The tissue origin of low back pain (LBP) or referred lower extremity symptoms (LES) may be identified in about 70% of cases using advanced imaging, discography and facet or sacroiliac joint blocks. These techniques are invasive and availability varies. A clinical examination is non-invasive and widely available but its validity is questioned. Diagnostic studies usually examine single tests in relation to single reference standards, yet in clinical practice, clinicians use multiple tests and select from a range of possible diagnoses. There is a need for studies that evaluate the diagnostic performance of clinical diagnoses against available reference standards.We compared blinded clinical diagnoses with diagnoses based on available reference standards for known causes of LBP or LES such as discography, facet, sacroiliac or hip joint blocks, epidurals injections, advanced imaging studies or any combination of these tests. A prospective, blinded validity design was employed. Physiotherapists examined consecutive patients with chronic lumbopelvic pain and/or referred LES scheduled to receive the reference standard examinations. When diagnoses were in complete agreement regardless of complexity, "exact" agreement was recorded. When the clinical diagnosis was included within the reference standard diagnoses, "clinical agreement" was recorded. The proportional chance criterion (PCC) statistic was used to estimate agreement on multiple diagnostic possibilities because it accounts for the prevalence of individual categories in the sample. The kappa statistic was used to estimate agreement on six pathoanatomic diagnoses.In a sample of chronic LBP patients (n = 216) with high levels of disability and distress, 67% received a patho-anatomic diagnosis based on available reference standards, and 10% had more than one tissue origin of pain identified. For 27 diagnostic categories and combinations, chance clinical agreement (PCC) was estimated at 13%. "Exact" agreement between clinical and reference standard diagnoses was 32% and "clinical agreement" 51%. For six pathoanatomic categories , PCC was 33% with actual agreement 56%. There was no overlap of 95% confidence intervals on any comparison. Diagnostic agreement on the six most common patho-anatomic categories produced a kappa of 0.31.Clinical diagnoses agree with reference standards diagnoses more often than chance. Using available reference standards, most patients can have a tissue source of pain identified. Different pathoanatomic conditions and mechanisms in the lumbar spine and pelvis region may produce low back pain (LBP), pelvic or lower extremity symptoms. The most frequent tissue sources of lumbopelvic and referred pain are the intervertebral discs, zygapophysial (facet) and sacroiliac joints . Nerve rThe clinical examination  is the basis upon which management rests. The diagnostic value of this examination is debatable for all but a minority of cases. A few symptomatic patho-anatomic entities such as disc herniations causing nerve root compression, symptomatic spinal stenosis, radiologically demonstrated fractures and neoplasms may be identified using the clinical examination in combination with advanced imaging studies. The current project was conceived to compare diagnoses derived from a detailed clinical examination by a physiotherapist, with expert diagnoses obtained using available reference standards for diagnosis of discogenic, facetogenic, SIJ, hip joint, nerve root pain and symptomatic spinal stenosis.A prospective, blinded, reference standard-related design was utilized. The Louisiana Institutional Review Board approved the study and all included patients signed an informed consent form. A physiotherapist with 30 years experience as a manipulative therapist attended a specialist spinal diagnostic clinic in Louisiana, for blocks of 4–8 weeks between May 2001 and October 2002 and examined consecutive chronic LBP patients during these periods. Clinical examinations required between 30 and 60 minutes and were carried out immediately before the reference standard diagnostic tests. A radiologist with 20 years experience in fluoroscopically guided diagnostic injections and interpretation of advanced imaging techniques attempted to identify the tissue origin of chronic LBP, based on imaging and responses to diagnostic injections. These diagnoses were the reference standards against which diagnoses arrived at by the clinical (physiotherapy) examination were contrasted. Another therapist with 17 years clinical experience carried out examinations of 13 patients. Figure The great majority of possible causes of LBP are uncommon, even rare. Appendix 1 presents those painful clinical entities believed to be most common and the procedures used as diagnostic reference standards [see additional file In addition, three other categories were available to the examining clinicians – "illness behaviour" where the patient's behaviour and responses to questioning and examination suggested psychosocial distress of some kind, "others" (for the more uncommon causes of pain) and an "indeterminate" category where no conclusion could be reached.At presentation, clinic staff collected medical history, demographic and questionnaire data. If informed consent was obtained, the physiotherapist examined the patient and the patient received scheduled diagnostic injection procedures in sequence.The physiotherapy examinations were conducted blind to the results of disability and self report questionnaires, the results of previous imaging studies and diagnostic injections. The physician was blinded to the results of the physiotherapy examination and diagnostic conclusions.The clinical reasoning by which the physiotherapist reached a diagnosis has been presented elsewhere in detail ,19. VerySome data on the diagnostic accuracy of the clinical tests used in the physiotherapy clinical examination was available prior to commencement of the study. A summary for key tests is presented in Appendix 2 [see additional file The physiotherapist and physician recorded their diagnoses on standardised forms. In January 2003 a meeting of researchers and experienced clinicians was convened at the Auckland University of Technology to recommend the method by which the diagnosis data were to be entered into an electronic database for analysis.© 2001). Two variables were constructed to record agreement between physiotherapy and reference standard diagnoses. "Exact agreement" was recorded when the two diagnoses were exactly the same in all respects, including multiple diagnoses. "Clinical agreement" was recorded when the physical therapy diagnosis was included within the reference standard diagnosis . All cases of 'exact' agreement are included within 'clinical' agreement. Confidence intervals (CI) for proportions were calculated using recommended methods [© T Bryant 2000 [Data were entered and stored in an electronic database , sacroiliac joint, nerve root, hip joint and spinal stenosis. Where more than one diagnosis was provided, the case was included in each diagnostic category. For example: If the physiotherapist diagnosis was: disk and nerve root, the counts for both disk pain and nerve root pain were incremented by one. If the reference standard diagnosis was disc, nerve root and spinal stenosis, each of these diagnostic categories were incremented by one. Consequently there were many more diagnoses than patients.During the study period, 296 patients were invited to participate in the project and 78 were excluded. Reasons for exclusion were: 53 declined to participate, ten had no injection or other procedure carried out because of insufficient pain on the day of examination, nine were excluded because of time constraints, three patients were deemed incompetent to understand study procedure, blinding was compromised in two cases, and contradictory diagnostic reporting of diagnostic injection results occurred in one case. Table 1 presents demographic, historical and profile data for included patients (n = 216) [see additional file Table 2 presents a cross-tabulation of physiotherapist diagnoses with diagnoses reached by the interventional radiologist [see additional file a priori in this study and "indeterminate" is the absence of a diagnosis. The primary objective was to evaluate agreement on patho-anatomic diagnoses. To evaluate agreement on diagnosis for the six main patho-anatomic diagnoses: discogenic pain, Z-joint pain, sacroiliac joint pain, nerve root (radicular) pain, hip joint pain and spinal stenosis, Table 3 was truncated (represented by the dashed lines), by removing the columns and rows for the other categories [see additional file Many of the diagnostic categories contained only one case, so diagnoses were grouped under nine general labels: disc, Z-joint, sacroiliac joint, nerve root, hip joint, spinal stenosis, "other", "illness behaviour" and "Indeterminate". A total of 368 diagnoses were provided by physiotherapy and reference standard clinicians through multiple diagnoses. "Illness behaviour" was the sole diagnostic conclusion or included in 79 (21.5%) of 368 conclusions by the reference standard clinician. The physiotherapy examiner used this description for 76 cases. "Indeterminate" was included in 84 cases by the reference standard clinician and in 91 cases by the physiotherapist. No reference standard for illness behaviour was established To our knowledge, this is the first study to estimate agreement between diagnoses based on blinded clinical (physiotherapy) examinations, and a range of diagnoses using available reference standards and other classification categories, in patients presenting with pain presumably of lumbopelvic origin. Overall agreement was better than could be expected on the basis of chance and ranged from 32% to 57% depending on agreement criteria and complexity of the diagnostic categorization analyzed. The proportion of patients indeterminate to reference standard diagnostic methods was 23%. However, the categories "illness behaviour", "indeterminate" and "instability" are non-pathoanatomic i.e. 'non-specific' in origin. There were 73 cases (34%) that the reference standard clinician classified using only these descriptions, and may be considered patho-anatomically 'non-specific'. This figure corresponds with claims that 46–75% of LBP patients have an identifiable tissue origin of pain using a reductionist approach to diagnosis [The kappa statistic measures strength of agreement between examiners discounting chance agreement. The achieved level of 0.31 is considered 'fair agreement' . HoweverThe data provides information about agreement on diagnosis between non-invasive and inexpensive clinical methods of diagnosis carried out by a physiotherapist and a radiologist using invasive and expensive diagnostic technology, over and above chance. Across the whole spectrum of possible reasons for patients attending a tertiary referral diagnostic clinic estimated exact agreement is 19% (32% versus 13%) over and above chance. In practical terms, exact agreement is not required or expected when examining complex patients. 'Clinical agreement' is a more appropriate measure in that it is a measure of the degree to which the physiotherapist can reach accord with at least one part of the diagnosis. Clinical agreement is also estimated to be 19% better than chance agreement. For patho-anatomic categories, agreement over chance is 24% (57% versus 33%). The greater agreement on the six patho-anatomic categories may be a result of clearer diagnostic criteria for categorization by both clinicians. Some discordance between the physiotherapy and reference standard diagnoses resulted from one examiner being able to reach a diagnosis where the other was unable to carry out the examination(s) needed. Restrictions inherent in some referrals, meant that with some cases, the physiotherapist was able to reach a diagnosis, but the radiologist could not use the appropriate procedure necessary to provide a diagnosis for comparison. Conversely, some patients could not tolerate some parts of the physiotherapy clinical examination, whereas a clear diagnostic result was possible using interventional diagnostic procedures. These cases of unilateral indeterminacy resulted in disagreements, whereas agreement may have been possible if both clinicians could have fully examined the patients.It was anticipated was that discogenic pain cases would be more numerous than other tissue sources of pain with 85 (39%) receiving this diagnosis and 59 (27%) having this as the sole diagnosis. This proportion is in concord with previous results . Fewer ZIn this sample 22 cases (10%) received two patho-anatomic diagnoses (by available reference standards), and two had three identified pain generators (Table 2). To our knowledge only one other study has reported multiple sources of nociceptive input to low back pain with about 3% having co-existent disc and ZJ pain . In the An issue for this study concerns generalizability. The patients were chronic and distressed and nearly 30% of included patients had a history of lumbar spinal surgery with persistent or recurrent pain. Physiotherapists do see patients in all stages and degrees of LBP and our results are arguably generalizable to more chronic patient populations. We did not exclude patients with a history of spinal surgery, so this study may be more representative of tertiary care patient samples than other back pain studies. Generalizability to acute and subacute LBP populations is not appropriate, but at the conceptual level at least, it may be argued that acute and subacute patients would be less complex than patients in this study. Consequently our results may represent the lower bound of potential agreement between physiotherapy diagnostic conclusions and reference standard diagnoses.Another issue involving generalizability concerns the examining physiotherapists. Are the diagnostic techniques and procedures used, representative of a special interest "craft" group and not within the normal domain of practicing clinicians? Physiotherapists have a wide range of special interests generally and there are many schools of thought within musculoskeletal practice. In the last 15 years, an 'extended practice' role for physiotherapists in orthopaedic musculoskeletal practice has emerged  requirinThe use of discography, ZJ and SIJ blocks as reference standards may be criticized on the basis that false positives may compromise their status as "gold standards" ,61. It iA comprehensive history and physical examination similar to that utilized in the current project has some potential to predict the diagnostic conclusions reached by an experienced physician using sophisticated and invasive technologies. Most of the agreement calculated was made up from identifying pain originating from the lumbar discs and the hip joints. Previous research has shown that pain arising from the ZJ joints cannot be characterized by clinical examination variables ,58,63, aThe diagnosis of instability is fraught with conceptual and terminological difficulties without widely accepted clinical diagnostic criteria ,32,64. INerve root pain was the second most common tissue-based diagnosis made by both physiotherapist and radiologist after discogenic pain. Although conceptually and clinically distinct, radiculopathy  and radicular pain  were combined in the diagnosis of "nerve root pain". It was differentiated from somatic referred pain believed to result from central nervous system convergence . In thisOn the surface, agreement does appear to be weak even though better than chance. However, this does not concern us greatly. This is a pragmatic report of the overall performance of a low tech clinical examination and diagnoses achieved, compared to highly sophisticated and predominantly invasive procedures with a complex group of patients. The high proportion of cases deemed to be diagnostically indeterminate or displaying confounding illness behaviours (in the opinion of the clinicians) attests to the complexity. The 50% agreement on patho-anatomic categories achieved in this study was about what was hoped for prior to commencement of these studies. As a consequence of this work, certain significant modifications to the clinical examination can be made and subsequent studies may demonstrate an improvement on what we achieved here. 'Exact agreement' is a very demanding requirement when multiple pathologies are present. 'Clinical agreement' as described in the paper is really all that can be expected of a low tech clinical examination of patients with low back pain – a symptom commonly described as 'non-specific' in the low back pain literature.Using available reference standard technique, two thirds of patients received a pathoanatomic diagnosis with multiple pain generators identified in 10% of cases. Diagnoses of the tissue origin of chronic LBP or referred lower extremity symptoms by experienced physiotherapy clinicians agreed with available reference standard diagnoses 19–24% over and above expected chance agreement.The authors declare that they have no competing interests. All authors declare that their contributions to this paper have been independent of influence from funding agenciesConcept and research design provided by ML, CA, BÖ and HT. Project management provided by ML. Facilities and equipment provided by CA. Writing provided by ML, BÖ and BM with manuscript review by HT. Data analysis, statistical support and manuscript review provided by BM. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Flow diagram of patient recruitment patterns in the project.Click here for fileTable 1. Demographic, medical and psychometric profile of chronic low back pain patients.Click here for fileTable 2. Cross tabulation for physiotherapist and reference standard / expert opinion diagnosesClick here for fileCross-tabulation of reference standard / expert opinion and physiotherapy diagnostic groupsClick here for fileAppendix 1. Description of reference standards used in pathoanatomic diagnoses in low back painClick here for file


Gabapentin is an antiepileptic drug used in a variety of chronic pain conditions. Increasing numbers of randomized trials indicate that gabapentin is effective as a postoperative analgesic. This procedure-specific systematic review aims to analyse the 24-hour postoperative effect of gabapentin on acute pain in adults.Medline, The Cochrane Library and Google Scholar were searched for double-blind randomized placebo controlled trials of gabapentin for postoperative pain relief compared with placebo, in adults undergoing a surgical procedure.Qualitative analysis of postoperative effectiveness was evaluated by assessment of significant difference (P < 0.05) in pain relief using consumption of supplemental analgesic and pain scores between study groups.Quantitative analyses of combined data from similar procedures, were performed by calculating the weighted mean difference (WMD) of 24-hour cumulated opioid requirements, and the WMD for visual analogue scale (VAS) pain, (early (6 h) and late (24 h) postoperatively), between study groups. Side-effects  were extracted for calculation of their relative risk (RR).Twenty-three trials with 1529 patients were included. In 12 of 16 studies with data on postoperative opioid requirement, the reported 24-hour opioid consumption was significantly reduced with gabapentin. Quantitative analysis of five trials in abdominal hysterectomy showed a significant reduction in morphine consumption  -19 to -8 mg), and in early pain scores at rest  and during activity , favouring gabapentin. In spinal surgery, , analyses demonstrated a significant reduction in morphine consumption (WMD of – 31 mg (95%CI – 53 to -10 mg) and pain scores, early  and late  also favouring gabapentin treatment. Nausea was improved with gabapentin in abdominal hysterectomy . Other side-effects were unaffected.Perioperative use of gabapentin has a significant 24-hour opioid sparing effect and improves pain score for both abdominal hysterectomy and spinal surgery. Nausea may be reduced in abdominal hysterectomy. Prevention and treatment of postoperative pain and complications such as nausea and vomiting, continues to be a major challenge in postoperative care and plays an important role in the early mobilization and well-being of the surgical patient. Opioid analgesics, with their well-known side-effects, continues to represent a cornerstone in postoperative pain control, and testing new analgesics as well as combinations of analgesics in order to reduce the need for opioids, is a key area in acute pain research. 2δ subunit of voltage dependent calcium channels [Gabapentin, an anti-epileptic drug that has demonstrated analgesic effect in both diabetic neuropathy, post-herpetic neuralgia and neuropathic pain -4, affecchannels . In painAn increasing number of randomized trials indicate that gabapentin is effective as an postoperative analgesic. Until now, four meta-analyses with pooled data from rather few studies  , demonstRelevant randomized controlled trials were identified by performing a Medline , a CochrReports were considered if they were double-blind, randomized controlled trials of gabapentin  for postoperative pain relief compared with placebo (control intervention group) in adult patients (> 18 years) undergoing a surgical procedure. Only studies, in which data on either pain  or verbal score (VRS)) or supplemental postoperative analgesic consumption were stated, were included. Studies with less than 10 patients in treatment arms were not included .Each identified study was read and scored independently by two authors (OM + JBD), using a 5-point scoring system as described by Jadad et al . If the Data from the studies were extracted onto a datasheet by one of the authors (OM). This included type of surgery; number of patients in intervention and control groups; time of administration and regimen of gabapentin treatment; mean VAS pain scores at rest and during mobilization early (at 4 or 6 hours) and late (at 24 hours) after surgery; supplemental analgesic regimen; type of and amount of supplemental analgesic consumption; and possible side-effects . Side-effects reported as somnolence or drowsiness were grouped under sedation, and reports of light-headedness and vertigo were grouped under dizziness. Pain reported on a 0 – 10 scale was converted to a 0 – 100 scale. In dose-finding studies, we extracted data from each dose-group onto the data sheet. When data in a study was only shown graphically, we extracted data from graphs. We contacted eight authors to get supplemental data for analysis, and received requested information from all.Qualitative analysis of postoperative effectiveness was evaluated by assessment of significant difference  in pain relief using consumption of supplemental analgesic and pain scores between study groups, and by an assessment of clinical importance of observed findings. In addition, internal sensitivity was evaluated by an assessment of pain scores. It has been recognised that adequate sensitivity in trials of analgesics for acute pain, may only be achieved when patients are experiencing at least moderate pain (VAS pain score > 30 mm) with placebo, as it is difficult to detect an improvement with a low degree of pain ,17.Quantitative analyses of combined data were only performed with data from similar procedures (e.g. hysterectomy), but not across trials with different surgical procedures.Quantitative analyses of combined data from similar procedures were performed by calculation of the weighted mean difference (WMD) of the 24-hour cumulated opioid use between study group, and by calculation of WMD of VAS pain scores between study groups early (4 – 6 h) and late (24 h) after surgery, whenever sufficient data were provided in original papers (e.g. standard deviation (SD), number of included patients in each study group and the relevant mean value).Opioids other than morphine were converted to their morphine equivalents, based on the equivalence of 100 μg fentanyl, 5 mg ketobemidone, and 100 mg tramadol respectively to 10 mg morphine.From papers where data were available, dichotomous data were extracted for calculation of the relative risk (RR) of side-effects .Quantitative analyses were performed using the Review Manager (RevMan) software . A random effect model was used if the statistical test for heterogeneity was positive, and a fixed effect model if the test came out negative.Our Medline and Cochrane Library search revealed 28 relevant randomized trials published in the period from 2001 to 2006. One additional paper was identified by the Google Scholar search, giving a total of 29 relevant trials. All trials were published in English.Six trials were subsequently excluded. One  was onlyThus, data from 23 trials including a total of 1529 patients, of which 810 received gabapentin were included.One trial  tested fAn overview of the included trials is presented in Table The surgical procedures were abdominal hysterectomy in five studies -31, spinIn most studies gabapentin was administered one to two hours preoperatively, but in three studies ,34,36 a In sixteen studies a single dose of gabapentin, varying from 300 mg to 1200 mg was administered and in seven studies ,36,39,46Supplemental analgesia was in fourteen trials administered as intravenous patient controlled analgesia (PCA), in four studies ,36,37,46Morphine was used as postoperative analgesic in most studies, but four studies ,26,32,37Sixteen studies provided data on 24-hour opioid consumption. The 24-hour morphine or calculated morphine equivalent usage was ranging from 4 to 99 mg in the treatment groups, and from 6 to 122 mg in the placebo groups, with a large variation between surgical procedures .  VAS pain scores at rest. WMD between treatment groups was significant in favour of gabapentin . Figure The WMD of late 24 h) VAS pain scores between treatment groups was non-significant .  Figure .Four trials including 112 patients receiving gabapentin provided data on postoperative nausea, and the combined data showed that the RR was significant in favour of gabapentin  Figure .Three trials including 89 patients receiving gabapentin reported on the incidence of dizziness, and the combined data showed that the RR was non-significant   Figure .In summary, cumulative 24-hour opioid consumption and early pain scores were significantly reduced with gabapentin. Nausea, but not vomiting, dizziness and sedation, was significantly reduced with gabapentin.Three studies administered a single dose of preoperative gabapentin and one study a multiple doses regimen.   Figure .In the same trials the WMD of late VAS pain scores at rest was also significant in favour of gabapentin  Figure .Pain scores during activity early after operation were only provided in one trial  and founFour trials provided data on postoperative nausea and vomiting. The combined data showed that the RR's were non-significant  Figure  + 15 .Three trials including 133 patients receiving gabapentin reported on the incidence of postoperative dizziness. Combined data showed that the RR was non-significant  Figure .Three trials including 135 patients receiving gabapentin provided data for the incidence of postoperative somnolence and sedation, and combined data showed that the RR was non-significant. . Figure .In summary, cumulative 24-hour opioid consumption, and early and late pain intensity at rest was significantly reduced with gabapentin. Nausea, vomiting dizziness and sedation was not affected by gabapentin.This is the first systematic review with focus on procedure-specific effects of gabapentin in postoperative pain, and we have demonstrated that preoperative gabapentin reduces 24-hour postoperative opioid consumption for patients in abdominal hysterectomy and spinal surgery. For abdominal hysterectomy pain scores at rest and during activity were significantly improved with gabapentin in the early but not the late postoperative phase, whereas pain scores for patients in spinal surgery were improved at rest both early and late. Furthermore, an improvement in the incidence of nausea for abdominal hysterectomy patients was demonstrated, whereas no other side-effects  showed significant differences between treatment groups.The overall 24-hour reduction in opioid consumption following abdominal hysterectomy as well as spinal surgery, confirm the results from reviews with pooled data from a variety of surgical procedures -9, and tIn our review the opioid sparing in abdominal hysterectomy (13 mg morphine), is somewhat different from that of spinal surgery (32 mg morphine), and several reasons for this result could be thought of. First, data for spinal surgery might have been skewed, since one trial  used verThe relevance of the pain score improvement demonstrated in the quantitative analysis is debatable. A minimal clinical significant change in patient pain severity has previously been measured as 13 mm in trauma patients ,48, and However, comparison of pain scores during PCA treatment is problematic since the patients can avoid uncontrolled pain in both treatment groups. Accordingly, our primary outcome parameter was morphine consumption.max in plasma is 2–3 h, the plasma level of gabapentin accordingly is higher in the early postoperative phase. One study [Our analyses indicate, that preoperative gabapentin reduces postoperative pain scores more effectively in the early rather than the late postoperative period. Several explanations may be possible. Most studies used a single dose of gabapentin, and since Tne study  has demoIn the most recent review  the authOne of the major challenges in postoperative pain treatment is to combine different treatment modalities, in order to improve patient analgesia and potentially reduce side-effects . A corneIn this light it is noteworthy, that despite of the opioid sparing effect with gabapentin, our analyses of side-effects showed a just significant lower incidence of nausea in favour of gabapentin for abdominal hysterectomy, but not spinal surgery patients, while vomiting and sedation were non-significant between treatment groups. These disappointing results correspond with results from another review on opioid sparing with the use of COX-2 inhibitors and the lack of evidence for reduction of opioid related side-effects .One of the reasons for this finding could be the relatively small number of patients and thereby low statistical power of our analyses. A post-hoc statistical power calculation of the non-significant quantitative analyses of adverse events, using a risk of Type I error on 5% and the observed cumulated difference between treatment groups, revealed a statistical power of less than 50% on analyses of most adverse events in both abdominal and spinal surgery.Another reason could be the lack of quality of data on adverse events from the original papers, as in most reports adverse events were not well defined and only reported as present or absent. Furthermore, data of adverse events were a mixture of spontaneous reporting and specific questioning.We did not find any sign of clinically limiting side-effect with the use of gabapentin, and especially the data for sedation and dizziness were non-significant. It is possible that the well-known sedative effect of gabapentin may be masked by the use of opioids in the studies and the fact that we monitor patients in the early phase after general anaesthesia.The wide variability of gabapentin dosing regimens, and the differences in pain score- and side-effect evaluation, undoubtedly influences the outcome of this review, as do the pooling of different rescue analgesics . By making this review procedure specific we tried to minimize variability in the pooled outcome parameters, but differences in e.g. surgical techniques among the different centres may still limit our analyses.Another important limitation for the interpretation of the analgesic effect of gabapentin is the low VAS pain score in many of the included trials, both early and especially 24 hour postoperatively, since previous studies has emphasized the importance of moderate to high initial pain intensity in postoperative assessment of analgesic drugs .In our quantitative analysis the primary outcome is PCA or "on demand" opioid consumption with simultaneous VAS-pain measurement. The assumption is that patients in the active and control treatment groups will titrate "down" to the same low VAS-pain, and the difference in opioid consumption at the same VAS-pain gives us the valid difference in opioid consumption. This only happens in three of nine trials which is a limitation when the analgesic effect of gabapentin is interpreted.All trials in this review were randomized and the methodological quality satisfactory, the median Oxford quality score being 5, and so selection bias should not have been a problem. Most trials reported of a positive outcome of either opioid reduction or pain score improvement, and publication bias  cannot be ruled out. Given the nature of abdominal hysterectomy gender bias is not the case here, whereas for the spinal surgery trials twice as many male patients were included as women (173 vs. 93). However, since the male/female distribution generally was equal among treatment groups, we find no tendency to gender bias in the trials. Language restriction to only articles published in English could be a potential bias, but we did not find any non-English published articles. Many analyses revealed heterogeneity among the included studies, and in these cases we used a random-effect model in the analyses to compensate. Finally almost all studies represent small sample sizes with the increased likelihood of Type 2 errors.The development of chronic post surgical pain has attracted increased attention  and withIn the qualitative analysis of the trials we found no obvious dose-response relationship for the use of perioperative gabapentin. One trial  investigIn a recent pilot trial by Leung and colleagues , preoperIn conclusion, the perioperative use of gabapentin has a significant 24-hour opioid sparing effect for both abdominal hysterectomy and spinal surgery patients, whereas the reduction in pain score is more inconsistent. Nausea may be reduced in abdominal hysterectomy. All other side-effects were non-significant between treatment groups.Future trials in this area should include gabapentin as part of a multimodal postoperative treatment strategy, with focus on both acute and chronic pain states. Pain score during mobilisation is mandatory, and the effect of gabapentin on postoperative delirium needs further exploration.Dr. Dahl has received an unrestricted research grant from Pfizer, Denmark.OM was involved with searching, data extraction, quality scoring, analysis and writing, SM was involved with analysis, writing and JBD was involved with quality scoring and writing.The pre-publication history for this paper can be accessed here:Search strategy. the search strategy for trials included in the review.Click here for file


Spinal pain is a common problem, and disability related to spinal pain has great consequence in terms of human suffering, medical costs and costs to society. The traditional approach to the non-surgical management of patients with spinal pain, as well as to research in spinal pain, has been such that the type of treatment any given patient receives is determined more by what type of practitioner he or she sees, rather than by diagnosis. Furthermore, determination of treatment depends more on the type of practitioner than by the needs of the patient. Much needed is an approach to clinical management and research that allows clinicians to base treatment decisions on a reliable and valid diagnostic strategy leading to treatment choices that result in demonstrable outcomes in terms of pain relief and functional improvement. The challenges of diagnosis in patients with spinal pain, however, are that spinal pain is often multifactorial, the factors involved are wide ranging, and for most of these factors there exist no definitive objective tests.The theoretical model of a diagnosis-based clinical decision rule has been developed that may provide clinicians with an approach to non-surgical spine pain patients that allows for specific treatment decisions based on a specific diagnosis. This is not a classification scheme, but a thought process that attempts to identify most important features present in each individual patient. Presented here is a description of the proposed approach, in which reliable and valid assessment procedures are used to arrive at a working diagnosis which considers the disparate factors contributing to spinal pain. Treatment decisions are based on the diagnosis and the outcome of treatment can be measured.In this paper, the theoretical model of a proposed diagnosis-based clinical decision rule is presented. In a subsequent manuscript, the current evidence for the approach will be systematically reviewed, and we will present a research strategy required to fill in the gaps in the current evidence, as well as to investigate the decision rule as a whole. Chronic spinal pain is an increasingly common problem in Western Society . Spinal It has been repeated over the years that only in 15% of patients with spinal pain can a definitive diagnosis be made -6. HowevThe purpose of this paper is to present the theoretical model of a diagnosis-based clinical decision rule (DBCDR) for the diagnosis and non-surgical management of patients with spinal pain. The model considers a number of known or suspected factors that contribute to the clinical picture and allows for the development of a management strategy that is derived from the multifactorial diagnosis. This paper presents the conceptual model of this clinical decision rule and its application in the clinical setting. In a subsequent manuscript we will systematically review the evidence regarding the components of the approach, and present those areas of research needed to investigate its validity and usefulness to spine clinicians.The DBCDR is based on what the authors refer to as the 3 essential questions of diagnosis. It is suggested here that the answers to these questions supply the clinician with the most important information required to develop a specific diagnosis from which a management strategy can be derived. The 3 questions are:There are several diseases for which spinal pain may be among the initial symptoms. It is important for any physician seeing patients with spinal pain to be aware of these disorders and to be skilled enough in differential diagnosis to detect, or at least suspect, their presence. The most important diagnoses are listed in Table In asking this question, the clinician is not necessarily attempting to determine the precise tissue of origin, but rather is trying to identify characteristics about the pain source that allow treatment decisions to be made. There are a number of tissues in the spine that have the potential to generate pain. However, while a few studies have suggested that clinical factors can be used to detect specific pain generators in some instances ,8, to a Centralization signs are detected through methods originally developed by McKenzie ,10. The Examination for pain provocation signs involves the clinician attempting to reproduce the patient's pain by apply maneuvers designed to stress segmental tissues. In the cervical, thoracic and lumbar spine, this involves segmental palpation. This palpation is designed to assess for pain response, not necessarily movement abnormality -25. In tNeurodynamic signs involve the reproduction of pain resulting from tests designed to apply stress to neural structures. In the spine, neurodynamic signs most likely arise from radicular pain, most commonly arising from lateral canal stenosis and disc protrusion ,30. NeurMuscle palpation signs involve the reproduction of pain from direct palpation of muscles. These signs have typically been thought to implicate the presence of myofascial trigger points (TrPs) . Again, Pain referral pattern maps from various muscles have been developed  and are With this question, the clinician attempts to determine if there are any factors other than the pain generating tissue that serves to maintain or perpetuate the pain experience. It would appear that an essential aspect to effective management of patients with spinal pain would include the identification and management of those factors that place the acute or subacute spinal pain patient at risk of developing ongoing problems or, in the case of the chronic or recurrent spinal pain patient, that contribute to the perpetuation of pain and dysfunction. Table Several studies have demonstrated alteration in motor control strategies in patients with spinal pain -38. It iCPH is a state in which an alteration has occurred in the manner in which nociceptive information is received, processed and modulated, which serves to heighten the pain experience -53. IncrThe examination for Waddell's nonorganic signs  is a popMany studies have found impairment of oculomotor reflexes in patients with chronic neck pain after trauma -67 and iSimple and practical tests for oculomotor reflex function for use in the typical clinical setting are nonexistent. However, Heikklla and Wenngren  found siBoth fear and catastrophizing have been shown to be important predictors of present pain intensity and disability ,73 and oAs with fear and catastrophizing, passive coping has been shown to contribute to present disability  and to pAs with the psychological factors discussed previously, depression has been shown to contribute to present disability ,81 and pThe DBCDR is not a classification method. It is a diagnostic method. However, the "diagnosis", using the DBCDR, is not a traditional diagnosis, in which a diagnostic label is given to a disease entity based on the unique pathophysiology of the particular entity. Rather, it is a collection of signs, sometimes single and sometimes multiple, from which the clinician can make treatment decisions. Also, because of the absence of definitive findings on tests such as imaging in the majority of spinal pain patients, the diagnosis using the DBCDR is a working hypothesis that is tested through treatment. Figure Some examples of diagnoses using the DBCDR might be:1. Segmental pain provocation signs (question #2) and significant fear beliefs (question #3); rule out infection (question #1).2. Centralization signs (question #2) with impaired motor control and CPH (question #3).3. Segmental pain provocation signs with neurodynamic signs (question #2) and fear and catastrophizing (question #3); rule out myelopathy (question #1).Once the clinician has established a working diagnosis (based on the answers to the 3 questions), a management strategy would be developed. An important concept of management in this model is that none of the important factors that may be present in any given spinal pain patient occurs in isolation. Pain generators and perpetuating factors interact in producing the clinical picture that practitioners see. Figure In the model presented here, these are the management decisions that the clinician might make based on the findings of the diagnostic process:Any significant findings suggestive of visceral disease or serious or potentially life threatening illness would be investigated with further diagnostic work up and/or referral.The recommended treatment of choice for centralization signs is end range loading maneuvers in the direction of centralization , which iThe DBCDR does not depend on a known tissue of origin of the patient's pain; however, as centralization signs may be associated with disc pain in the lumbar spine , anotherIn the context of the DBCDR, it is recommended that in patients with segmental pain provocation signs as well as centralization signs, end range loading maneuvers be utilized first, with no action being taken regarding the segmental pain provocation signs until end range loading has been fully explored. In patients with segmental pain provocation signs who do not exhibit centralization signs, manipulation is the recommended treatment. The rationale for this is that it is known that manipulation has segmental effects, ,92 and sZygapophyseal  or sacroIn the acute stage, especially with disc protrusion, radicular pain is thought to be largely chemical, as a result of inflammation . As suchIn chronic stages, many patients  many pathoanatomic entities occur in the absence of spinal pain and 2) many people with spinal pain do not have identifiable pathoanatomic or pathophysiologic processes that would explain their pain.This led to the categorization of patients into 2 groups – "specific" spinal pain, i.e., those in whom a reliable and valid pathoanatomic diagnosis can be made, and "non-specific", i.e., those in whom the source of pain could not be identified. In recent years, a response to this limited categorization has come in the form of attempting to identify "subgroups" of spinal pain patients. This has resulted in various "classification systems" that have attempted to identify common characteristics in groups of spinal pain patients in the hope that certain treatments can be targeted to certain classifications of patients.The Quebec Task Force on Spinal Disorders  developeOne classification system is that of McKenzie . In thisAccording to McKenzie, the largest of these is the "derangement syndrome". In this group of patients, end range loading maneuvers are used to identify a characteristic pattern of "centralization" of symptoms when loading maneuvers are applied in a certain direction, and "peripheralization" of symptoms when loading maneuvers are applied in another direction .The McKenzie system, at least as it applies to the derangement syndrome, has been found to be efficacious for those patients for whom it applies ,123,124.So it appears that the McKenzie classification is useful in identifying at least one aspect of a diagnosis in most spinal pain patients. However, half the chronic LBP patients and an unknown percentage of cervical and thoracic pain patients do not have derangements and require some other methods with which to make a diagnosis. Nonetheless, the McKenzie approach plays a key role in the DBCDR presented here.Another classification system was initially developed by Delitto  and used1. Immobilization2. Mobilization3. Specific exercise4. TractionA similar classification system was developed for neck pain patients by Childs, et al . In this1. Mobility2. Centralization3. Conditioning and increased exercise tolerance4. Pain control5. Reduce headacheSo, with these classification schemes, patients are categorized into one of four or five groups, rather than into one of two groups . Evidence suggests that this has been a significant step forward, as patients with LBP who are treated according to this classification scheme have better outcomes than patients who are treated according to the two-category scheme . It is uWhile this classification is a significant advancement in that it attempts to identify those patients who are most likely to respond to specific treatments, it has its limitations. For example, patients with LBP are placed in the "mobilization" (or manipulation) category based on the following features :1. Symptom duration < 16 days2. No symptoms distal to knee3. < 19 on a Fear-Avoidance Beliefs Q4. At least 1 hypomobile lumbar segment5. At least 1 hip with > 35 degrees of internal rotationIn the classification system for the cervical spine, patients are placed in the "mobility" category based on these features:1. Recent onset of symptoms2. No radicular or referred symptoms into the upper quarter3. Restricted range of motion (ROM)4. No signs of nerve root compression or peripheralization of symptoms with ROMEvidence suggests that there are many patients who respond positively to manipulation who do not fit into these groups. For example, patients with chronic LBP and neck pain often respond to manipulation , as do mThe proposed DBCDR is different from these other systems in that it is not a classification system; there are no classifications in which patients are placed. Rather, those factors that are known or suspected to contribute to the clinical picture of spinal pain and all are considered in each patient, with the recognition that many patients have a variety of factors involved in his or her clinical picture, and thus defy easy classification. It also attempts to find those clinical features that play a role in each individual case, and apply treatments designed to address those features. Thus, the clinician in not limited to 3, 4 or 5 classifications, but is free to manage each patient according to those clinical features that are deemed most relevant in each case. Further research is needed to determine whether the DBCDR is truly a useful "rule" in helping clinicians make diagnostic and treatment decisions.The traditional management of patients with spine related disorders has typically been driven more by the training of the individual clinician than the needs of the patient. Research on treatments for spinal pain has placed patients into homogeneous groups, as if all patients had the same diagnosis. This has led to the conclusion among many that no treatment for spinal pain has a great deal to offer ,134. A nThe answers to these questions may allow the clinician to develop a working diagnosis from which a management strategy can be developed. This strategy is designed to address the most important factors suspected to be contributing in each case.The theoretical model of this proposed diagnosis-based clinical decision rule is presented here. In a subsequent paper, the evidence as is currently exists related to this model will be systematically reviewed and a research strategy will be presented, the purpose of which is to determine whether the model has sufficient reliability, validity and efficacy to recommend it as an alternative approach to patients with spinal pain.The author(s) declare that they have no competing interests.DRM conceived of the idea of the diagnosis-based clinical decision rule and was the principal author of the manuscript.ELH was responsible for help with design and presentation and with conceptualization of the presented research strategy.The pre-publication history for this paper can be accessed here:


Acute low back pain is a common condition resulting in pain and disability. Current national and international guidelines advocate general practitioner care including advice and paracetamol (4 g daily in otherwise well adults) as the first line of care for people with acute low back pain. Non-steroidal anti-inflammatory drugs (NSAIDs) and spinal manipulative therapy (SMT) are advocated in many guidelines as second line management options for patients with acute low back pain who are not recovering. No studies have explored the role of NSAIDs and/or SMT in addition to first line management for acute low back pain. The primary aim of this study is to investigate if NSAIDs and/or SMT in addition to general practitioner advice and paracetamol results in shorter recovery times for patients with acute low back pain. The secondary aims of the study are to evaluate whether the addition of SMT and/or NSAIDs influences pain, disability and global perceived effect at 1, 2, 4 and 12 weeks after onset of therapy for patients with significant acute low back pain.This paper presents the rationale and design of a randomised controlled trial examining the addition of NSAIDs and/or SMT in 240 people who present to their general practitioner with significant acute low back pain. Low back pain is a common condition with lifetime prevalence rates reported between 59 and 84% . On any A recent review of international guidelines  for the Each of the guidelines also recommended that if first line management options provide insufficient pain relief then additional therapies could be considered. However, there is no clear agreement on what the second line management options should include or at what time it/they should begin. All the guidelines endorsed the appropriate use of NSAIDs but only some guidelines (8 of 11) endorsed spinal manipulative therapy (SMT).Research to date has primarily addressed the issue of whether SMT and/or NSAIDs are more efficacious than placebo, however, this question does not reflect contemporary evidence-based practice in the management of low back pain. For the practitioner following the available guidelines the salient question is whether either of these two treatments are effective when delivered in addition to first line care universally endorsed in the low back pain treatment guidelines.The recent Australian National Health and Medical Research Council (NHMRC) acute low back pain guidelines 2003  concludeThe issue of whether spinal manipulation is more effective than placebo in patients who receive general practitioner (GP) advice and paracetamol as first-line care was not directly investigated in these systematic reviews. However, in the study by Curtis et al  all patiThe Cochrane Review on the role of NSAIDs in the management of low back pain  located In summary, there is high quality level I evidence that both SMT and NSAIDs are more efficacious than placebo treatments in patients with acute low back pain who receive no additional care. This evidence is of limited use to GPs managing patients with acute low back pain according to the widely accepted first line care. The most important clinical question is whether NSAIDs and/or spinal manipulation are effective when delivered in addition to the first line of care. At present there is no high quality evidence for this. In 2003, the NHMRC clinical practice guidelines for the evidence-based management of acute low back pain identified the need for research into the use of NSAIDs and spinal manipulative therapy and recommended testing these interventions in well-designed randomised controlled trials (RCTs) with 'advice to avoid bed rest and maintain usual activities' as the appropriate comparator .The primary aim of this study is to investigate whether the addition of SMT and/or NSAIDs to GP advice and paracetamol results in shorter recovery times for patients with significant acute low back pain. The secondary aims of this study are to evaluate whether the addition of SMT and/or NSAIDs to GP advice and paracetamol influences pain, disability and global perceived effect at 1, 2, 4 and 12 weeks for patients with significant acute low back pain.This randomised controlled trial will be conducted at approximately 20 general practice clinics and 10 private physiotherapy clinics within Sydney, Australia. Ethics approval has been gained from the University of Sydney Human Research Ethics Committee.Two hundred and forty participants with a new episode of significant acute non specific low back pain who present to GPs will be recruited. GPs will screen potential participants to ensure they satisfy the inclusion and exclusion criteria and will provide participants with an information sheet. The GP will then contact one of the researchers by phone and pass on the patient's contact details. The researchers will then organise an appointment within two days (excluding Sundays) to meet with the participant, formally enrol them in the trial if eligibility is confirmed at which time they will be randomised to a treatment arm of the study.To be eligible for the trial participants must meet all of the following criteria as assessed by the GP:th rib and buttock crease. This may or may not be accompanied by leg pain.• Primary complaint of pain extending in an area between the 12• New episode of low back pain. This is defined as an episode which was preceded by a period of at least one month without low back pain where the participant was not consulting a health care practitioner or continuing with medication for their low back pain .• Pain of less than six weeks duration.• Low back pain severe enough to cause moderate pain and moderate interference with normal work including work outside the home and housework (as measured by adaptations of items 7 and 8 of the SF-36).• No known or suspected serious spinal pathology .• No nerve root compromise evidenced by at least two of the following (i) myotomal weakness, (ii) dermatomal or widespread sensory loss, (iii) hypo or hyper-reflexia of the lower limb reflexes.• Not currently taking NSAIDs.• Not currently receiving SMT.• No spinal surgery within the preceding six months.• No history of peptic ulcer.• No allergy to aspirin.• Not currently receiving anticoagulant therapy.• No serious co-morbidities preventing prescription of NSAIDs or paracetamol eg: cardiac, liver or renal failure.• No contraindications to SMT or NSAIDsAt the first meeting with the researcher, baseline data will be collected from the participant. This will include contact details, personal details, outcome measures, and variables that will be assessed as predictors of response to treatment. Contact details for both the participant and a friend or relative who does not live with them will be collected to optimise follow up rates. Personal details recorded will include age, length of time symptoms have been present and the number of previous episodes of low back pain. The following baseline measures of outcome will be recorded:• Numerical pain rating scale on a 0–10 scale ;• A back specific disability scale  ;• A patient specific measure of disability ;Immediately after completing baseline measures participants will be allocated into treatment groups. Prior to the start of the study a researcher not involved in data collection or analysis will develop a randomisation schedule and produce consecutively numbered sealed opaque envelopes containing each participant's allocation. Randomisation will be performed using randomly permuted blocks of 4, 8 and 12. The researcher will select the next numerical randomisation envelope and open it. This envelope will contain a plastic bottle with the active or placebo NSAIDs which will be given to the participant along with a consumer medicine information sheet for diclofenac. The participant's name will be fixed to the medication. Placebo tablets with an identical shape and colour (including dose form excipients and coating) are dispensed making it impossible for the researchers or participant to differentiate between the active and placebo NSAIDs. The randomisation envelope will also contain a second smaller envelope containing the participant's allocation into active or placebo SMT. The researcher will give this envelope to the treating physiotherapist to open after the researcher has left. The researcher will therefore remain blinded to allocation for the NSAIDs and SMT arms. Treating physiotherapists can obviously not remain blinded to SMT allocation however they will be trained to respond identically to all patients regardless of treatment group except for the treatment provided.Patients will be allocated to one of four treatment groups as follows:• Control group (placebo NSAIDs and placebo SMT)• NSAIDs group (active NSAIDs and placebo SMT)• SMT group (placebo NSAIDs and active SMT)• SMT and NSAIDs group (active NSAIDs and active SMT)All participants in the study will receive standard care from their GP before baseline and allocation into a treatment group. Standard care in this study will involve advice and paracetamol (1 g four times daily), this being the first line of care advocated in both national and international clinical practice guidelines. Advice will include reassurance of a favourable prognosis and encouragement to avoid bed rest and stay active. Paracetamol will be prescribed at 4 gm per day (Two 500 mg tablets every 6 h). Paracetamol is to be continued at this dosage for a maximum of four weeks. If subjects recover before four weeks (zero or one out of ten pain for seven consecutive days) paracetamol will be stopped. All participants will also receive two follow up visits with their GP, one week and two weeks after their initial visit. At follow up visits GPs will reinforce the initial advice and ensure participants have no adverse reactions to the treatments. GPs will remain blinded to group allocation and instructed not to ask about the physiotherapy management.Participants allocated to receive active or placebo NSAIDs (diclofenac) will be instructed to take them according to an identical schedule. Dosage will be 50 mg bd taken with food for a maximum of four weeks or until the participant has recovered (zero or one out of ten pain for seven consecutive days).Participants allocated to receive SMT will receive treatment two or three times per week (at the therapist's discretion) for a maximum of 12 treatments over four weeks. If the subject recovers (zero or one out of ten pain for seven consecutive days) before four weeks the SMT will be stopped. Patients will receive spinal manipulative therapy according to a treatment algorithm developed by the researchers based on the views of expert clinicians and researchers in the field  17-20].-20.17-20SMT will be delivered by physiotherapists who have postgraduate training in manipulative therapy and who regularly use manipulative therapy in their clinical practice. Participating physiotherapists will be supplied with documentation defining their role in the trial and will undergo one hour of training from a researcher who is a physiotherapist. These physiotherapists will have as minimum training a Graduate Diploma in Manipulative Physiotherapy and two years clinical experience using manipulative therapy techniques.Therapists will be asked to keep a record of the number of times the participant attended for SMT and details of the treatment including the techniques and dosage. These will be used to ensure compliance with the protocol and to help describe the treatment given in this study.Placebo SMT will be prescribed using exactly the same schedule as active SMT. The placebo therapy used will be detuned ultrasound (US). The detuned US will be performed in a manner that mimics real US around the area involved for 5–12 minutes. Treatment sessions will last for the same time as for active SMT . Follow ups will include reassessing the participant's history and physical examination findings however no palpation of the spinal joints will be performed after the initial assessment. A re-evaluation of pain or range of motion will be done after the placebo treatment. In this way we will achieve close matching of the active and inactive interventions in terms of treatment duration and patient/therapist contact.Patients will be asked not to seek other treatments for their low back pain during the treatment period. In cases where this is unavoidable a record of additional treatments will be kept . Several mechanisms will be used to ensure that the trial protocol is consistently applied. Protocol manuals will be developed and all involved researchers  will be trained to ensure that screening, assessment, random allocation and treatment procedures are conducted according to protocol. An independent researcher will monitor adherence to assessment, randomisation and treatment procedures in a random group of participants.After four weeks all interventions will cease and participants will be asked not to seek other treatment before the three month follow-up if possible. Participants who do have further treatment will be asked to record the type and amount received.Outcome measures will be recorded by an assessor blinded to group allocation. Outcome measures will be collected using both a daily pain diary completed by the participants and weekly phone follow-ups for the first four weeks and at three months.The primary outcome is the number of days to recovery, with recovery defined in two ways. Firstly recovery is defined as a pain score of 0 or 1 on a 0–10 pain scale  that is maintained for seven consecutive days. Secondly recovery is defined as the first day that the patient has a pain score of 0–1 on a 0–10 pain scale. To ensure a precise estimate of the time to recovery, subjects will complete a daily pain diary (completed either first thing in the morning or last thing at night determined by the participant) until recovery. To minimize potential for lost data pain scores from the diaries will be read to the researcher at each of the phone follow ups. The researcher will then transcribe these into a second participant record. Diaries will be kept until the patient has scored 0 or 1 out of 10 for seven consecutive days or for a maximum of three months.The secondary outcomes are pain  , disabilCompliance with physiotherapy will be recorded by the treating physiotherapists. Compliance with the medications will be assessed by collecting unused medications at the end of the treatment period (4 weeks).Data will be analysed by a statistician who is blinded to group status. The primary analyses will be by intention-to-treat and we will restrict the number of analyses in order to reduce the possibility of Type I errors. For primary outcomes, a p value of <0.05 will be considered statistically significant. For the secondary outcomes a p value of <0.01 will be considered significant.For the primary outcome of days to reach recovery we will use survival curves with a log-rank statistic to assess differences between groups  and, if For secondary outcomes we will use a mixed model with group as a fixed factor. In these analyses, if there is a significant difference in secondary outcomes between treatment groups, we will conduct post-hoc analyses to inspect differences in secondary outcome variables at 1, 2, and 4 weeks and 3 months. We will also test for any additive or multiplicative effects between treatments on the outcome variablesSample size was calculated using equations for survival data. Two hundred and forty participants was determined to provide 80% power to detect a 20% difference in recovery rates between the control and intervention groups with an alpha level of 0.05. These calculations were based on a 50% recovery rate in the control group by three months. These numbers are probably conservative and based on results from our recent prognostic study of over 1000 subjects with acute low back pain. Higher rates of recovery will increase the statistical power. We allowed for 10% loss to follow up.We have presented the rationale and design for an RCT examining the effects of SMT and/or NSAIDs on patients with significant acute low back pain. The primary outcome will be days to recovery and secondary outcomes include pain, disability and global perceived effect at 1 week, 2 weeks, 4 weeks and 3 months. The results of this trial will be available in 2007.The author(s) declare that they have no competing interests.MH, CM, JL, AM, CC, RD, MS and JM were responsible for the design of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Description of active SMT.Click here for file


Management of pain related to advanced or metastatic cancer, although the availability of several pharmacological and non-pharmacological interventions and the existence of well-known guidelines and protocols, is often difficult and inadequate. Evidence of the relative effectiveness of current options for treating cancer pain from comparative randomized studies is scanty.In the context of a wider project, a multicenter, open label, prospective Outcome Research study will be launched in Italy in 2006 to investigate the epidemiology of cancer pain and of its treatments, the quality of analgesic-drug therapy and the effectiveness of alternative analgesic strategies in a large, prospective, unselected cohort of cancer patients using the state-of-the art of patient-reported-outcomes. About 100 Italian centers will recruit 2500 patients with advanced/progressive/metastatic cancer with pain (related to the cancer disease) requiring analgesic treatments. Each center is expected to recruit 25 consecutive and eligible patients during the study inception period. Approximately two months will be allowed for subject recruitment and enrollment. Subject evaluation and follow-up will be for 3 months. The effect on outcomes of various therapeutic analgesic options administered by physicians, given the observational approach where patients are not assigned at random to different treatments, will be compared using the propensity score approach, allowing the adjustment for treatment selection bias. Later, after the launch of the observational study and on the basis of results, in specific subsamples of patients and in select centers of the network, a Randomized Controlled Trial will be carried out to formally compare the efficacy of alternative analgesic strategies, with particular emphasis on oral morphine (as comparator) and buprenorphine patch . Results from the outcome (cohort) and experimental  studies will ensure both the external and internal validity. Pain afflicts most cancer patients, mainly in the advanced and metastatic phase of the disease . Recent Despite the existence of published and well-known guidelines for cancer pain management recommended by the World Health Organization (WHO) and effective treatments are available for 70–90% of cases , under tEvidence about pain prevalence, drug utilization and treatments effectiveness in cancer patients are scanty, most deriving from placebo trials, with very few comparative studies in large and well characterized cohorts of cancer patients. Furthermore, it is not available in medical literature any large parallel randomized controlled trial conducted in advanced cancer patients suffering from severe pain (step 3 in the WHO's pain ladder), comparing any alternative opioids to oral morphine -10.a) Opioids consumption is ranked among the lowest in Europe until 2000, with some improvements at least in terms DDD/100,000 people after the introduction of new opiods in the list of reimbursable drugs  in 2000 [b) Until January 2005, when a new bill was introduced at national level, no WHO-step II analgesic products were available in the list of reimbursable drugs in most of Italian regions, as well as some "strong" WHO-step III opioids, making it difficult for physicians the appropriate prescription of drugs and creating variability in drugs utilization across different Italian regions. c) A non appropriate use of transdermal fentanyl can be suspected, as too many patients received it as first option, although recommended only when oral morphine is inadequate [The general picture that derives from the analysis of experiences carried out in international settings does apply to Italy also, with some peculiarities:  in 2000 . b) Untiadequate .A multidisciplinary Advisory Board of experts in the field of cancer and pain treatments from Industry, Scientific Societies and Patients Associations was convened by the Mario Negri Institute on November 2003 to discuss the quality of pain management in cancer patients in Italy and, eventually, to recommend possible ameliorative educational and research strategies. Member of the Boards highlighted the lack of and the need for new empirical evidence about the epidemiology and the effectiveness of available therapeutic strategies, and called for a prospective program of research aimed at making available to treating physicians, patients and families valid information about pain management in cancer. Two main lines of activities were identified as necessary: information and education activities addressed to physicians, care givers and patients/citizens, and prospective data collection to document patterns of care and outcomes.Operationally, some working groups met several times during 2004, identified a selected sample of about 100 centers treating cancer patients with advanced/metastatic disease and pain that could be potentially eligible for a prospective study, and planned 3 types of activities to be implemented during the following 3 years (2005–2007): a) information and education: a prototype of educational course for professionals (physicians and nurses) has been assembled and tested on a sample of participants ; a critical appraisal of information available in the web (Internet) was also carried out with the preparation and publication of a meta-site that facilitates the use of selected (internet) resources for people interested and/or involved in issues related to cancer pain ; b) drugThe above initiatives are fully described elsewhere ,15. In tEvidence of the relative effectiveness of current options for treating cancer pain from comparative randomized studies is scanty. This study will investigate the epidemiology of cancer pain and of its treatments, the quality of analgesic-drug therapy and the effect of alternative analgesic strategies in a large, prospective, unselected cohort of cancer patients using the state-of-the art of patient-reported-outcomes. Later, Later, after the launch of the observational study and on the basis of results, in specific subsamples of patients, in select centers, a Randomized Controlled Trial (RCT) will be carried out to formally compare the efficacy of alternative analgesic strategies, with particular emphasis on oral morphine as comparator and buprenorphine patch as experimental arm. Results from the outcome and experimental studies will ensure both the external and internal validity. This kind of approach - a comprehensive cohort design study where all participants are followed up regardless of their randomization status, and outcomes of people who participated in the RCT can be compared with those who participated in the cohort study to assess their similarities and differences - is ideal for trials in which large proportions of eligible individuals are likely to be not entered in the RCT ,16-18.- To describe the characteristics of a large sample of cancer patients in terms of case mix (patients characteristics), pattern of care  and relevant efficacy  outcomes such satisfaction, quality of life measures) and safety outcomes .- To assess the quality of analgesic treatments in terms of congruence between patients' reported level of pain (intensity) and the potency of the prescribed analgesic drug  .The database will be used to evaluate the effects of various therapeutic analgesic options administered by physicians to patients. Given the observational setting, outcomes of subjects who were not assigned at random to different treatments will be compared using the propensity score approach, allowing the adjustment for treatment selection bias , as rece- To evaluate the effectiveness of treatment regimens on pain intensity and patient-reported quality of life- To evaluate the effect of treatment regimens on patient-reported satisfaction- To evaluate the safety profile (adverse and side effects) of alternative treatment regimensThis study will be designed as a multi-center, open-label, observational non-interventional trial in at least 100 centers, in Italy. Approximately 25 subjects will be enrolled in each center. Subjects will be treated by physicians according to the usual practice (standard of care) and followed over time using standardized methods and forms to make possible a valid and reliable description of case-mix, pattern of care and outcomes. Subjects will be monitored to evaluate the analgesic effects for 28 days (4 weeks) and then with a simplified scheme for further 8 weeks.- Baseline assessment (First visit).- Telephone contacts 24 and 48 hours after the inclusion (facultative).- Visit at day 7,14,21,28.- Final complete assessment at month 3  regarding patients'  outcomes and vital status; a summary of treatments delivered during the period is also planned.All patients, either new cases or already followed-up at the participating centers, with eligible (advanced or metastatic) solid cancers and with pain (related to cancer disease) requiring any treatment are eligible to be included during the study inception period.Each center is expected to recruit 25 consecutive and eligible patients during the study inception period.Approximately two months will be allowed for subject recruitment and enrollment. Subject evaluation and follow-up will be for 3 months.In order to be able to conduct and monitor the progress of the trial for the patients' safety and according to the World Medical Association Declaration of Helsinki and the European and Italian Good Clinical Practice guidelines, as well as to establish and guide the Group publication policy, several Committees, Boards and Groups have been assembled and organized in a pre-planned Trial Structure and Organization, with explicit guidance for its functioning. Basically, 4 hierarchical bodies will be created: an Advisory Board, a Steering Committee, a Protocol Writing Committee and a Project Management Group (Appendix 1 see ). If necAll patients seen at the participating centers during the study inception period will be screened, and if considered eligible included, registered and monitored over time. After a check of the eligibility and inclusion in the study, the investigator will assign treatments to patients according to the standard practice . In the case of prescription of WHO step-II and -III drugs, appropriate strategies will be recommended to reach the adequate individual pain control, with particular attention to titration, identification and management of side effects.The study will include patients:1. with diagnostic  evidence of advanced/progressive/metastatic solid tumor;average intensity of his/her pain over the last 24 hours), related to cancer, requiring analgesic treatment or already on analgesic treatment;2. with pain, any degree of intensity .All medications must be documented on the CRF.Subjects must be able to provide valid written consent, approved by the local Ethics Committee centrally by the study coordinating center.After consent is obtained, a subject will be enrolled when he/she meets all the inclusion criteria and none of the exclusion criteria. A sequential site-patient number will be assigned.After enrollment/inclusion, the following screening assessments will be performed and recorded: a) medical history including past cancer history, b) physical examination, c) recording of medications and recent therapies, including analgesic consumption, d) pain assessment using the Brief Pian Inventory (BPI), e) symptoms and side effects assessment, f) patient and physician global assessment (PGA), g) patient's self-reported health-related quality-of-life (HRQOL).According to the flow-chart Table , some evAt week 12 (3 months after the inclusion) a complete re-assessment is required: a) medical history including past cancer history, b) physical examination, c) recording of medications and recent therapies, including analgesic consumption, d) pain assessment using the BPI, e) symptoms and side effects assessment, f) patient and physician global assessment, g) patient's self-reported health-related quality-of-life.Pain will be assessed with the BPI ,23,24 whThe quality of analgesic treatments will be cross-sectionally assessed in terms of congruence between the patients' reported level of pain (intensity) and the potency of the prescribed analgesic drug . Operationally, self-reported pain intensity (from the BPI) and the level of most potent analgesic prescribed (from the CRF) will be combined to assemble a Index of Pain Management (IPM) that ranges from -3  to +3  . Data coQuality of life, satisfaction measures and symptoms/side effects check-lists will be administered to patients when planned during the follow-up -27.Information about all pain medications and number of rescue doses assumed by patients will be also recorded in the CRF.All adverse events, serious and non-serious, as well as generic, disease and treatment specific symptoms, encountered during the clinical study will be reported on the appropriate page of the CRF.According to data available from the literature and to preliminary results from an ongoing observational Italian study , we may Overall, considering the inception and the longitudinal evaluation, the entire duration of the study is estimated around 5 months. At the moment, more than 160 centers accepted to participate and 130 have successfully carried out a pilot phase of the study to test the study feasibility (Appendix 2 see ).According to the first main objective of the study , all patients enrolled in the study and eligible will be included in the statistical descriptive analyses. To avoid and minimize the impact of missing data, a bias that may be present in the case of using patient-reported measures as principal outcomes/endpoints -32, partAs to the assessment of the quality of analgesic care, the adequacy of pain management will be assessed firstly using the IPM, an index assembled by grouping with explicit and pre-planned rules patient with different intensity of pain and level of analgesic therapies . AlthougAs to the secondary objective of the study , given the non-randomized design the propensity score approach -22 will The Study will collect, describe and assess a vast array of outcomes measures related to pain and to its impact on patients' life. Some of these measures will be collected and reported by physicians and other directly by patients.average pain score of ≥ 2 points  at week 4 (day 28 from inclusion) over baseline.The predefined primary outcome measurement is the pain intensity over the first weeks, assessed with four questions from the BPI, that will be used either individually or after the computation of their mean, as indicated by developers ,23,24. TEscape/Rescue pain medications: counts of rescue/escape medications taken to control pain from inclusion to week 4 (day 28 from inclusion).Adequacy of analgesic-drug therapy: Patient Management index (PMI), categorized in a binary variable according to negative  and positive (conservative indicator of acceptable treatment) levels.Other patient-reported endpoints:HRQOL, Satisfaction with (drugs) treatment, rate and severity of symptoms, adverse and side effects.Before entering patients into the cohort study, clinicians/investigators must ensure that the Protocol has received clearance from the Local Research Ethics Committee (L-REC). The patients' consent to participate in the studies should be obtained after a full explanation has been given. Particular attention should be given to explaining the purposes, manner of the management and use of the patients' data from questionnaires and diaries. The right of the patient to withdraw from the studies in any time, without giving reasons, must be respected.The responsibility for drafting the manuscripts related to the analyses described in this protocol will lie with the WPC whose members will be the primary Authors. At least one representative from high-recruiting centers will be included among the co-authors, and all participants will be acknowledged in the Appendices. All authors should review and approve the manuscript before submission. At least two papers are expected: the first reporting on the results of the "epidemiological" part of the study, including a description of patients' characteristics in terms of baseline socio-demographic and clinical variables, pattern of care and main outcomes, and a discussion of the feasibility of this kind of approaches in the specific setting, the second about the effects (effectiveness) of treatments on patients (and physicians) reported outcomes.Appendix 1. Advisory Board, Steering Committee, Protocol Writing Committee and Project Management GroupClick here for fileAppendix 2. Members of the Cancer Pain Outcome Research Study GroupClick here for file