 per minute small bowel contractions, lasted for more than 2 minutes with normal antegrade propagation ii) there was normal stomach antrum and small bowel response to a meal . Colon mAll colon manometry studies were reviewed by an experienced gastroenterologist and artifact was removed. The area under the curve was calculated by measuring the area under the pressure line for one 60 minutes period during fasting, following erythromycin administration and after a meal. Increase in motility index following a meal is considered a gastro-colonic response. The CM recordings were also evaluated for HAPCs.We used SPSS software, version 10 for Windows . We compared the mean (SE of mean) AUC using Student's t test. To compare the effect of erythromycin and bisacodyl on colon contractions, we used McNemar's test for disagreement.The mean age of the patients at the time of the study was 9.6 years (range 4–12 years); there were five females. In all patients, we recorded phase 3 of the MMC following intravenous erythromycin and a normal postprandial antro-duodenal manometry.The mean (SE of mean) AUC in the colon during the fasting, post erythromycin and postprandial phases of the study was 2.1 mmHg/sec (0.35), 0.99 mmHg/sec (0.17) and 3.05 mmHg/sec (0.70), respectively . McNemar's test for disagreement between erythromycin and bisacodyl induced HAPC was statistically significant (p = 0.004). The mean interval of first HAPC after bisacodyl was 7.18 minutes (range 1–10 minutes).This retrospective study evaluates the effect of erythromycin on colon motility in children with chronic constipation using colon manometry. All our patients had normal antro-duodenal and colon manometric studies. The two recognizable features of normal colon motility in children are an increase in colon contractions following a meal (gastrocolonic response) and HAPCs. If sponAll patients showed normal phase 3 MMC activity following intravenous erythromycin lactobionate (1 mg/kg dose). This shows that the dose of erythromycin lactobionate used was adequate to stimulate the motilin receptors in the foregut. In the colon there was a significant decrease in the frequency and amplitude of contractions following erythromycin lactobionate when compared to the fasting period. This may be because the motilin receptors in the colon have a higher threshold of activation compared to small bowel. An adult study reported no prokinetic effect of erythromycin on colon motility as determined by colon manometry . This suThere is heterogeneity in the motilin receptor affinity for erythromycin in the gastrointestinal tract . It is pOur study suggests that erythromycin lactobionate at 1 mg/kg does not have a colon prokinetic effect in children with chronic intractable constipation. Further studies are needed, using a higher dose of erythromycin, to evaluate the dose response curve and affinity of the colon motilin receptors to erythromycin.MMC: migrating motor complex, AUC: area under the curve, ADM: antroduodenal manometry, CM: colon manometry, HAPCs: high amplitude colon contractionsThe authors declare that they have no competing interests.All authors read and approved the final manuscript.NVS: Data analysis and manuscript writing. CR: Helped with manuscript writing and providing patients. MS: Helped with manuscript writing, data analysis and providing patients.The pre-publication history for this paper can be accessed here:


Massage is increasingly used to manage chronic pain but its benefit has not been clearly established. The aim of the study is to determine the effectiveness of a single session of nurse-administered massage for the short term relief of chronic non-malignant pain and anxiety.A randomised controlled trial design was used, in which the patients were assigned to a massage or control group. The massage group received a 15 minute manual massage and the control group a 15 minute visit to talk about their pain. Adult patients attending a pain relief unit with a diagnosis of chronic pain whose pain was described as moderate or severe were eligible for the study. An observer blind to the patients' treatment group carried out assessments immediately before (baseline), after treatment and 1, 2, 3 and 4 hours later. Pain was assessed using 100 mm visual analogue scale and the McGill Pain Questionnaire. Pain Relief was assessed using a five point verbal rating scale. Anxiety was assessed with the Spielberger short form State-Trait Anxiety Inventory.101 patients were randomised and evaluated, 50 in the massage and 51 in the control group. There were no statistically significant differences between the groups at baseline interview. Patients in the massage but not the control group had significantly less pain compared to baseline immediately after and one hour post treatment. 95% confidence interval for the difference in mean pain reduction at one hour post treatment between the massage and control groups is 5.47 mm to 24.70 mm. Patients in the massage but not the control group had a statistically significant reduction in anxiety compared to baseline immediately after and at 1 hour post treatment.Massage is effective in the short term for chronic pain of moderate to severe intensity.[ISRCTN98406653] Complementary therapies, such as massage, are increasingly used by health professionals to manage a wide range of symptoms, including pain . A literThe use of complementary therapies is steadily growing, both in Europe and in the US -4. HealtThe holistic nature of nursing means massage is an attractive intervention for nurses to be able to offer patients. In addition to any direct therapeutic benefit, it allows nurses time with patients. It may be particularly relevant in settings where patients need immediate relief. Many nurses have undertaken courses in massage, however there is little robust evidence of its effectiveness. In today's evidence driven health care environment, if nurses are to justify the resources involved in training and delivery, they need evidence that massage is an effective treatment.A literature search of Medline, EmBase, Cinahl and the Cochrane Controlled Trials Register and Cochrane Database of Systematic Reviews was undertaken, using free text and MeSH terms. Studies were sought which were randomised controlled trials, of manual massage therapies with or without oils, and which compared massage to at least one other treatment group  in patients with chronic non malignant pain. Studies were excluded if they used non-manual massage or where massage was administered as part of a combination of therapies or was used for acute pain. Twenty eight studies were identified, of which eight met the criteria for inclusion.After the RCT described in this paper was completed, a systematic review of massage for low back pain was published . OutcomeIn summary, despite the widespread and increasing use of massage for chronic pain, evidence of effectiveness is lacking, studies tend to be small and properly controlled studies are needed. An RCT to assess the effectiveness of massage for chronic pain was thus designed to add to the knowledge base in this area.The aim of the study is to determine the effectiveness of a single session of nurse-administered massage for the short term relief of chronic non-malignant pain and anxiety.A randomised controlled trial design was utilised, in which the patients were assigned to two groups by simple block randomisation, using blocks of 10. Randomisation was carried out by use of a computerised random number generator and provided from a central office unconnected with the study. After obtaining informed consent from the patient, the allocation was obtained by telephone from the central office, thus allocation was concealed.Patients aged 18 and over and attending a regional pain relief unit in England as in or out patients, who had experienced pain for three months or longer, whose pain was described as moderate or severe on the four point verbal rating pain intensity scale were eligible for the study. Patients were excluded if they did not speak English, did not consent or if they had taken any analgesics in the two hours prior to treatment. Outpatients were being followed up for the management of their chronic pain, and inpatients were admitted to the pain unit where patients stayed for one or more days in order to investigated ways of controlling their pain. The participants were a consecutive series of eligible patients and data collection took place between 1998 and 2000.The experimental group received a 15 minute manual massage of their back, neck and shoulders using sweet almond oil. The control group received a 15 minute visit to talk about pain clinic treatment. The treatment for both the experimental and control groups was carried out by two registered nurses qualified in massage (ITEC diploma). Each therapist  performed a sequence of the same massage techniques with the patients in the massage treatment group. This involved effleurage, petrissage and kneading techniques. For patients in the control group the therapist visited the patient for 15 minutes and encouraged them to talk about their pain and pain treatment. This is representative of usual care in this pain clinic, where health care staff talk to patients about their pain and its management, and no massage was performed for the control group. Patients in both groups were asked to try and complete at least one full hour after the intervention before requesting analgesics, but could request analgesics at any time after the intervention. If they received an analgesic, they were then excluded from any further follow-up assessments.An independent nurse observer (DC), blind to the patients' treatment group, carried out assessments of the patient. These were carried out immediately before treatment (baseline), immediately after treatment (post treatment) and at 1, 2, 3 and 4 hours after treatment. The observer also recorded whether or not the patient had broken the blinding by inadvertently revealing their group allocation . Once blinding was broken, it was considered unblinded for all subsequent assessments for that patient.Pain intensity was assessed using a 0–100 mm visual analogue scale (VAS), the four point verbal rating pain intensity scale with descriptors of none = 0, mild = 1, moderate = 2 and severe = 3, both have been shown to be reliable, valid and appropriate for clinical use , and TheThe sample size was calculated for comparing mean difference in pain score and for the study to have a power of 90% . The resThe study received ethical approval from the Local Research Ethics Committee (Study Code NAPREC 97.053). All participants recruited to the study had received a verbal explanation of the study and were provided with a written information sheet. All potential participants had at least 24 hours between receiving information and deciding whether or not they wished to take part in the study. All participants gave written consent.th, 50th and 75th percentiles; the whiskers indicate the range of the data, with asterisks indicating outliers. Statistical significance was set at the 5% level. The data were analysed using SPSS version 12 and MINITAB version 13.In the analysis baseline pain and anxiety scores are compared for the two treatment groups using t-tests. To investigate the treatment effect, for each patient their pain scores after treatment are compared to their baseline pain score (pre-treatment). The mean difference in change in pain score for the two treatment groups is compared using a 2 sample t-test. Similarly changes in anxiety between baseline and post treatment are compared for the two groups sample t-test. Box plots are used to show graphically the differences between groups. The box includes the 25In total 103 patients participated in the study of whom 52 were randomly allocated to the massage group and 51 to the control group. Two patients allocated to the massage group withdrew at baseline, one because they received morphine just prior to starting the study and the other because they were unable to understand the assessment scales, thus the analysis reports results for the 101 patients who completed the baseline assessments. The patients were aged between 21 and 81 years, with mean age 53.4 years (SD 13.3 years) and 58.4% were female. The mean time that the patients had experienced chronic pain was 10.4 years (SD 8.94 years). 87% of the patients had a diagnosis which included back pain and 58% had more than one pain site. At baseline, 60.4% had moderate and 39.6% had severe pain as recorded on the verbal rating scale.Figure The assessment of the patients at all time points was by an observer who was blind to the treatment that the patient received (DC). Occasionally the patient would break the blinding by comments that they made to the observer. For 89 of the 100 patients in which a record of blinding was made, the observer remained blind throughout the assessment, so blinding was maintained in 89% of patients.The demographic characteristics and baseline scores for the massage and control groups are compared in Table The pain verbal rating scale scores are "moderate" or "severe" for all patients, with 40% of the massage group and 39% of the control group recording severe pain at baseline. The similarity of the distribution of pain scores between the two groups is shown in the boxplot in Figure Comparisons post-treatment of pain VAS scores are shown in Figure Table Figure The results from the four point verbal rating pain, the four point pain distress scale and the McGill Pain Questionnaire produce the same findings as the pain VAS scale. That is, statistically significant differences between massage and control groups immediately and one hour post treatment.An example of these similarities is shown in comparisons of McGill Pain Questionnaire scores from baseline to immediately post treatment. The massage group experience a statistically significant (p < 0.001 using paired t-test) mean reduction in McGill pain score of 11.5 (SD 9.93). For the control group the mean change in McGill pain score is 1.22 (SD 7.16) which is not statistically significant (p = 0.237 using paired t-test).Table Table 2 = 46.6, df = 2, p < 0.001).At the final assessment for the patient, either at 4 hours post treatment or at the point that they requested an analgesic and thus withdrew from the study the patient was asked to assess whether the treatment they had received was poor, fair, good, very good or excellent. In the massage group, 34 rated the treatment as good, very good or excellent, 12 as fair and 4 as poor. In the control group, 4 rated it as good, very good or excellent, 14 as fair and 33 as poor. A chi-squared test for the patients' assessment of the treatment demonstrates that those receiving the massage rate this treatment statistically significantly better than the control group  said they would like the treatment again. Of the 49 patients in the massage group who were asked this question all 49 (100%) said yes they would like the treatment again. Of the 42 patients in the control group asked this question, 25 (60%) said yes they would like the treatment again.At the final assessment the patient was asked whether they would like to have the treatment again. A significantly higher proportion of those in the massage group  of massage patients remained compared to only 8% of those in the control group. This gives at least an indication that because patients who dropped out did so because they requested an analgesic, those in the massage group who stayed in the study did so because they had less pain.The study had aimed to recruit 120 patients, 60 in each group. In the event, 101 were included in the study. This was based on a previous study of relaxation in hip fracture patients which had a standard deviation of 25 mm and a mean difference of 15 mm . If we tThe extent of a statistically significant reduction of pain and whether it is clinically significant is important to consider. Compared to baseline, those in the massage group had a mean reduction in pain of 16.7 mm on a 0–100 scale immediately after treatment. If 50% pain relief is taken as clinically important, 36% of the massage group reported at least this level of relief immediately post treatment, compared to 0% of the control group. This provides some evidence that the massage can have quite a large effect in just over a third of patients. Although a benefit of reduced pain for one hour may seem a limited effect, it does provide something of a break from pain.It is then a clinical question whether the 15 minute investment of time in doing the massage is worth the benefits outlined in the paper. When patients either completed the study or withdrew, 68% of massage patients compared to only 8% of control patients said the intervention had been good, very good or excellent, so it would seem over two-thirds of patients did find the treatment beneficial. This could be one area where carers may be able to take on this role, although anecdotally, we are aware that some clinicians may be reluctant to make this suggestion to carers, fearing litigation if there are any adverse effects. Health professionals wishing to integrate massage into their practice need to consider professional training, and the requirements of the regulatory bodies of their own country. For example, in the UK, the Royal College of Nursing produced guidance on integrating complementary therapies into clinical care . It woulThis study adds to the international knowledge base about the effectiveness of massage for chronic pain. It has demonstrated that massage can produce short term reductions in pain and anxiety, and improvements in pain relief which are valued by patients. These are important potential benefits for people in whom the management of pain is often a challenge.Massage is effective in the short term for chronic pain of moderate to severe intensity, and has a small anxiety reducing effect. It could be a useful addition to techniques offered to patients as part of their care. Nurses are well placed to be trained in and to deliver massage. More research is needed to explore the benefits of repeated treatments of massage in patients with chronic pain.The authors declare that they have no competing interests.KS conceived the study and participated in its design and coordination and drafted the manuscript. NC participated in the design, conducted the statistical analysis and helped to draft the manuscript, JM and KC were involved in the data collection, delivering the intervention and helped draft the manuscript, DC participated in the design of the study and the data collection and helped draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Nociceptive stimuli may evoke brain responses longer than the stimulus duration often partially detected by conventional neuroimaging. Fibromyalgia patients typically complain of severe pain from gentle stimuli. We aimed to characterize brain response to painful pressure in fibromyalgia patients by generating activation maps adjusted for the duration of brain responses.2 of pressure on the thumb. Nine additional control subjects received 6.8 kg/cm2 to match the patients for the severity of perceived pain. Independent Component Analysis characterized the temporal dynamics of the actual brain response to pressure. Statistical parametric maps were estimated using the obtained time courses. Brain response to pressure (18 seconds) consistently exceeded the stimulus application (9 seconds) in somatosensory regions in all groups. fMRI maps following such temporal dynamics showed a complete pain network response  to 4 kg/cm2 of pressure in fibromyalgia patients. In healthy subjects, response to this low intensity pressure involved mainly somatosensory cortices. When matched for perceived pain (6.8 kg/cm2), control subjects showed also comprehensive activation of pain-related regions, but fibromyalgia patients showed significantly larger activation in the anterior insula-basal ganglia complex and the cingulate cortex.Twenty-seven women (mean age: 47.8 years) were assessed with fMRI. The sample included nine fibromyalgia patients and nine healthy subjects who received 4 kg/cmThe results suggest that data-driven fMRI assessments may complement conventional neuroimaging for characterizing pain responses and that enhancement of brain activation in fibromyalgia patients may be particularly relevant in emotion-related regions. Nociceptive stimulation can trigger complex behavioral responses involving both local pain sensations and general affective phenomena Functional imaging has notably contributed to delineating the functional anatomy of the brain network mediating pain responses Fibromyalgia is a syndrome expressed mainly as chronic complaints involving augmented subjective pain of mechanical origin This study was conducted according to the principles expressed in the Declaration of Helsinki. The study was approved by the Ethics and Institutional Review Board of the Autonomous University of Barcelona (reference number SAF2007-62376). All patients and healthy subjects provided written informed consent for clinical and fMRI assessment and subsequent analyses.Twenty-seven subjects participated in the study, including nine patients with fibromyalgia and two groups of nine healthy subjects (control group 1 and 2) matched to patients for gender and age, and recruited from the same sociodemographic environment. Control group 1 served to compare brain response to a fixed mechanical stimulus pressure able to provoke severe pain in fibromyalgia patients. Control group 2 was matched to fibromyalgia patients for levels of perceived pain by increasing stimulus intensity.The patients were consecutively selected during clinical follow-up to make up a homogeneous sample showing severe and durable symptoms. The series included nine right-handed females with a mean±SD age of 47.9±9.4 years and education level of 11.0±2.1 years. All patients met the American College of Rheumatology criteria for fibromyalgia Patients were allowed to continue with their stable medical treatment, but were required to refrain from taking analgesic drugs 72 hours prior to fMRI. Six patients were on anti-inflammatory drugs in a stable regime . The remaining 3 patients were taking: antidepressants, benzodiazepines and carbamazepine (1 patient), antidepressants and benzodiazepines (1 patient), and no medication (1 patient).The control group 1 included nine right-handed females with a mean age of 47.2±8.9 years and education level 12.4±4.3 years, and the control group 2 nine right-handed females with a mean age of 48.2±5.5 years and education level 13.0±3.0 years. Subjects with relevant medical or neurological disorder, substance abuse, or psychiatric disease were not considered for inclusion. None of the healthy subjects was undergoing medical treatment.2 surface placed on the subject's thumbnail. As in other studies Pressure stimuli were delivered using a specially designed hydraulic device capable of transmitting controlled pressure to 1-cm2, were administered pseudo-randomly. Conventional pain thresholds corresponded to the least pressure intensity at which subjects perceived pain in two trials. In this session, pain threshold was 1.6±0.5 kg/cm2 in the 9 patients and 4.0±1.0 kg/cm2 in the 18 healthy subjects (P<0.0005). The minimum pressure intensity to provoke severe pain (NRS above 70) in patients was 3.6±0.9 kg/cm2 and 6.8±1.4 kg/cm2 in healthy subjects (P<0.0005).Pain thresholds were also assessed during the session and the intensity of pressure producing severe pain in both patients and control subjects was estimated. To determine individual thresholds, different stimulus intensities were applied lasting 5 seconds each, with an inter-stimuli interval of 20 seconds. The selected pressure stimuli, ranging from 2–9 kg/cm2 pressure was delivered to the subjects' right thumbnail. Pressure was partially removed for 1 second in the middle of each pain block to reduce the probability of tissue damage in the thumb. The entire imaging sequence involved 12 rest-pressure cycles lasting 6 minutes in total. Immediately after image acquisition, each subject provided a single score to globally rate pain intensity perceived during the 12 pressure blocks.During the primary study assessment, identical stimulation was applied to both patients and healthy subjects (control group 1). A block-design paradigm was used consisting of 21-second resting-state periods interleaved with pressure stimulation blocks of nine seconds. During pressure blocks, sustained 4 kg/cm2, which produced a pain severity level similar to that experienced by fibromyalgia patients using 4 kg/cm2 (NRS above 70).The control group 2 was assessed using identical procedures, but applying 6.8 kg/cmA 1.5 T Signa system  equipped with an eight-channel phased-array head coil and single-shot echoplanar imaging (EPI) software was used. Functional sequences consisted of gradient recalled acquisition in the steady-state  within a field of view of 24 cm, a 96×64-pixel matrix, and slice thickness of 5 mm . Seventeen slices parallel to the anterior-posterior commissure line covered the whole-brain. The first two images in each run were discarded to allow the magnetization to reach equilibrium.Imaging data were processed using MATLAB version 7  and Statistical Parametric Mapping software . Preprocessing involved motion correction, spatial normalization and smoothing using a Gaussian filter . Data were normalized to the standard SPM-EPI template and resliced to 3 mm isotropic resolution in Montreal Neurological Institute (MNI) space. We excluded data from two subjects from an original sample of 29 subjects due to excessive head movement (z-axis translation>2 mm).fMRI data are commonly analyzed using ‘model-based’ statistical methods that require a specific assumption about the time courses of activation. Typically, model-based analyses estimate the contrast between signal intensity of images obtained during stimulus application and signal intensity of images obtained without stimulation or during a control condition. In experiments where response durations cannot be completely anticipated, as in pain assessment and in the assessment of emotions in general, the standard model-based approach may underestimate the evoked brain response. In contrast, “data-driven” statistical methods are used to identify actual brain activation without a priori hypothesis on the expected activation time course. These methods estimate the best fitting of the data, but do not directly test the statistical significance of the activations Spatial Independent Component Analysis is a data-driven statistical analysis method that is able to decompose whole brain fMRI data into independent networks of brain regions  involving voxels following similar temporal dynamics. Results are presented as a set of spatial maps with their associated time courses.http://icatb.sourceforge.net), with previously described algorithms Stage 1: The dimensionality of the fMRI data and the optimal number of components for each group were estimated using the minimum description length (MDL) criterion in GIFT Stage 2: Group estimation of spatially independent sources was then performed using the Infomax algorithm. Stage 3: During the final stage of back-reconstruction to the original dimensionality, individual subject image maps and time courses were estimated using the group solution Group ICA for fMRI Toolbox was used  of the brain regions activated by nociceptive stimulation. In selecting these time courses for further analysis, we considered those components involving regions known to mediate brain response to pain 1st-level (single-subject) SPM contrast images were estimated to characterize the functional anatomy of pain-related brain activations. For this analysis, the BOLD response at each voxel was modeled using (i) data-driven response function generated from the Group ICA; and (ii) conventional (SPM5) model-driven canonical hemodynamic response function. Resulting 1st-level contrast images for each subject were then carried forward to 2nd-level random-effects (group) analyses using one-sample t-tests. A two-sample t-test analysis was performed to compare activation maps between study groups. Spatial coordinates from the obtained maps were then converted to standard Talairach coordinates P value less than 0.05 False Discovery Rate (FDR) corrected for the volume of activated regions (pain network).We mapped voxel-wise correlations between subjective pain scores and brain activation. Separate correlation maps were obtained for both the data-driven and model-driven approaches including 18 study subjects (patients and control group 1). Correlations were considered significant at a In addition, we assessed the extent to which brain activation in the region showing the highest correlation with subjective pain (the anterior cingulate cortex) was able to account for group differences in perceived pain. This was carried out by comparing group differences in subjective reported pain both before and after controlling for (regressing out) the effect of cingulate activation using analysis of covariance (ANCOVA).2 of pressure. Healthy subjects reported mild-to-moderate pain and fibromyalgia patients the most severe scores during this stimulation . The group of healthy subjects (n = 9) receiving 6.8 kg/cm2 (control group 2) reported severe pain at rating levels comparable to the fibromyalgia group .The range of subjectively reported pain varied from 20 to 100 points across the 18 subjects  assessed using 4 kg/cmICA estimated 34 spatially independent components in patients and 31 in healthy subjects (control group 1). The time course of nine components in patients and three components in healthy subjects showed a signal increase  coinciding with each pain stimulation block. Two such components involved pain-related brain regions in each study group. That is, in both patients and healthy subjects, a “somatosensory” and an “insular” component met the double criterion of showing signal increase in each pain block and involving regions known to mediate brain response to pain.t = 0.28 and P = 0.782. Activation duration was 18.6±3.6 s in patients and 18.9±3.6 s in control subjects, showing t = −0.19 and P = 0.848.The somatosensory component included bilateral parietal cortex in both groups and a small portion of the dorsal anterior cingulate cortex in fibromyalgia . The assThe “insular” component involved bilateral insulo-opercular cortex in both groups. In fibromyalgia patients, the time course of this component followed the dynamics of the somatosensory component, showing a fast initial signal increase and duration of 18 seconds. By contrast, healthy subjects, showed much less consistent signal changes in the insular region, as not all the stimulation blocks showed a definite signal increase see .The time course of the somatosensory component was averaged across groups (patients and control group 1) and was used as the reference function in a conventional fMRI analysis. The assessment of brain activations from the conventional block-design analysis adjusted to stimulus duration  resulted in notably smaller pain-related activation in patients and control group 1 , Table 22 of pressure . Pain scores were widely correlated with brain activation in the data-driven approach involving the contralateral sensory-motor cortex, supplementary motor area, anterior cingulate cortex, anterior insula and basal ganglia ; a finding that was reversed  when removing (regressing out) this effect.The plot in 2 and reporting severe pain (control group 2). This procedure estimated 37 spatially independent components. As in the above analysis, the time course of the obtained somatosensory component was averaged with the somatosensory time course of fibromyalgia patients and was used as the reference function in a new conventional fMRI analysis to compare patients with this control group. An ICA was carried out for the control group stimulated at pressure 6.8 kg/cmThis study aimed to characterize brain response to local pressure stimulation in fibromyalgia patients using an fMRI approach based on the temporal analysis of brain activation. Somatosensory areas showed consistent activation to each block of pressure stimulation that characteristically persisted beyond stimulus application. The fMRI maps adjusted for response duration showed robust activations in regions known to mediate brain responses to pain. Importantly, a strong correlation was observed between the rating of subjective pain during the fMRI assessment and the magnitude of the activation. Fibromyalgia patients showed significantly greater activation than comparative control subjects. Response enhancement was observed in fibromyalgia patients for most pain-related regions compared to the control subjects receiving identical stimulation, and for specific regions when the groups were matched for subjective pain levels.This data-driven imaging analysis allowed us to compare specific temporal and anatomical features of nociceptive processing between fibromyalgia patients, who reported severe subjective pain to the relatively mild local pressure stimulus, and healthy subjects reporting only mild-to-moderate pain from this stimulation. We observed a similar activation time course in somatosensory cortices in both groups, which suggested relevant and durable responses to mechanical stimulation at the “sensory” stage of nociceptive processing, irrespectively of subjective pain severity. For the insula component, consistent long-lasting responses were observed only in fibromyalgia patients.2 of pressure differed between patients and control subjects (control group 1). Healthy subjects showed mainly a sensory response with relevant activation in contralateral somatosensory cortices and moderate activation in the insular cortex. By contrast, fibromyalgia patients showed a full response to pain with robust sensory, limbic and motor activations. Functional MRI changes in these regions showed a significant correlation with the severity of experienced pain and largely accounted for group differences in subjective pain scores at low pressure stimulation. That is, increased activation in pain-related regions explained the increased subjective pain ratings in fibromyalgia patients.The anatomy of the activations in response to 4 kg/cmIt is noteworthy that all the “efferent” elements of the pain response  are represented in the voxel-wise map of the correlation between pain severity and brain activations, including contralateral sensory-motor cortex, supplementary motor area, anterior cingulate cortex, anterior insula and basal ganglia. Several fMRI studies have reported a close relationship between anterior cingulate cortex activation and the subjective experience of pain or its “suffering” component This closer correlation of subjective pain with the efferent brain response seems to further support proposed mechanisms for enhancement of emotions, including pain. Such models suggest that efferent somatic and visceral bodily responses to emotive stimuli originate backward afferent stimulation of the body representation in the brain, in turn amplifying emotional states Our results are consistent with most of previous fMRI studies on fibromyalgia, but expand the reported data by assessing the temporal dynamics of brain activity, which led to a more comprehensive activation mapping. All the reports coincide in showing abnormal brain responses to painful stimuli in fibromyalgia patients Functional MRI research is now focused on assessing the different dimensions of nociceptive processing. The presence of mood depression in fibromyalgia patients was associated with increased activation in regions processing affective components of pain Conventional block-design fMRI is based on detecting brain activations following a specified paradigm of stimulus duration. These methods provide reliable and accurate activation patterns when stimulus duration corresponds well to brain activation . Nevertheless, for painful or emotional stimuli that may evoke responses of variable duration, the temporal analysis of brain activity may provide more informative activation maps and correlate better with subjective pain scores. Data-driven methods, however, are inherently biased to the actual response in a given population or experiment, which may hinder the generalization of conclusions Despite the small number of subjects included in this study, we observed robust activation maps reflecting the consistency of brain activation across all 12 pressure stimulation blocks. This may have particular relevance in the clinical fMRI setting as discussed in recent studies Fibromyalgia has often been a controversial medical syndrome since patient identification is based largely on subjective symptoms


Regional pain in the hip in adults is a common cause of a general practitioner visit. A considerable part of patients suffer from (greater) trochanteric pain syndrome or trochanteric bursitis. Local corticosteroid injections is one of the treatment options. Although clear evidence is lacking, small observational studies suggest that this treatment is effective in the short-term follow-up. So far, there are no randomised controlled trials available evaluating the efficacy of injection therapy.This study will investigate the efficacy of local corticosteroid injections in the trochanter syndrome in the general practice, using a randomised controlled trial design. The cost effectiveness of the corticosteroid injection therapy will also be assessed. Secondly, the role of co-morbidity in relation to the efficacy of local corticosteroid injections will be investigated.This study is a pragmatic, open label randomised trial.A total of 150 patients (age 18–80 years) visiting the general practitioner with complaints suggestive of trochanteric pain syndrome will be allocated to receive local corticosteroid injections or to receive usual care. Usual care consists of analgesics as needed. The randomisation is stratified for yes or no co-morbidity of low back pain, osteoarthritis of the hip, or both. The treatment will be evaluated by means of questionnaires at several time points within one year, with the 3 month and 1 year evaluation of pain and recovery as primary outcome. Analyses of primary and secondary outcomes will be made according to the intention-to-treat principle. Direct and indirect costs will be assessed by questionnaires. The cost effectiveness will be estimated using the following ratio: CE ratio = /.This study design is appropriate to estimate effectiveness and cost-effectiveness of the injection therapy. We choose to use a pragmatic study design and are thus not able to study specific effects of the injection with corticosteroids. A distinction between placebo effect of the injection and specific effects of the corticosteroids is therefore not possible.The trial is listed in the Dutch Trial Registry with the number ISRCTN16994576 One of the more common pain syndromes of the in the hip in adults is known as trochanteric pain syndrome (TPS) or trochanteric bursitis. It is considered to have the following characteristics: chronic, intermittent pain at the lateral site of the upper limb, sometimes radiating to the lateral aspect of the hip or lateral thigh and increasing at physical activity -4. LyingThe prevalence is higher among females than among males rate 4:1) and the incidence is highest between the ages 40 to 60 years :1 and th. A recenEarlier, the same clinical manifestations were known as trochanteric bursitis, although clinical manifestations of inflammation almost never occur ,2,4. TenObservational studies showed that in most of the cases with local pain at this site co-morbidity exists. About two-thirds of the patients with TPS have also low back pain or osteoarthritis of the hip ,3,6,7.Many GPs inject corticosteroids combined with an anaesthetic agent at the most painful site with the expectation that the pain will decrease. There is no conclusive evidence that these injections are effective, although small observational studies suggest that injections with corticosteroids are effective in the short-term follow-up ,5,7,8. NThis study we will investigate the efficacy and cost effectiveness of local corticosteroid injections in TPS, using a randomised controlled trial design. We also investigate the role of co-morbidity in relation to the efficacy of this local corticosteroid injection.This study is a pragmatic, open label randomised trial.The local Medical Ethics Committee of the Erasmus University Medical Center, Erasmus MC, has approved the trial. The trial is included in the Dutch Trial register (ISRCTN 16994576).All patients will give written informed consent.GPs participating in the HONEUR research network of the Erasmus MC and other interested GPs in the area will be invited to participate in the study. The HONEUR GP research network consists of 40 GP practices which are connected to the Department of General Practice in order to participate in regular research projects. They will be asked to select patients aged 18 to 80 years visiting the GP with the following symptoms: pain persisting for more than one week in the lateral region of the hip or thigh with tenderness at palpation of the greater trochanter with one of the two following characteristics :1). Severe pain at palpation of the greater trochanter, but uncertainty as to whether the patient recognizes the pain as that for which he or she visits the GP.2). Local tenderness when the area of the great trochanter is palpated and the patient recognizes the pain as that for which he or she visits the GP.Excluded are patients who are unable to understand the Dutch questionnaires, patients who have consulted the GP with the same complaints in the previous year and had any intervention, or are operated on in the same region, or have systemic neurological or rheumatologic disorders.Patients who are eligible for the study and show interest to participate will receive written study information from their GP, as well as the baseline questionnaire and the informed consent form. If they show interest the GP will fax their contact data to the researcher together with the findings of physical examination on a standardized form. One of the investigators will contact the patient to ask if they have any additional questions and will assess the suitability to participate in the study. If the patient still wants to participate and is eligible, we ask them to return the baseline questionnaire and informed consent form.When we receive the baseline questionnaire, the patient will be classified as having comorbidity or not. If the question: "Do you suffer from low back pain" is answered positively as often or continuous, we classify the patient as having low back pain comorbidity. The ACR criteria for osteoarthritis of the hip, using history and physical examination  are used to decide whether the patient has osteoarthritis of the hip as comorbidity .After receiving the baseline questionnaire and informed consent, an independent person will randomise each patient based on computerized randomisation lists to either receive the injection therapy or the usual care, consisting of analgesics as needed. This randomisation is stratified for yes or no comorbidity and uses randomisation block sizes of ten, yielding four strata: one lacking comorbidity, one with low back pain, one with osteoarthritis, and one stratum with both.The GP and the patient will be informed about the treatment that the patient will be given as soon as randomisation has taken place. The GPs participating in the study have been trained by us to give the injection according to a standard procedure: i.e. to use 40 mg triamcenolon acetate combined with lidocaine 1 or 2% in a 5 ml syringe. They are trained to mark the most painful point with a pen or pencil and desinfect the site. The needle is inserted perpendicular to the skin and directed down to the point of maximal tenderness, 1 ml of the substance will be injected at that point, then the needle should be moved to another place in the painful area and the same procedure should be repeated until the syringe is empty. In case of lack of efficacy, or only temporary effect, this procedure may be repeated after a period of 3 weeks up to 3 monthsAfter the injection the GP will fax us a form with details of the injection given, e.g. the volume that is injected, if the injection was painful, or if there was pain relief after injection or direct side effects.The control group will receive usual care consisting of analgesics as needed; all patients are free to receive additional treatment from a physiotherapist, although this is not advocated by the investigators.The primary outcome measurements will be experienced recovery at 3 months and at 1 year, measured on a 7-point Likert scale  and severity of pain during the last week measured with a numeric rating scale . Medical consumption of the patient  will be measured as direct cost. The PRODISC questionnaire will be used to measure the cost effectiveness and will measure the indirect costs, expressed in work staff absence and loss of productivity in paid work, or loss of productivity in not-paid work . The WOMFinally, we ask the patients who received an injection, to report any side effects of the injection. Table The sample size was calculated to detect an increase in recovery rate of 25% in the intervention group after three months of follow-up (45% recovery in the control group versus 70% recovery in the intervention group). With power 0.8 and alpha 0.05 (two-sided tested) and with a dropout rate of 10%, a total number of 75 patients in each group are needed.Difference between the groups in the primary outcome will be analysed based on the basis of the "intention-to-treat" principle. Differences in continuous outcome measures between the groups will be analysed with linear regression techniques and differences in dichotomous outcomes  will be analysed with logistic regression techniques. Baseline differences between the groups will be assessed and checked whether these influence the outcome of the study. Baseline variables that change the outcome by 10% or more will be regarded as confounders and will therefore be added to the regression models.Regression models will also be used to study effect modification of comorbidity. A cost-effectiveness analyses will be performed from a social and a patient perspective, looking at differences in direct and indirect health care cost between the two groups.If the trial does not show a difference in disease parameters (VAS and WOMAC) and quality of life (EuroQol) between the groups, the analysis will be reduced to a cost minimisation analysis. This form of analysis evaluates the efficacy of treatment based solely on direct and indirect costs. If the study does find a positive difference in disease parameters and/or quality of life in the injection group, a cost-effectiveness ratio can be determined.In this study design we compare two types of therapy which are frequently used in general practice. This study design is appropriate to estimate effectiveness and cost-effectiveness of the injection therapy. We choose to use a pragmatic study design and are thus not able to study specific effects of the injection with corticosteroids. A distinction between placebo effect of the injection and specific effects of the corticosteroids is therefore not possible.The study is executed in general practice and may therefore not apply to patients in secundary care.No disease specific questionnaires are available for this disorder. Therefore generic outcome measures (recovery and pain severity) were chosen as primary outcome measures. However, region specific questionnaires for osteoarthritis were included as secondary outcome measures. These questionnaires allow us to analyse subscales like for instance the WOMAC pain and the WOMAC function; subsequently osteoarthritis specific questions on stiffness (WOMAC stiffness) can validly be omitted.Patients included in our trial have symptoms of TPS solely, or have these symptoms in co-occurrence with low-back pain or osteoarthritis of the hip. To include patients with such co-morbidity maybe questionable because the TPS may be due to such morbidity. Therefore injection therapy for TPS in such morbidity possibly shows different effectiveness. We chose to include these patients because in common practice these patient also receive injection therapy. We, however, used a design in which we stratify for co-morbidity or not.The current status of the study is that of a total of the 80 GPs participating in the study. However, until now only 43 GPs included 90 patients. The total study population is expected to be recruited by February 2008. The first short-term results (3 months of folluw-up) will be available at mid-2008.ZonMw, the Netherlands Organisation for Health Research and Development supported this study.The authors have no competing interests.SMABZ, AMB, JANV, BWK and GLJS participated in the design and coordination of the study. AB and RMR coordinate the trial and are responsible for data acquisition. AB and SMABZ prepared the article.All authors have read and approved the final article.The pre-publication history for this paper can be accessed here:


Prognosis has been described as an important but neglected branch of clinical science. While patients' views have been sought in the context of life-threatening illness, similar research is lacking for patients presenting with common, non-life-threatening musculoskeletal complaints. The aim of this study was to gauge whether and why older patients with musculoskeletal pain think prognostic information is important, and how often they felt prognosis was discussed in the general practice consultation.A cross-sectional survey of consecutive patients aged 50 years of over presenting with non-inflammatory musculoskeletal pain to 5 Central Cheshire general practices. The frequency of responses to the prognostic questions were described and the association with sociodemographic, presenting pain complaint, and psychosocial variables explored using logistic regression.502 participants (77%) responded to the postal questionnaire. 165 (33%) participants reported discussing prognosis in the consultation with their GP. Discussions about prognosis were more often reported by male patients  and those for whom this was their first consultation . 402 (82%) participants thought that prognostic information was important. This was highest among those currently in paid employment . The reasons patients gave for believing prognostic information was important included 'knowing for the sake of knowing' and planning future activity. Reasons for not believing prognostic information to be important included the belief that progression of pain was inevitable and that nothing could be done to help.Prognostic information is thought to be important amongst older people with musculoskeletal pain yet discussions occur infrequently in primary care. Barriers to effective prognostic communication and the exact information needs of patients are still unknown and warrant further research. Prognosis is the forecast of the probable course and (or) outcome of a disease and has been described as an important but neglected branch of clinical science -3. PrognWe present the findings of a survey of older adults presenting to the general practitioner (GP) with musculoskeletal pain. Our objectives were to determine what proportion of patients think prognostic information is important, the reasons they give for (not) why they feel prognostic information is important, and to ascertain how often patients feel that their prognosis is discussed in the consultation.We conducted a survey of consecutive patients aged 50 years and over consulting one of five Central Cheshire general practices with non-inflammatory musculoskeletal pain between September 2006 and March 2007. Data for this analysis is restricted to the cross-sectional baseline questionnaire data, although the PROG-RES study is a longitudinal cohort, with multiple data collection points  . EthicalPatients consulting with eligible Read codes were identified through weekly electronic downloads from the general practice records. Read codes are a hierarchy of morbidity, symptom and process codes that enable UK primary care workers to code consultations by either presenting symptom, the working or established diagnosis or the procedure undertaken .Potential participants were mailed a 16-page self-completion questionnaire within one week of consulting their doctor. Those not responding to the initial questionnaire were sent a reminder postcard at two weeks and a repeat questionnaire at four weeks.Full details of the questionnaire content have been presented elsewhere . In brieThe following questions about the provision of, and desire for, prognostic information were asked in the questionnaire:• 'Did your doctor tell you what was likely to happen to this pain?' (Response options: Yes/No/Don't know)• 'Do you think it is important to know what is likely to happen to this pain?' (Response options: Yes/No/Don't Know)• If you answered yes (no) to the question above, please explain in your words why you think it is important (not important) to know what is going to happen to your pain (Response options: free text).For the analysis described below, 'No' and 'Don't Know' categories were combined.Responses to the first two prognostic questions were summarised as simple frequencies Binary logistic regression was used to investigate the role of sociodemongraphic status, characteristics of the presenting pain complaint, and psychosocial variables as determinants of recalled prognostic discussion and perceived importance. Results were expressed as odds ratios (OR) with 95% confidence intervals (95% CI), both crude and adjusted for all other covariates .Content analysis was used to identify themes in the free text responses provided by participants to the question asking about the importance of knowing what is likely to happen to their pain over the next six months. Content analysis has been broadly defined as "a research technique for the objective, systematic and quantitative description of the manifest content of communication" . ContentA total of 502 (77%) of 650 potential participants identified from the electronic record download responded to the self-completion questionnaire . The most common presenting complaints were back pain (29%), shoulder pain (26%) and knee pain (25%). 32% (n = 155) of participants described their physical health as being poor or fair, 14% (n = 67) had moderate or severe depressive symptoms and 21% (n = 103) having moderate or severe anxiety symptoms.165 (33%) participants recalled discussing prognosis in the consultation with their GP . The proportion recalling prognostic discussion was similar across all participating practices. Discussions about prognosis were more often reported by male patients  and those for whom this was their first consultation  (see Table 402 (82%) participants thought that prognostic information was important  , knowing about pain in order to them help cope with it and allowing them to alter activity to prevent deterioration.Reasons given for why it was not important to know what was likely to happen to the pain they consulted with included there being no point in knowing, that nothing could be done anyway, that progression was inevitable, that nothing could be done and that it couldn't be accurately predicted.This is the first study to investigate how often prognostic discussion occurs during the consultation and how important patients feel prognostic discussion is for musculoskeletal pain. We found that while over 80% of older people with musculoskeletal pain feel prognostic discussion is important (and give clear reasons for this), prognosis may be discussed in only a third of consultations.This study included a relatively large number of patients recruited from consecutive consulters presenting to several general practices, and representing a range of common musculoskeletal pain complaints. Although the response to the baseline questionnaire was high (77%) some groups, such as those with poor literacy skills, lower levels of formal education or non-English language speakers may be under-represented amongst responders, affecting the generalisability of our findings. Some information on the demographics of these groups is available. The population of East Cheshire is predominantly white British . Furthermore, the percentage of participants describing their ethnic group as white in participating practices ranges from 97.5% – 98.7% and as such English language difficulties may be less of problem for this study than for similar research conducted elsewhere . For thiThe relatively low frequency of prognostic discussion in the consultation is based on patient recall and although the average time between consultation and receipt of the completed questionnaire was only 16 days, 40–80% of information in consultation is immediately forgotten by patients and recall may be poorer in older age groups . It is pThe proportion of older patients with musculoskeletal pain thinking prognostic information is important is similar to previous studies of other conditions including metastatic cancer, breast cancer, chronic obstructive pulmonary disease, congestive heart failure, dementia, and a range of physical symptoms -7,23 givA minority of participants did not think that it was important to know what was likely to happen to their pain. The reasons for this are revealing. Some relate to common misconceptions that patients and professionals may have about musculoskeletal disorders  . A balanWe asked participants if they felt prognostic information on the likely course of their musculoskeletal pain was important. A majority of participants thought it was. Yet it cannot be assumed that all patients favourably disposed to receiving prognostic information would necessarily wish prognostic discussion to take place in their consultation or that such discussion would influence their health outcomes. These considerations are important and need to be evaluated before recommending that prognostic dialogue should become a routine part of the consultation for older people with musculoskeletal pain.The value of prognostic information may be depend upon the specific nature, extent, and timing of such information. Our findings merely indicate the general beliefs in the importance of prognostic information and the apparent shortfall of information provision in practice. Further work is needed on which outcomes are of interest to patients , how much information is most useful, and in what form prognostic information should be given. Although only a minority of patients in this study recalled discussing prognosis with their general practitioner, the problem may not be a lack of prognostic discussion in the consultation, but a lack of simple, useful, explicit information that patients understand and retain.Giving greater priority to prognostic discussion in the time-constrained consultation must presumably be at the expense of something else. Our study did not ask patients to rate the importance of other aspects of the consultation  or rank the relative importance of prognostic information, although studies that considered this for other conditions have found that patients consistently rank prognostic information highly .In conclusion, our findings suggest that whilst most older patients with musculoskeletal pain felt information on prognosis is important, prognostic discussion within the consultation is only infrequently recalled. Researching the views of prognostic discussion with older patients with musculoskeletal pain is currently not as advanced as for other conditions such as cancer and COPD. The precise information needs of patients, the most suitable way to communicate this information, and the potential health consequences of such dialogue remain unknown, making the delivery of accurate and appropriate prognostic information a continuing challenge to healthcare professionals.The authors declare that they have no competing interests.CM and GP designed the study, were responsible for data collection, conduct and analysis. CM and GP wrote and revised the manuscript. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here: