Intra-articular anesthetic drug injections are claimed to confirm the localization of the pain in order to treat the pain. The aim of the present study was to evaluate whether a positive effect of injection could be indicative for a successful outcome of future arthrodesis.74 Patients underwent fluoroscopically guided and contrast confirmed anesthetic joint injections for diagnostic reasons. Before and after injection, pain was measured by use of the Visual Analogue Scale (VAS) in rest and after exercise. Pain reduction was expressed as delta VAS (dVAS). Also, the Foot Function Index (FFI) was obtained. Based on the effect of the diagnostic injection and various clinical factors, patients were advised a conservative treatment  or an arthrodesis of the affected joint . After a median follow-up period of 3.6 years (range 2.1 to 4.3 years) patients were again invited to complete the FFI and VAS in rest and after exercise. For data-analysis purposes the patients were assigned to four different groups, based on the result of injection and the occurrence of surgery. Wilcoxon signed rank tests and Mann Whitney U tests were used for statistical analysis.Based on the analysis of the four groups we found that surgery, irrespective of the presence of pain reduction after injection, was related to improvement of VAS and FFI. Patients with conservative treatment always showed worse VAS and FFI scores, even when previous injections showed an improvement of VAS.Fluoroscopically-guided anesthetic injections of the supposed painful foot-ankle joint seem not to be indicative for a successful outcome of an arthrodesis of the affected joint. However, the sole occurrence of surgery shows a significant difference in VAS and FFI scores, where conservative treatment does not. The local hospital review board granted permission for this study. Ethical approval was not required for this study. The precise treatment of foot and ankle pain depends on accurate assessment with regard to the cause and the site of origin of the pain. However, this assessment, accurately identifying the source of pain, can be difficult in the complex hindfoot with its numerous joints and ligaments -4. Most Intra-articular fluoroscopically-guided anesthetic drug injections may help to confirm the alleged localization of the source of pain by differentiating between two separate joints and between intra-and extra-articular origin of pain, and thus may help in predicting therapeutic outcome. This technique has been described as an aid to the diagnosis of shoulder pain, chronic wrist pain, referred pain in the upper limb and in the diagnosis of nerve entrapment syndromes -9. This We evaluated whether pain reduction after intra-articular anesthetic drug injection could be indicative for a successful outcome (i.e. pain and function) of arthrodesis or conservative treatment in foot and ankle pathology. Our hypothesis states that pain reduction after intra-articular anesthesia could be indicative for a successful outcome of future arthrodesis.Between September 2002 and December 2004, 99 patients (> 18 years of age) underwent a diagnostic fluoroscopically-guided joint injection. Out of these 99 patients 25 patients were excluded from this study for the following reasons. Six patients who after surgery developed a non-union, thus compromising the outcome by other means than a correct or not correct indication for surgery were excluded. Five patients with contrast leakage, two with CRPS, and four patients with additional surgery were also excluded. Finally, eight patients were lost to follow-up. In patients with bilateral injections only the first injection was included . Thus, 7All affected joints were injected by a skeletal oriented radiologist under fluoroscopic control  using an antiseptic technique and a standardized protocol ,11. ConfA Visual Analogue Score measuring pain (VAS) was obtained closely before and 30 minutes after the injection in rest and after exercise . Foot FuFour groups were distinguished and analyzed in this study:Group 1: Preoperative successful anesthetic injection resulting in successful surgery (34 patients). In this group there was a positive result on injection resulting in a VAS decrease of at least 3 points. Based on the effect of the diagnostic injection and various clinical factors the doctor would advise surgery and the patient agreed to have surgery. The VAS postoperative was at least three points lower than preoperatively. This group seems to show an association between positive result on injection and success after surgery.Group 2: Preoperative successful anesthetic injection and refusal to surgery (19 patients). This group consists of patients who had a successful preoperative anesthetic injection with a VAS decrease of at least 3 points and choose not to have surgery although they were advised to. No significant improvement was seen from conservative treatment in this group.Group 3: Preoperative unsuccessful anesthetic injection but surgery anyway (six patients).In this group the unsuccessful injection did not deter the doctor or the patient from surgical intervention. These patients did actually gain from the surgery as their VAS decreased more than three points, a significant decrease. This would argue against our hypothesis that preoperative anesthetic injection would predict the result of surgery.Group 4: Preoperative unsuccessful anesthetic injection and no surgery (15 patients). This is the group in which the negative result to anesthetic injection resulted in the decision not to operate. No significant improvement was seen from conservative treatment in this group.After a mean follow-up of 3.6 years (range 2.1 to 4.3 years), all patients were requested to complete a VAS for pain in rest and after exercise and the FFI. The conservative group was asked if they had undergone surgery elsewhere during the follow-up period and if they were using any kind of foot/ankle orthotics or shoe adaptations. When complications such as non union occur after surgery the VAS for pain and FFI measurements are gravely influenced and it was decided not to include these patients in the study to prevent a bias. Thus these patients were excluded from the study as mentioned earlier.Wilcoxon signed rank tests and Mann Whitney U tests were used for statistical analysis. We evaluated whether pain reduction after intra-articular anesthetic drug injection could be indicative for a successful outcome (i.e. pain and function) of arthrodesis or conservative treatment in foot and ankle pathology. The local hospital review board granted permission for this study. Ethical approval was not required for this study.Table The aim of the present study was to evaluate whether a positive effect of injection could be indicative for a successful outcome of future arthrodesis. The results indicate that arthrodesis has a positive effect on pain and function, irrespective of pain reduction after injection. We found that only the intervention of surgery has a predictive value for the relief of pain and improvement of function, and the effect on injection is not related to the outcome of either surgery or conservative treatment. The only way to make this observation possible, is that by coincidence the patients who postponed or chose not to have surgery even with a positive effect on injection formed a very interesting control group, unforeseen by the investigators. Also the group of patients without effect on injection but with surgery formed a small but interesting control group and proved the hypothesis to be false. In our goal to investigate the predictive value of anesthetic injection on the outcome after arthrodesis of the hindfoot or midfoot the injection was defined as an important, but not the only, criteria to either perform surgery or not. A plausible explanation is that the clinical view of the orthopedic surgeon ultimately determines best whether a positive result after surgery is to be expected.The results of our study are in contrast to the conclusion of various authors mentioning a correlation between a positive result on anesthetic injection and successful outcome after surgery ,7,16. PrOur study does have limitations. The design of the study was primarily focused on the predictive value of injections, but the surgeons also focused on X rays, CT scans, physical examination and questionnaires in advising the patient surgery or conservative treatment. Also the role of the surgeon is a confounding factor because the decision for operative or conservative treatment was made with full knowledge of the result of the injection. The cutoff point of VAS 3 was chosen based on publications by DeLoach  stating For future research we suggest the regular workup for hindfoot arthrodesis followed by a decision to operate or not. The intra articular anesthetic injection should be performed in all cases blinded to the surgeon and the patient. When a true correlation between injection and outcome after surgery or after conservative treatment is found, we can decide whether anesthetic injections are a diagnostic tool of value or not. An example of a good study design is presented in the study of Lucas as the focus in this study has been on the level of confidence of the surgeon before and after a blinded intra articular injection . The injIn the range of additional diagnostic techniques either MRI, CT or diagnostic injections are favored ,18,20. BPain reduction after intra articular injections seems not to be indicative for successful outcome after arthrodesis in the foot. This finding contradicts with many published articles on this subject. We found that a careful history, thorough physical examination and radiology imaging will provide the necessary information to recommend surgery and combined with informed consent from the patient predict a good outcome.VAS: Visual analogue scale; FFI: Foot function index.The authors declare that they have no competing interest.MS participated in the design and coordination of the study and drafted the manuscript, BvG performed the statistical analysis and helped to draft the manuscript, BB participated in the design, collected data and helped revising the manuscript, MT participated in the design, collected data and helped revising the manuscript, JL participated in the design and helped revising the manuscript, BS participated in the design and coordination of the study and helped revising the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/15/11/prepub


They applied a 12 cm layer of cream three times daily for 5 days. The primary efficacy variable was the area under the curve (AUC) of the visual analogue scale (VAS) on active standardised movement values at visits 1 to 4. Secondary measures included back pain at rest, pressure algometry, consumption of analgesic medication, functional impairment measured with Oswestry Disability Index, and global assessment of response. The AUC of the VAS on active standardised movement was markedly smaller in the combination treatment group than in the methyl nicotinate and in the placebo group (ANOVA: p < 0.0001). The combination demonstrated superiority to the two other treatment arms, while methyl nicotinate displayed a considerable effect as well. Copyright © 2012 John Wiley & Sons, Ltd.This randomised, multicentre, double-blind, three-arm, placebo-controlled trial compared a topical combination of 35% comfrey root extract plus 1.2% methyl nicotinate versus a single preparation of methyl nicotinate or placebo cream for relief of acute upper or low back pain. 379 patients were randomly assigned to three groups (combination,  Acute back pain of the upper or low back is a widespread condition that impairs quality of life and functional movement in a large number of people .The topical pharmacotherapeutic approach has generally included hyperaemising topical drugs such as nicotinates with the intention to soften and relax the contracted muscle area, thereby indirectly alleviating the pain caused by this contraction. In addition to heat or hyperaemia, the treatment strategy has recently been augmented by a direct anti-inflammatory topical approach – for instance with diclofenac.Topical treatments with anti-inflammatory and analgesic properties provide an interesting alternative, taking into account the potential adverse effects of oral therapies . Extracts of comfrey in mono preparations and in combination with methyl nicotinate have a long tradition of use as topical treatment  In cliniThe efficacy of comfrey root extract ointment was evaluated in a randomised, double-blind, placebo-controlled multicentre study involving 142 patients with a unilateral ankle sprain. Compared to placebo, the superiority of the verum treatment was significant (p < 0.001) of the verum group over the placebo group was confirmed. Pain was reduced, mobility of the knee improved, and quality of life increased . Compared with placebo, superiority of the verum treatment was significant with regard to secondary efficacy variables (each p < 0.001). Both the AUC of the reported back pain at rest, the AUC of the pressure algometry in the trigger point, as well as the global assessment of the efficacy by the patients and the investigators showed a clinically relevant effect in reducing acute back pain. For the first time, a fast-acting effect of the ointment (1 h) was also observed. After 1 h, the pain intensity had already decreased about 33.0% in the comfrey group  and 12.0% in the placebo group  indicating an early onset of the treatment effect.The results were clear-cut and consistent across all primary and secondary efficacy variables. Comfrey root extract showed a remarkably potent, fast-acting, and clinically relevant effect in reducing acute back pain. The pain intensity on active standardised movement decreased on average (median) approximately 95.2% in the comfrey extract group  and 37.8% in the placebo group   Age range 18–45 years; (ii) Good general condition; (iii) Written informed consent; (iv) Acute back pain (either upper or low back pain), not in combination; (v) Sensitivity to algometric pressure on the site contralateral to the painful trigger point at least 2.5 N/cm²; (vi) Back pain on active standardised movement of at least 50 mm on a 100 mm VAS; (vii) Basic value of the pressure algometry on the trigger point should not exceed 50% of the respective value of the site contralateral to the painful trigger point.Among the exclusion criteria were: (i) Upper or low back pain that was attributable to any identifiable cause ; (ii) Any recent trauma; (iii) Any recent strains of the back muscles documented by the clinical evaluation and anamnesis; (iv) Chronic back pain; (v) Likelihood of prolapsed spinal disc documented by clinical symptoms ; (vi) Back pain caused by metabolic or neurological diseases documented by anamnesis (i.e. toxic neuropathy); (vii) Diabetes mellitus; (viii) Risk factors for spinal infection; (ix) Recent onset of bladder dysfunction or severe or progressive neurological deficit in the low extremity (as a possible indication of prolapsed disk); (x) Concomitant use of any anti-inflammatory drugs, heparinoids, or analgesics including herbal preparations  for the same indication or other indications (e.g. rheumatoid arthritis); (xi) Analgesics or NSAIDs applied by any route of administration within 10 days before study entry or corticoid drugs applied by any route of administration within 60 days before study entry; (xii) Any other concomitant treatment  or medication that interferes with the conduct of the trial. Patients with depression or other psychiatric disorders were not excluded. The distribution of those patients in the groups is stated in The Phase III trial was conducted as a double-blind, multicentre, randomised, placebo-controlled clinical trial with three independent treatment groups . After obtaining written informed consent and after all patient eligibility reviews had been performed, patients were randomised and subsequently treated until Day 5 (fourth day after enrolment). One group of patients received a combination cream containing 35% of comfrey root extract , and 1.2% methyl nicotinate , the second group a cream containing 1.2% methyl nicotinate, and the third a placebo cream. Treatment was started after trial enrolment (visit 1). Patients were seen for evaluation of treatment effects after 1 h (visit 2) and after 3 and 5 days (± 1 day) (visits 3 and 4).For scientific reasons, a parallel-group design was selected as the most suitable and generally accepted method. A double-blind treatment was chosen to avoid bias in the assessment of treatment success, and a randomisation was carried out to avoid a bias of treatment allocation. A placebo concurrent control was used because the aim of the study was to verify the combination's efficacy in patients with acute upper and low back pain. Placebo treatment was justified because the patients to be included in this clinical trial could ethically be treated with paracetamol as rescue medication. The study was to show that combination treatment is superior to single component. Therefore, a methyl nicotinate arm was included.The randomisation ratio 3:3:1 was chosen because placebo was expected to be detectable by some of the patients due to the absence of the visible effects on the skin caused by methyl nicotinate. In order not to treat more patients than absolutely necessary only with placebo, and knowing the possibly limited feasibility of blinding the placebo arm, the placebo group was limited to the minimum number required to form a baseline.This trial design was discussed and agreed in a scientific advisory procedure with the relevant German national authority, Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM). Parties agreed to conduct this trial as a sibling study of the above mentioned back pain trial with comfrey root extract  were included as postulated in the inclusion criteria. Moreover, only acute back pain cases were enrolled in order to exclude upper or low back pain that is attributable to any identifiable cause or trauma.A 12 cm long cream layer (corresponding to about 4 g) was spread onto the area of treatment and distributed by soft massage. A glove must be worn. The cream had to be administered three times a day in intervals of about 8 h and applied for 5 days. To ensure the patients applied the cream every time to the same area of the skin, the investigator marked the treatment area at the edges by means of a water-resistant pen.In order to be able to control the applied amount of cream, patients were supplied with packs of gloves which were equipped with a printed measuring scale. The investigators as well as the patient information instructed the patients to squeeze out a continuous strand of cream to the hand wearing the glove and to compare it to the scale. Moreover, at each visit, the tube weight was measured with standardised weighing machines at the study centres. The tube weight was recorded in the CRF. Values for mean daily cream doses used by the patients are shown in Paracetamol tablets were allowed as rescue medication for breakthrough pain  and had to be documented.The primary efficacy variable was the AUC of the VAS on active standardised movement values at visits 1 to 4 . For the calculation of the primary variable, the sum of the VAS for low back pain and for upper back pain was calculated using the actual measurement times, respectively. The AUC was determined using the cumulative trapezoidal rule. Higher values of the AUC of VAS sum on active standardised movement indicate higher pain.The tests on active standardised movement were performed in a specific manner for each muscle . For M. Secondary objectives of the study were the investigation of the following variables: Back pain at rest, assessment by patient on VAS, pressure algometry , Global assessment of efficacy by patient, Global assessment of efficacy by investigator, Functional impairment measured with the Oswestry Disability Index, consumption of analgesic medication. Moreover, the safety was assessed by means of general physical examinations, vital signs, and the occurrence of adverse events (AEs) and serious adverse events (SAEs), respectively.α = 5%, power 1-β = 80%, two-sided t-test situation, standardised difference (mean difference divided by standard deviation) δ = Δ/SD = 0.40 between the combination comfrey plus methyl nicotinate and single methyl nicotinate. At least 100 evaluable patients per treatment group had to be enrolled in the two active treatment groups. As the BfArM recommended to observe at least 300 patients under methyl nicotinate for safety reasons, it was decided to enrol a total of 350 patients . However, a total of 378 patients had to be enrolled, because an approximate drop-out rate of 7% was expected. Each centre had to enrol at least 20 and at most 115 patients.The sample size for this study was calculated based on the results of previous trials in particular involving patients with acute back pain. The sample size estimation was carried out by means of the software program Nquery and based on the assumption on a level of significance All randomised patients were assessed in the Full Analysis Set/intention-to-treat (FAS/ITT) population. Moreover, a per protocol analysis (PP) was performed. The PP population included all patients who met the inclusion and exclusion criteria and showed no major protocol violations. The FAS/ITT-evaluation was the primary analysis set in this superiority trial. All patients treated at least one time with one of the study drugs were assessed for safety.n = 163, methyl nicotinate: n = 164, placebo: n = 52). For efficacy, all enrolled patients were evaluated as the FAS/ITT population. After exclusion of 17 patients due to major protocol violations, a total of 362 patients  were evaluated as PP population   was markedly smaller in the combination treatment group than in the methyl nicotinate and in the placebo group (ANOVA:  0.0001) .t-test: p < 0.0001). The combination proved superiority to the two other treatment arms , and values 50% lower in favour of the combination compared to placebo . Methyl nicotinate alone reached a reduction in this variable of 31% compared to placebo . All pairwise comparisons were statistically significant . The AUC of the pressure algometry values in the trigger point was much higher in the combination group, which means significantly less inducible pressure pain than in both comparator groups .The pairwise comparisons of the AUC of VAS values on pain at rest at actual measurement times were 27% lower, comparing the combination with methyl nicotinate , and 54% lower comparing the combination to placebo ; all pairwise comparisons were again statistically significant (p < 0.0001) in the actively treated groups compared to placebo  by 25.2% in the combination group, by 15% in the methyl nicotinate group, and by 4,1% in the placebo group. The VAS sum of pain at rest reduced at the same visit 2 by 29% in the combination group, by 18.1% in the methyl nicotinate group, but only by 1% in the placebo group.p < 0.0001). The percentage of patients who were assessed as ‘good’ or ‘excellent’ in terms of global efficacy was markedly higher in the combination group (93.3%) compared to methyl nicotinate (51.2%) and placebo (7.6%). Moreover, ‘no’ or ‘poor’ global efficacy was rarely documented in actively treated patients, in contrast to placebo. The assessment of global efficacy coming from the patients was very similar. In the comfrey group, the rating of ‘good’ or “excellent” was 93.9%, compared to methyl nicotinate (49.4%) and placebo (7.7%).The global assessments of efficacy by investigators and patients showed that the difference between the treatment groups was statistically significant at visit 4 . The average total dose of rescue medication was higher in the placebo group (9929 mg) than in the active treatment groups  in the subgroup of patients who took rescue medications at least once.The Oswestry Disability Index between visit 1 and visit 4 (FAS/ITT) improved by 80% in the combination group  compared to 54% in the methyl nicotinate group  and 22% in the placebo group .The combination ointment was thus consistently more effective in the treatment of acute upper or low back pain than both comparators, while methyl nicotinate displayed a non-negligible effect as well. The results are consistent across the primary and all secondary variables in this clinical trial. Patients treated with the combination had significant reductions in pain scores and were more satisfied with the treatment effect than those receiving only methyl nicotinate. A clear benefit of the combination product compared to the mono substance methyl nicotinate could thus be proven. Methyl nicotinate alone, however, proved to have a noticeable effect on the disease under investigation as well.n = 163, methyl nicotinate: n = 164). Fifty-two patients received placebo. AEs reports, which included multiple descriptions, were split into single AEs for analysis purposes and counted separately. Four drug-related AEs were recurrent, meaning they were recorded more than once in the same patient.All 379 patients enrolled, who received at least one dose of study medication, were included in the safety population (SAF). A total of 327 patients received at least one dose of one of the nicotinate-containing preparations (combination: n = 10 (6.1%), methyl nicotinate: n = 9 (5.5%), placebo: n = 0) showed at least one AE during the course of the clinical trial . 9 patients (2.4%) showed at least one AE, which was classified as drug-related (combination: n = 3 (1.8%), methyl nicotinate: n = 6 (3.7%), placebo: n = 0). In total, 22 drug-related AEs were recorded.A total of 19 patients (5%) ; they represent typical reactions caused by the topical application form of the treatments. It is remarkable that the majority of AEs out of these drug-related cutaneous side effects (88%) occurred in the methyl nicotinate group (15 application site reactions), not in the combination group (two application site reactions).n = 7, methyl nicotinate: n = 15). The causality of the seven drug-related AEs in the combination group was assessed as ‘probably’ drug related. The 15 drug-related AEs in the methyl nicotinate group were classified as ‘certainly’ drug-related. All above drug-related AEs were assessed as mild or moderate by the investigators.The 22 drug-related AEs (certain or probable) also included recurrent events, and all occurred in the two treatment groups, none in the placebo-group (combination: Two unrelated AEs were classified as serious: recurrent depressive disorder and pancreatic insufficiency. Both of these cases occurred in the combination treatment group.The results demonstrate that the topical combination of comfrey root extract and methyl nicotinate has a clinically relevant, favourable impact on the outcomes of patients suffering from acute upper or low back pain. Patients treated with the combination had statistically significant and clinically relevant reductions in pain scores and increases in tenderness. Significantly more patients in the combination group reached a virtually pain-free status at visit 4 compared to the placebo group as well as compared to the methyl nicotinate group, as documented by the results of the global assessment of efficacy by the patients and by the investigators. They reached a pain-free condition significantly earlier than patients in the methyl nicotinate and those in the placebo group.Further, the clinical trial showed that methyl nicotinate contributes substantially to the efficacy of the combination product, reducing the primary parameter by 31% compared to placebo.Patients using topical drugs for self-medication do not usually know the precise cause of their pain; however they do seek pain relief. This trial might have limitations as we did not include, for example, a pain diary, which may have allowed further, relevant, detailed data analysis. However, the efficacy demonstrated reflects the pharmaceutical treatment routine of this patient group to quite an extent.The combination of comfrey root extract plus methyl nicotinate was consistently more effective in the treatment of acute upper or low back pain than both comparators, while methyl nicotinate displayed an effect as well. The clinical trial at hand confirms the topical combination is an effective and well-tolerated treatment option for acute back pain.Helmut Pabst and Axel Schaefer were investigators, Hans-Georg Predel was principal investigator of this RCT, Marc Junker-Samek was project manager, Christiane Staiger was project manager and wrote most of the article.Merck Selbstmedikation GmbH sponsored the study. The study was conducted by the CRO CRM clinical trials GmbH, Rheinbach, Germany.


P < 0.009). Although the older subgroup had higher back pain scores and poorer HRQoL at baseline than the younger subgroup, both age groups showed significant reductions in back pain and improvements in HRQoL postbaseline. In conclusion, women aged ≥75 years with severe postmenopausal osteoporosis treated with teriparatide in normal clinical practice showed a reduced clinical fracture incidence by 30 months compared with baseline. An improvement in HRQoL and, possibly, an early and significant reduction in back pain were also observed, which lasted for at least 18 months after teriparatide discontinuation when patients were taking other osteoporosis medication. The results should be interpreted in the context of an uncontrolled observational study.This predefined analysis of the European Forsteo Observational Study (EFOS) aimed to describe clinical fracture incidence, back pain, and health-related quality of life (HRQoL) during 18 months of teriparatide treatment and 18 months post-teriparatide in the subgroup of 589 postmenopausal women with osteoporosis aged ≥75 years. Data on clinical fractures, back pain , and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. A repeated-measures model analyzed changes from baseline in back pain VAS and EQ-VAS. During the 36-month observation period, 87 (14.8 %) women aged ≥75 years sustained a total of 111 new fractures: 37 (33.3 %) vertebral fractures and 74 (66.7 %) nonvertebral fractures. Adjusted odds of fracture was decreased by 80 % in the 30 to <36–month interval compared with the first 6-month interval ( Osteoporotic fractures are a significant cause of morbidity and mortality –3. Such Osteoporosis treatment aims to reduce the risk of fracture, but evidence on the efficacy and use of medications in those at greatest risk, including elderly frail subjects, is limited. Subgroup analyses from pivotal randomized controlled trials (RCTs) have indicated that osteoporosis medications, such as calcium and vitamin D, alendronate, risedronate, zoledronic acid, strontium ranelate, and denosumab, are effective at reducing the fracture risk in older postmenopausal women with osteoporosis –20. TeriThe European Forsteo Observational Study (EFOS) was an observational study in postmenopausal women with osteoporosis treated with teriparatide in normal clinical practice . The parThe aim of the present predefined analysis was to describe the fracture outcomes, back pain, and HRQoL of the subgroup of older women aged ≥75 years and to compare the findings with those of the younger participants (<75 years) of EFOS.EFOS was a multicenter, prospective, observational study conducted in eight European countries . The study design and characteristics of the patient population have been described in detail elsewhere . BrieflyWomen provided written informed consent prior to enrollment and were able to withdraw without consequence at any time. The study was approved by local ethics committees or review boards, depending on local requirements, and was conducted in accordance with the ethical standards of the Declaration of Helsinki. The study was conducted from April 2004 (first patient enrolled) until February 2009 (last patient completed).Data collected at the baseline visit included patient demographic characteristics, risk factors for osteoporosis and falls, drugs related to the risk of osteoporosis, and disease status . The numTeriparatide (20 μg once daily by self-administered subcutaneous injection) was initiated at the baseline visit, and women attended follow-up visits at approximately 3, 6, 12, and 18 months after teriparatide initiation and at 6 and 18 months after discontinuing teriparatide treatment. All osteoporosis treatment was at the discretion of the physician.Diagnosis of osteoporosis was based upon axial or peripheral dual-energy X-ray absorptiometric (DXA) measurements of BMD and confirmed following review of medical reports. Incident clinical vertebral and nonvertebral fragility fractures during the observational period were diagnosed and confirmed by review of the original X-rays and/or the radiology or surgical reports at the study site. A new or worsened clinical vertebral fracture was defined as the presence of a confirmed radiographic vertebral fracture associated with signs and/or symptoms suggestive of a new vertebral fracture .Back pain was self-assessed by patients at each study visit using a 100-mm visual analogue scale (VAS), ranging from 0 = no back pain to 100 = worst possible back pain. Patients also completed a back pain questionnaire that captured the frequency and severity of back pain, limitations of activities, and days in bed due to back pain in the previous month .HRQoL was measured at each visit using the European Quality of Life Questionnaire (EQ-5D) , where pFor data analyses, the total study cohort included all patients with a baseline visit and at least one follow-up visit. Patients were retrospectively categorized into one of two subgroups according to their age at baseline: ≥75 or <75 years.Descriptive statistics, such as frequencies, percentages, means, standard deviations (SDs), and ranges, were used to describe patients in the two subgroups. Between-group comparisons were made using chi-squared or Fisher’s exact tests  or the Kruskal-Wallis test (continuous variables).The number of fractures occurring in patients aged ≥75 or <75 years was summarized in 6-month intervals. For each subgroup, a logistic regression with repeated measures was used to assess the change in number of patients with one or more fractures over time , 30, givBack pain and HRQoL were summarized over the teriparatide treatment period and after teriparatide discontinuation for both age groups. Changes in back pain VAS from baseline were analyzed using a mixed model of repeated measures (MMRM), adjusting for back pain VAS at baseline, number of previous fractures, age, diagnosis of rheumatoid arthritis, duration of prior bisphosphonate therapy, and history of fracture in the 12 months before entering the study. Changes from baseline in severity of back pain, frequency of back pain, and limitation of activities due to back pain at each follow-up visit were categorized as improvement, no change, or worsening ; and the number/percent of patients improving/worsening was analyzed using the sign test.A similar MMRM was used to assess the change from baseline in EQ-VAS, including its baseline value. The sign test analyzed the number/percent of patients reporting an improvement or worsening from baseline in each of the five EQ-5D domains, which was determined by assigning a number to each of the three possible responses for each domain and then determining whether the numerical difference between baseline and each time point was an increase (improvement), no change, or a decrease (worsening). Changes from baseline in EQ-5D HSV were assessed using the Wilcoxon sign-rank test because this parameter has a nonparametric distribution.Of the 1,581 patients in the total study cohort, 589 (37 %) were aged ≥75 years and 992 (63 %) were <75 years. The disposition of patients during the study by age subgroup  for patients ≥75 years and 543 days  for patients <75 years. The reasons for discontinuation of teriparatide in the subgroups aged ≥75 and <75 years, respectively, were treatment completed (70.4 and 81.9 %), patient decision (13.9 and 9.0 %), adverse event (9.0 and 6.8 %), physician decision (4.4 and 1.8 %), death (1.5 and 0.8 %), and noncompliance (0.8 and 0.3 %).Of the 298 patients aged ≥75 years with data available on osteoporosis medication taken after teriparatide was discontinued, 95.6 % took some type of osteoporosis medication. Most women took calcium (83.6 %) and vitamin D (85.6 %), and 63.4 % were prescribed a bisphosphonate. Likewise, of the 611 patients aged <75 years with data on osteoporosis medication taken after teriparatide was discontinued, 93.6 % took an osteoporosis medication, mainly a bisphosphonate (63.2 %), with most women also taking calcium (84.9 %) and vitamin D supplementation (86.5 %).n = 16), leg (n = 13), hip (n = 11), sternum/ribs (n = 8), and humerus (n = 6). The adjusted odds of fractures was not reduced during the teriparatide treatment phase in the older subgroup but was significantly lower in the last two time intervals (24 to <30 months and 30 to <36 months) compared with the first 6-month interval (0 to <6 months); there was an 80 % decrease in the odds of fracture in the 30 to <36–month period compared to the first 6-month period (P < 0.009) (Table Table P < 0.001)  sustained a total of 147 clinical fractures during the 36-month follow-up (Table P = 0.010) and at 12 to <18 months . There was no difference in the odds of fracture between the older and younger groups at the other time intervals.Comparisons between the two age groups at each time period showed that patients aged ≥75 years had a significantly higher adjusted odds of fracture at 6 to <12 months  but was less than 5 mm at each visit . Of the variables included in the MMRM, three were significantly associated with the change in back pain VAS: each additional 5 mm in baseline back pain VAS was associated with a greater reduction in back pain of −2.89 mm , a fracture in the 12 months before study entry was associated with a greater reduction in back pain VAS of −2.48 mm  vs. no fracture, and each additional previous fracture was associated with an increase in back pain VAS of 1.09 mm .The older subgroup of patients (≥75 years) had significantly higher mean back pain VAS scores (unadjusted) at baseline and at 12, 18, and 24 months compared with the younger subgroup (<75 years). There were statistically significant reductions in adjusted back pain VAS scores from baseline in both subgroups at each postbaseline visit . The same was true for severity of back pain and limitation in activities due to back pain.At every postbaseline visit, more patients in both subgroups reported an improvement than a worsening in back pain frequency relative to baseline  compared with the younger patients (<75 years).There were significant improvements from baseline in adjusted mean EQ-VAS at all postbaseline visits in both age groups of patients Fig. . The incP < 0.001).A significantly higher percentage of patients in the older subgroup reported some/extreme problems for each of the EQ-5D domains compared with the younger age group Table . For allP < 0.001) from baseline at all postbaseline visits and were 0.69  at both 18 and 36 months. The same was observed in the younger age group, where the median  HSVs were 0.73  and 0.76  at 18 and 36 months, respectively.In the older subgroup of women, median  HSVs were increased significantly  occurs with advancing age, with decreases in both bone mass and bone quality . Bone frOur findings in patients treated in normal life conditions are consistent with and complement those of the randomized, placebo-controlled Fracture Prevention Trial, where the incidence of new vertebral fractures during approximately 18 months of teriparatide treatment (relative to placebo) was comparable in younger (<75 years) and older (≥75 years) patients . Thus, iBecause this is an observational, nonrandomized study, it is difficult to compare the incidence of fractures between the two age groups. Nevertheless, the adjusted odds of fracture were higher in the elderly group during the 6–18 months of teriparatide treatment compared with the younger group but were similar between age groups during the 18-month post-teriparatide treatment period. The higher fracture risk during the 6–18 months of teriparatide treatment in patients aged ≥75 years may be a consequence of the additional age-related risk factors in these older women and their higher risk of fracture at baseline, as reflected in the greater frequency of prevalent fractures, falls, and dementia as well as use of concomitant medications.Evidence for the antifracture efficacy of other antiosteoporosis drugs in postmenopausal women aged ≥75 years with osteoporosis is also based on subgroup analyses of data from randomized, placebo-controlled studies. These studies have shown that treatment with alendronate, risedronate, zoledronic acid, strontium ranelate, and denosumab is associated with a reduction in the risk of new clinical fractures after 3 years , 20, 33.A main finding of the present study is that both age groups experienced rapid and significant improvements in back pain and HRQoL during teriparatide treatment. These benefits were maintained after teriparatide was discontinued when most patients were receiving other osteoporosis medication. The higher back pain scores and poorer HRQoL in the older subgroup (≥75 years) throughout the study may reflect greater severity of osteoporosis in this subgroup of patients.There are several limitations of the EFOS study that should be considered when interpreting the data from these analyses. First, as this was an observational study, patients were not randomized by age or to treatment, and there was no comparator group to teriparatide. As a result, we cannot attribute the observed changes to teriparatide treatment. Moreover, as the majority (>93 %) of patients took an osteoporosis medication during the 18-month post-teriparatide treatment period, we cannot exclude the effects of this sequential therapy on the observed responses. Second, we may have underestimated the fracture incidence because only symptomatic vertebral fractures were confirmed by radiology. Third, data on analgesic use during the study were not gathered; this may have affected the back pain results.The strengths of this study include the large sample size, with no age limit restrictions, and inclusion of a diverse range of patients, many of whom had comorbidities and were taking concomitant medications. Another advantage of the study is that the participating postmenopausal women with severe osteoporosis received teriparatide as part of different sequential therapies, reflecting treatment as it occurs in the normal clinical practice setting. Moreover, we examined fracture incidence, back pain, and quality of life both during and after teriparatide treatment and adjusted for factors that may influence the changes, including previous bisphosphonate use and fracture in the 12 months before starting teriparatide.The need for osteoporosis medications that are safe and well tolerated is especially important in elderly patients, who are likely to have comorbidities and to be taking concomitant medications. The safety of teriparatide has already been established, and results from the placebo-controlled Fracture Prevention Trial have shown that teriparatide was well tolerated in elderly patients, with no significant differences in the safety profile between patients ≥75 and <75 years . Safety Patients with severe postmenopausal osteoporosis aged 75 years or above treated with teriparatide showed a reduced incidence of clinical fractures by 30 months compared with baseline, together with improvements in HRQoL and possibly an early and significant reduction in back pain. These outcomes lasted for at least 18 months after teriparatide discontinuation when patients were taking other osteoporosis medication. These results should be interpreted in the context of an uncontrolled observational study.


Low-back related leg pain with or without nerve root involvement is associated with a poor prognosis compared to low back pain (LBP) alone. Compared to the literature investigating prognostic indicators of outcome for LBP, there is limited evidence on prognostic factors for low back-related leg pain including the group with nerve root pain. This 1 year prospective consultation-based observational cohort study will describe the clinical, imaging, demographic characteristics and health economic outcomes for the whole cohort, will investigate differences and identify prognostic indicators of outcome (i.e. change in disability at 12 months), for the whole cohort and, separately, for those classified with and without nerve root pain. In addition, nested qualitative studies will provide insights on the clinical consultation and the impact of diagnosis and treatment on patients' symptom management and illness trajectory.Adults aged 18 years and over consulting their General Practitioner (GP) with LBP and radiating leg pain of any duration at (n = 500) GP practices in North Staffordshire and Stoke-on-Trent, UK will be invited to participate. All participants will receive a standardised assessment at the clinic by a study physiotherapist and will be classified according to the clinically determined presence or absence of nerve root pain/involvement. All will undergo a lumbar spine MRI scan. All participants will be managed according to their clinical need. The study outcomes will be measured at 4 and 12 months using postal self-complete questionnaires. Data will also be collected each month using brief postal questionnaires to enable detailed description of the course of low back and leg pain over time. Clinical observations and patient interviews will be used for the qualitative aspects of the study.This prospective clinical observational cohort will combine self-reported data, comprehensive clinical and MRI assessment, together with qualitative enquiries, to describe the course, health care usage, patients' experiences and prognostic indicators in an adult population presenting in primary care with LBP and leg pain with or without nerve root involvement. Low back pain (LBP) is common, affecting 70-80% of the population at some point in their lives . The preCompared to the literature investigating prognostic indicators of outcome for LBP, there is limited evidence on prognostic factors for low back-related leg pain including the group with nerve root pain . It is uRecent LBP research has moved away from a "one-size fits all" approach, where heterogeneous groups of patients receive broadly similar treatments, to studies which address the question of 'who does better with what'. This new approach investigates whether outcome is better when subgroups of LBP patients identified according to their prognostic profile or to specific characteristics, are matched with appropriate treatments. Preliminary findings support the view that different categories of 'symptoms and signs' in LBP patients can be identified, which seem amenable to specific treatments -22. Our Clinical characteristics and indexes of risk however, are not the only variables affecting outcome. The effect of interaction style  on patient health outcomes has received limited attention in the literature. However, research has shown that the specific approach adopted by clinicians in the consultation may lead to significant improvements in health outcomes ,25. Cons(i) The primary aims of this study are: for patients presenting in primary care with low back and leg pain, managed according to currently agreed "best practice" and followed up for 12 months, to describe the clinical, imaging, demographic characteristics and health economic outcomes for the whole cohort, and to investigate differences between those classified with and without nerve root painand(ii) to identify prognostic indicators of outcome (i.e. change in disability at 12 months), for the whole cohort and, separately for those classified with and without nerve root painSpecific objectives include:(a) identification of prognostic subgroups of patients with distinct trajectories of pain and disability over 12 month follow-up(b) description of health care resource use and work productivity within and between those with LBP and non-specific leg pain, and those with a clinical diagnosis of LBP with nerve root pain over 12 months follow-up(c) investigation of the effect of clinical assessment and treatment negotiation between physiotherapists and patients on decision-making(d) examination of whether the classification of leg pain (eg. either with or without nerve root involvement) impacts on patients' symptom management, help seeking behaviour and illness trajectoryEthical Approval for this study has been granted by the South Birmingham Research Ethics Committee (REC ref. 10/H1207/82).Primary care, multi-centre prospective observational cohort studyAdults aged 18 years and over consulting their General Practitioner (GP) with LBP and radiating leg pain of any duration at GP practices in North Staffordshire and Stoke-on-Trent, UK. Radiating leg pain is defined as pain spreading from the back beyond the gluteal fold to anywhere in the leg. In this context "pain" is taken to include all unpleasant/abnormal sensations such as 'pins and needles' or numbness.• Persons with "red flags" indicative of possible serious spinal pathology• Serious co-morbidity which prevents patients from being able to travel to the clinic and/or undergo a clinical assessment• Patients with serious mental health problems who the GP considers to be vulnerable and for whom participation in the study would be detrimental• Previous spinal surgery• Pregnancy• Currently receiving physiotherapy  or under a secondary care consultant for the same problem• Not able to read and speak EnglishPotentially eligible participants will be identified at the GP consultation and referred to a Community Low Back and Leg Pain Clinic where they will be invited to take part in the study. When a patient with back pain consults their GP, and the GP enters an appropriate Read Code on the computer system, a "pop-up" prompt screen will ask the GP if they think the patient has leg pain associated with their back problem, and if so to consider whether the patient is suitable to be invited to the Community Low Back and Leg Pain Clinic. The GP will have the facility to enter "yes" or "no" on the computer system to flag if patients are suitable or unsuitable for referral to the clinic. Whilst desirable, it is not imperative that the GP informs the patient about the clinic for example, if the GP enters the patient as suitable on the system but after the consultation has ended and the patient has left, the patient will still be invited through the process described below.On a weekly basis West Midlands North Primary Care Research Network (WMN PCRN) staff will facilitate the mailing of letters to all patients who have been flagged as suitable. The letter will invite patients to telephone the clinic administrator to make an appointment at the clinic, it will explain that there is a research study being hosted at the clinic but that attendance at the clinic does not oblige them to take part. Patients who telephone the clinic administrator will be offered a clinic appointment within 10 working days. A letter will be sent to patients to confirm their appointment time--a study baseline questionnaire and patient information sheet will be enclosed with this letter. Approximately 2 days before the clinic, a clinic nurse will telephone patients to remind them about their appointment time and ask those who are interested in taking part in the research to bring their completed questionnaire.There will also be a separate referral pathway to capture patients who contact PhysioDirect (Physiotherapy Direct Access Service), a community physiotherapy service allowing patients to telephone directly through to a physiotherapist without needing to first consult their GP. Following the usual PhysioDirect assessment, suitable patients will be asked whether they would be interested in being invited to the Community Low Back and Leg Pain Clinic. Referrals will be faxed to the research centre and a letter will be sent to the patient inviting them to telephone the clinic administrator to make an appointment for the clinic as described above.See Additional file Physiotherapy assessment and management will be provided to all patients attending, irrespective of whether or not they are eligible or agree to take part in the study. The clinic will be operated as an integrated service/research clinic, with NHS treating clinicians being fully supported by WMN PCRN clinical and administrative staff working as a single team. At the clinic, a nurse will check potential eligibility and if the patient wishes to take part in the study gain signed informed consent. The study questionnaire which had been mailed to patients with their appointment letter will be received and checked and participants will be asked to complete a further brief baseline questionnaire during the clinic.All study participants will receive a standardised assessment at the clinic by a study physiotherapist, at which full eligibility will be established by, for example, by excluding patients whose leg pain is not considered to be associated with their back pain (e.g. hip osteoarthritis). This standardised assessment has been developed following a Delphi study aimed at developing consensus on the content of the clinical assessment for adults presenting in primary care with low back-related leg pain . Each elClinical management will follow agreed care pathways, based on current best clinical evidence, practice guidelines and local services and resources. In addition to clinical examination findings simple self-reported clinical markers of severity and risk of poor outcome measured using the STarT Back tool , will bePatients in this group are expected to have mild/improving symptoms and be classified at low risk of a poor outcome according to the STarT Back tool. Patients will receive a brief physiotherapy intervention (one or two sessions) according to their needs consisting of advice, education and home exercises. The physiotherapist will emphasise messages about promoting speedy return to normal activity, avoiding rest, appropriate use of pain relieving modalities (such as painkillers), and work issues. Patients will be encouraged to ask questions relating to any specific concerns about their back and leg pain. As appropriate to their presentation, patients will be given some written educational information--if it is suitable this may be the 'Back Book' , or patiPatients in this group are expected to have moderately severe pain and disability and most likely be at "moderate" or "high" risk of poor outcome according to the STarT Back tool. For those patients classified as 'moderate risk' of a poor outcome, the physiotherapist will negotiate an individualised treatment plan with the patient according to their need and best current evidence. The physiotherapist will address any worries or fears and unhelpful beliefs patients' may have about their back and leg pain, will emphasise messages as for group (i), and will use a range of pre-agreed physiotherapy techniques, including manual therapy and exercises where appropriate. For those patients classified as 'high risk' of a poor outcome, in addition to appropriate treatments for their back-related physical symptoms (e.g. pain), treatment may also include cognitive behavioural approaches specifically addressing the main psychosocial risk factors for chronicity .The group (ii) intervention will be delivered in one 45-min session with a target of up to 6 further 30-min sessions  over 6-8 weeks. Pathways will be in place to refer patients that fail to improve or worsen to the dedicated Back Pain Service, for further assessment and management. The Back Pain Service is a pathway run by spinal physiotherapy specialists and there is access to and input from orthopaedic surgeons, pain clinic anaesthetists and rheumatologists as appropriate. Management of patients referred to the Back Pain Service will be at the discretion of the treating specialist, but may involve invasive procedures such as injections or surgery where indicated.Patients in this group will have severe levels of back and leg pain-related symptoms with associated functional limitations, and/or progressive neurological symptoms or signs, with or without significant levels of psychological distress (they are expected to be classified as "moderate" or "high" risk of poor outcome according to the STarT Back tool), and are thus considered not appropriate for conservative primary care physiotherapy interventions and/or cognitive behavioural approaches. In addition Group (iii) may include patients in whom such treatments have been tried previously without any benefit. After the initial clinic assessment these patients will be referred directly to the dedicated Back Pain Service as described above.Seven senior, experienced musculoskeletal physiotherapists will undertake 21/2 days training led by the study Principal Investigator (KK) and including sessions with a GP with special interest in musculoskeletal conditions (GPwSI MSK), a Rheumatologist, and a Consultant in Pain Management. The focus of the training is on carrying out the standardised assessment according to agreed protocols, and on equipping the physiotherapists to assess and target back pain, leg pain, co-morbid pain, disability and psychological risk factors for chronicity such as pain related distress, fear of movement, unhelpful beliefs and expectations. Emphasis is given on the differentiation between back pain with leg pain due to nerve root involvement and back pain with referred leg pain. The training includes the evidence-based assessment of LBP, including the use and interpretation of the STarT Back tool to guide treatment in addition to the role of diagnostic investigations , medication, epidural injections and surgery in back pain and radiculopathy. Current guidelines for managing LBP in primary care will be discussed, including appropriate reassurance and advice about analgesia, the maintenance of, or return to, usual activities (including work) and patients who present a clinical or management concern . The training includes current best physiotherapy practice for the management of disability, back pain and leg pain, including the role of exercise and manual therapy as well as strategies for equipping patients with the skills to manage future recurrences. Goal setting, pacing and graded exercise will also be covered.The training will be supplemented by a comprehensive manual, providing clear guidelines and treatment algorithms for the evidence based assessment and treatment of patients with LBP, either with or without leg pain. Patients exhibiting many psychosocial risk factors for chronicity may be treated, if necessary, by physiotherapists that have already undergone extensive appropriate training in the context of our previous STarT Back trial ,29 and iAll participants will be invited for a Magnetic Resonance Imaging (MRI) scan, providing there are no contraindications, unless they have had an MRI scan in the past 6 months and their clinical presentation has not changed. MRI is the best available diagnostic imaging modality for LBP and leg pain as it provides excellent resolution of both nerve roots  and bony structures. MRI is non-invasive for the patient and does not require any ionising radiation exposure. MRI will be performed using 1.5T magnetic resonance units. A body spine surface coil will used for imaging the lumbar region. Patients will undergo a standard lumbar spine MRI , similar to that undertaken in routine clinical practice. This will take approximately 30 min with the patient lying in the supine position in the scanner.A summary report on the MRI scan will be provided by a Consultant Radiologist at the NHS Trust Hospital. The primary purpose for the MRI scan is to provide data for the research study  and will be completed within 10 working days of the clinic appointment. However, any relevant clinical findings from the scan will be acted upon by the treating clinician. The patients and their GPs will be notified of the results as a matter of course.Qualitative research methods will be used to address the study's specific objectives (c) and (d). This will involve a series of observations (approximately 30) during the standardised clinical assessments and subsequent treatment consultations, as well as interviews with a sample of patients (approximately 20). Consultations for observation and participants for interview will be selected 'opportunistically' from each of the three care pathways ensuring that a wide range of patients  are included ('maximum diversification sample'). Observations will be conducted in person by a qualitative researcher using a topic guide in order to gain experiential insights and understanding of the consultation, the participants, and wider organisational influences. Researcher field notes will be supplemented with audio-recordings where participants have given consent.Observations will empirically examine the treatment decision-making process, the involvement of patients in these decisions, and the role of symptom severity/duration on 'process' issues. We hypothesise that these issues could have a bearing on future patient outcomes, which will be examined in more detail during the patient interviews. The consultations will compare patients with and without a clinical diagnosis of 'nerve root involvement'. Observations will examine whether diagnostic status appears to influence the clinical decision making process of physiotherapists, and choices of treatment expressed by patients at different stages of treatment within each care pathway. Hence, observations will be conducted at various stages of treatment in order to explore whether the physiotherapist-patient interaction changes over time and the potential impact on patient 'concordance to the treatment intervention.Patients will be invited to take part in the interview study following their consultation with a physiotherapist. Semi-structured qualitative interviews will be conducted using a topic guide to explore key themes systematically with all participants, but with emergent observations and insights from earlier findings feeding into subsequent interviews. This will allow examination of variation in perceptions between participants. Patients will be interviewed to explore: 1) patients' experiences of, and perceptions towards, decision-making with a physiotherapist, and 2) patients' illness trajectories and acceptability of the treatment plan. Interviews will specifically examine how patients' 'diagnostic status' (whether they receive a diagnosis of 'nerve root involvement' or not) affects their illness experience, pain management and help seeking behaviour.The study outcomes will be collected at 4 and 12 months using postal self-complete questionnaires. Data will also be collected each month using brief postal questionnaires to enable detailed description of the course of low back and leg pain. Reminders will be sent to non-responders at 4 and 12-months.The primary outcome for this study is disability at 12 months follow up as measured with the Roland and Morris Disability Questionnaire (RMDQ) leg pain version ,32. SecoThe study includes a health economic evaluation focusing both on a health care perspective and the wider societal perspective. A health care perspective addresses the direct health care costs incurred within both the public and private sectors. The societal perspective will incorporate the indirect costs of sickness absence and reduced productivity at work due to low back and/or leg pain. Health care use data will focus on key cost drivers including hospital attendances, surgery, inpatient stays, outpatient appointments and any other hospital visits to health care practitioners within the UK National Health Service (NHS) and private practice, consultations with NHS primary health care providers , prescribed medications, and over-the-counter treatments. This data will also capture resource use required to implement the care pathway. Unit costs assigned to these resources will be obtained from standard published sources reflecting UK national averages.A recruited sample size of 500 patients will be sufficient to detect, with at least 80% power, a difference of 15% in the proportion of people with poor outcome, in relation to back-related disability, between the subgroups of leg pain patients with and without nerve root pain, assuming 20% loss to follow up and 5% two-tailed significance level. Poor outcome is defined as less than 30% change on RMDQ score . This saClinical, imaging and demographic characteristics, health economic and clinical outcomes of patients with back and leg pain will be described for the whole cohort and separately according to the presence/absence of nerve root pain. Estimates of mean differences  in baseline and outcome measures across all endpoints will be evaluated between those with and without nerve root involvement. The mean absolute and change scores for the Roland and Morris Disability Questionnaire  will be analysed across all monthly time points.As stated, the primary outcome is "improvement" in the RMDQ: defined as a change of at least 30% improvement in an individual's RMDQ score . Direct Associations between baseline indicators  and back-pain related disability at 4 and 12 months will be investigated to identify indicators of poor outcome. Potential prognostic factors will be investigated for the total sample, and separately for those classified by nerve-root pain.Statistical modelling including linear and logistic regression methods will be carried out for numerical and categorical outcome measures, respectively, in order to investigate the association between potential prognostic factors and outcome. Inclusion of longitudinal terms within an appropriate repeated-measures framework will be adopted for the evaluation of the primary outcome measure. Random effects modelling and multiple imputation methods will be considered to address the limitations due to expected missing data during follow up assessments and to enhance the power of the statistical evaluation. Interaction terms  will be included and linear/non-linear associations explored.Longitudinal latent class analysis will be used to explore the course of the condition and identify clusters of patients with distinct trajectories of symptoms over 12 months follow up, making use of the monthly assessments of the primary outcome measure ,36.The health economic analysis will concentrate on how costs and outcomes vary between sub-groups of patients, including diagnostic sub-groups and severity of symptoms at baseline. In addition, patterns of cost and outcome change over time will be explored. Multiple imputation will be used if there is missing cost and/or outcome data. Descriptive statistical analysis will be undertaken to describe the health care resource use, outcomes and employment status (loss in productivity) within and between sub-groups during the one-year follow-up period. Regression-based analyses will be used to explore the variation in key outcome variables, notably costs and health measures such as EQ-5D, and their associations with a range of possible explanatory variables.how decisions are negotiated during consultations, whilst interviews will examine perceptions, or why things happen. The analysis will help to identify the factors affecting treatment negotiations between physiotherapists and patients by exploring the inter-personal dynamics of consultations, alongside patients' experiences of low back and leg pain, adopting a prospective and retrospective design.The analysis of the observations and interviews will commence during fieldwork. Early findings and insights will inform subsequent qualitative data collection. These findings will in turn inform the development of theory from the data (grounded theory). Both the qualitative interview and observation data will be coded using the N-Vivo qualitative data analysis software. Each data set will be coded using a separate coding frame reflecting the nature of the data (perceptions and process). The main themes in the interview and observation data will be identified and analysed using the 'constant comparative' method . The codRecruitment to the study began in April 2011 and is due to be completed at the end of 2012. The 12-month follow-up (including reminders and time for response) should be finished early 2014, which will be followed by final data cleaning and analysis.This study will provide information on the course and prognosis of pain, disability and other health outcomes in patients presenting with back and leg pain in primary care, assessed according to a standardised schedule for the presence or absence of nerve root pain and treated according to current best practice. The study will inform the approach to more effective targeting of treatment, which will be investigated in future trials. This proposed study will add to best practice for assessing and managing LBP with leg pain in the primary care setting, with the potential to improve patient outcomes and reduce costs to both society and the health care system. It may guide development of primary care services for back pain patients, locally and nationally. The qualitative observations will describe the content of the physiotherapist-patient interaction across the three care pathways, identify the possible effects on patient outcomes , and suggest improvements for delivering care to patients and for informing physiotherapist training. The patient interviews will elicit patients' perceptions of the different care pathways, and examine how patients with, and without, a clinical diagnosis of 'nerve root involvement' respond to treatment.The authors declare that they have no competing interests.All authors participated in the design of the study and the drafting of the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/4/prepubStudy Flowchart.Click here for fileClinical Assessment Form.Click here for file


Objective. With this review, we provide a comprehensive overview of the main aspects and currently used drugs for analgesia in shockwave lithotripsy. Evidence Acquisition. We reviewed current literature, concentrating on newer articles and high-quality reviews in international journals. Results. No standardized protocols for pain control in SWL exist, although it is crucial for treatment outcome. General and spinal anaesthesia show excellent pain control but are only recommended for selected cases. The newer opioids and nonsteroidal anti-inflammatory drugs are able to deliver good analgesia. Interest in inhalation anaesthesia with nitrous oxide, local anaesthesia with deep infiltration of the tissue, and dermal anaesthesia with EMLA or DMSO has recently rekindled, showing good results in terms of pain control and a favourable side effect profile. Tamsulosin and paracetamol are further well-known drugs being currently investigated. Conclusion. Apart from classically used drugs like opioids and NSARs, medicaments like nitrous oxide, paracetamol, DMSA, or refined administration techniques for infiltration anaesthesia show a good effectiveness in pain control for SWL. With the first serial lithotripter, the Dornier HM3 (Human Model 3), introduced in 1983 by Chaussy et al., treatment was painful and therefore the procedure had to be performed under general or spinal anaesthesia [The subsequent generations of shock wave lithotripsy (SWL) machines were optimized towards patient comfort and treatments became less painful. Modification of the shock wave generators towards a wider aperture led to a reduced intensity of the shock waves on skin entry level, a smaller focal zone and a lower energy output made the treatment under analgesia rather than under anaesthesia possible .But, also with a second-generation machine, the Dornier HM4, still 95% of SWL patients experienced pain during the treatment . EspeciaClinical outcomes and success as measured in terms of stone-free rate after SWL is strongly correlated to pain experienced during treatment . Pain duThe optimal anaesthesia technique should be easy to administer and have a high efficacy and minimal side effects. Adequate analgesia, sufficient sedation, and rapid recovery are needed, the latter especially in an outpatient setting. To achieve optimal pain control, the patient needs to be closely monitored regarding this during the treatment, ideally by the operator who is controlling the applied energy level and can immediately reduce it, should pain occur. For protocols, where opioids or sedatives are administered, a second person other than the operator needs to be present to monitor the patient's vital functions and to deliver drugs according to the patient's needs , 7. To date, there are no guidelines for pain therapy during SWL treatment and a variety of treatment protocols and drugs are being used. Traditionally, nonsteroidal, anti-inflammatory drugs (NSAIDs) such as diclofenac, ketorolac and piroxicam, as well as a variety of opioids like morphine, pethidine, and fentanyl are employed sometimes in combination with sedative hypnotics. In this review, we emphasize newer drugs and drugs in which interest has been rekindled recently such as inhalation anaesthesia with nitrous oxide, local infiltration techniques, topical creams, newer opioids, and NSAIDs.Shock-wave-induced pain is usually described as stinging and sharp. Its pathogenesis is not yet totally understood but cavitation seems to play a key role, rather than direct mechanical effects on nociceptive nerve endings , 9. FormA second component of shock-wave-related pain is the movement of the stone caused by the impact of the shock wave .Several physical variables influencing treatment-related pain have been identified: an important role is played by the type of the shockwave source, size, and site of stone burden , peak pressure of the shockwaves, diameter of the focal zone, and size of the aperture of the shockwave source reflecting the area of shockwave entry at the skin –14.Furthermore responsible for pain perception during SWL are patient-related factors like age, gender, and body habitus , and youGeneral anaesthesia (GA) for SWL treatment offers optimized pain control and controlled respiratory excursion. This creates optimal conditions for stone targeting and consecutive fragmentation. In modern anaesthetic practice, GA is considered to be safe with a low morbidity. However, it seems preferable to avoid, if not mandatory, especially in high-risk patients. Disadvantages are the need to involve an anaesthetic specialist and the need for postoperative recovery, increasing the overall costs and making GA less suitable in the common outpatient SWL setup of most urological departments. Solely in children or in extremely anxious patients, it is still the preferred option. Other potential indications are particularly long treatments as in patients with bilateral stones, concomitant renal and ureteral stones or in patients with very hard calculi , which are known to be resistant to fragmentation and require high, potentially painful energy levels , 17.Nitrous oxide is a medical anesthetic gas and on the market as Entonox, a mixture of 50% nitrous oxide and 50% oxygen. It was discovered in 1776 by Joseph Priestly  and consThis colourless gas is highly soluble in blood and the arterial concentration reaches a plateau 10 minutes after commencing the inhalation. It diffuses rapidly through the cellular membranes, does no bind to haemoglobin, and is eliminated unchanged via the lungs. The analgesic effect commences 20 to 30 seconds after inhalation and a peak effect is reached after 3 to 5 minutes. Reflexes of coughing and airway protection are not noticeable altered . This raAdverse effects of Entonox are mainly transient nausea and light headedness. A further issue can be slight cardiac depression; therefore, the gas should be used carefully in patients with congestive heart failure and in those with obstructive airway disease . It is cP = 0.001) for nitrous oxide could be shown and it proved as effective as intravenous administered pethidine [The use of Entonox during SWL was reported in only one RCT study up to now; 150 patients undergoing treatment where randomized into 3 groups, one to receive Entonox, the other to have intravenous pethidine, and the last one to inhale compressed air. A significantly reduced procedure-related pain  with significant discomfort at the site of injection and the need for additional IV analgesia and sedation made this approach inconvenient [The analgesic efficacy of subcutaneous (SC) infiltration of lidocaine with 1 : 100.000 epinephrine for SWL has early been demonstrated. However, infiltrating a relatively large area  was needed [Prilocaine has an equal analgesic efficacy, a more rapid onset, a similar duration, and is due to its rapid metabolism, less toxic. The target area is usually infiltrated only 1-2 min before the treatment. Yilmaz et al. infiltrated a limited area of 30 cms needed . By infis needed . Recentls needed .EMLA  cream is an eutectic mixture of lidocaine 2.5% and prilocaine 2.5% for topical application. It is commonly used for dermal anaesthesia, for example, in blood sampling, venous catheterization, condylomata acuminata excision, or debridement of leg ulcers. Its penetration depth through intact skin is about 4 mm after 60 minutes , 31. ItsTo maximize its local analgesic effect, EMLA should be applied under an occlusive dressing. Due to its comparable weak analgesic potential, it is usually used in SWL together with additional analgesic agents like opioids or NSAIDs . The ultWhilst earlier studies showed no reduction in the need for additional opioid analgesics after application of EMLA cream , a more Dimethyl sulfoxide (DMSO) acts as a topical analgesic and is at the same time a vehicle for the transport of other local acting pharmaceuticals through the skin . In addiFrequently used drugs are pethidine, the first synthetic opioid, fentanyl, tramadol, alfentanil, remifentanil, and sufentanil and a variety of administration techniques such as intramuscular bolus (IM) injection, or intravenous (IV) on-demand patient-controlled analgesia , 36.Opioids are delivered either alone or in combination with other forms of analgesia or sedation –41. Due μ-opioid receptors, provides an acceptable analgesia condition during SWL, and is therefore commonly used. One of its drawbacks is the need for continuous noninvasive pulse oximetry due to its marked respiratory depressive effect [Fentanyl is a potent synthetic narcotic, has a rapid onset and a short duration of action. It is a strong agonist at the e effect . The come effect , 46. Reme effect , 47–49. e effect . Both ofμ-opioid receptors, inhibiting the reuptake of noradrenalin and releasing 5-hydroxytryptamine (Serotonin) [Tramadol hydrochloride is a relatively weak, central active opioid analgesic, acting as an agonist at the rotonin) . Respirarotonin) . For a drotonin) , 52. Therotonin) .Patient-controlled analgesia avoids problems of IV opioid overadministration such as respiratory depression and the need for intra- and postoperative patient monitoring . Every tStaff administering the above listed substances should be trained in cardiopulmonary resuscitation and the appropriate reversal agents should be at hand: naloxone for opioid reversal and flumazenil for benzodiazepine reversal .Diclofenac, ketorolac, and piroxicam are widely used for SWL as they have a good analgesic effect , 17, 36.They can be given orally, intravenously, intramuscularly, or rectally , 27, 36.Lornoxicam is a short-acting, nonsteroidal anti-inflammatory agent, inhibiting COX-1 and COX-2 and belonging to the oxicam group . A singlSelective cyclooxygenase-2-inhibitors (COX-2) are particularly interesting for pain relief during or after surgical procedures such as SWL, as they have no effect on thromboxane and a potential better side effect profile. They are not yet widely in use for pain relief during SWL, only parecoxib, which can be administered IV or IM has recently been under investigation, showing a rather limited analgesic effect and proving to be remarkably less effective than fentanyl . after SWL treatment, but in the meantime this substance has been withdrawn from the market due to safety concerns [Rofecoxib is another COX-2 inhibitor, which showed to provide good pain relief concerns .p-aminophenol. It is not counted to the NSAIDs because it has no anti-inflammatory effect. It is commonly used for pain control after surgical procedures.Paracetamol is a derivative of There is only one study in the literature proving the efficacy of paracetamol in SWL .α1a-selective alpha blocker and widely used in urology for the symptomatic treatment of urinary outflow obstruction due to benign prostate enlargement. It has also been shown to increase stone-free rate after SWL treatment and to reduce the need for opioid analgesics in patients with renal colics [Tamsulosin is an l colics . It was l colics .α-2 agonists, gabapentin, magnesium, and neostigmine [Multimodal  analgesia represents a modern approach to pain control during surgery by administering a combination of opioid and nonopioid analgesics like local anesthetics, NSAIDs, COX-2 inhibitors, acetaminophen, ketamine, dextromethorphan, stigmine . These nstigmine , subcutastigmine  or NSAIDstigmine  is adminEven with latest generation lithotripters, SWL is still a potential painful procedure and sufficient analgesia is mandatory for good treatment results.General anaesthesia should be reserved for selected cases and for the treatment of children; the same applies to spinal anaesthesia. Both guaranty optimal pain control but have high demands of manpower, resources, and a lead to prolonged recovery, making them less suitable for SWL as an outpatient procedure. In this context, inhalational anaesthesia with nitrous oxide is another, very interesting option, as it delivers good analgesia, is easy to administer, and does not lead to prolonged recovery. Subcutaneous infiltration with local anaesthetics has proven to be effective in terms of pain control and safe, as it avoids side effects of opioids.The concept of dermal anaesthesia is not new but remains an interesting option due to the simplicity of its use and the convenience for the patient. Especially the combination of lidocaine with DMSO lately showed promising results.Opioids, sometimes in combination with sedatives are the classical substances for pain control in SWL. They have a very good analgesic action, but also inconvenient side effects, require patient monitoring and lead to a delayed patient discharge. Sedoanalgesia and patient-controlled analgesia lead to good pain relief and patient satisfaction but are costly and likewise limited in an outpatient setting. NSAIDs are very convenient for both surgeon and patient. They are easy to administer, do not require patient monitoring and patients can be discharged immediately after the procedure. The newer substance lornoxicam has proven to have a good analgesic effect, whereas selective cyclooxygenase-2-inhibitors have not yet proven to be equally effective.Substances like Paracetamol and Tamsulosin are widely in use for other indications and have recently been in the focus. Their very convenient side effect profile makes them very interesting, though the analgesic component, especially of Tamsulosin, is not convincing.Despite its crucial importance for the outcome, no standardized protocols for pain control in SWL exist. Whatever substances or ways of administration are used, it remains the duty of the operator to ensure a pain-free treatment, for example, by delivering additional opioids on demand.


Objective. To compare the effectiveness of supervised exercise program and Cyriax physiotherapy in the treatment of tennis elbow . Design. Randomized clinical trial. Setting. Physiotherapy and rehabilitation centre. Subjects. This study was carried out with 20 patients, who had tennis elbow . Intervention. Group A (n = 10) had received supervised exercise program. Group B (n = 10) was treated with Cyriax physiotherapy. All patients received three treatment sessions per week for four weeks (12 treatment sessions). Outcome measures. Pain was evaluated using a visual analogue scale (VAS), and functional status was evaluated by completion of the Tennis Elbow Function Scale (TEFS) which were recorded at base line and at the end of fourth week. Results. Both the supervised exercise program and Cyriax physiotherapy were found to be significantly effective in reduction of pain and in the improvement of functional status. The supervised exercise programme resulted in greater improvement in comparison to those who received Cyriax physiotherapy. Conclusion. The results of this clinical trial demonstrate that the supervised exercise program may be the first treatment choice for therapist in managing tennis elbow. The syndrome of persistent disabling pain in the elbow, predominantly in the radio humeral joint, is called as tennis elbow, lateral epicondylitis, or lateral epicondylalgia –5. The dThe main clinical presentation and the chief complaints in tennis elbow are decreased grip strength, decreased functional activities, and increased pain, which may have significant impact on activities of daily living. The diagnosis of tennis elbow can be made simple, and it may be confirmed by test which would elicit the pain, tenderness over on the facet of the lateral epicondyle on palpation, resisted wrist extension, resisted middle finger extension, and passive wrist flexion . Even though tennis elbow has well-defined clinical features, no proper treatment intervention has emanated . In liteThe conventional treatment intervention of tennis elbow is most often accompanied by exercise program which may include strengthening, flexibility, or endurance training exercises. For instance, Stasinopoulos et al.  recommenA randomized clinical trial was conducted between March 2011 and September 2011 in an outpatient department, Physiotherapy and Rehabilitation centre, Alleppey, Kerala, India. Patients were referred by orthopaedic consultant, health care providers, and also self-referral to the centre. Patients were included if they were between 30 to 45 years of age and had been diagnosed with tennis elbow, and the duration of symptoms was between 8 and 10 weeks.Pain with gripping.Pain with resisted wrist extension.Pain with passive wrist flexion with the elbow extension.Tenderness on palpation over the lateral epicondyle of humerus.Cardiovascular diseases.Neurological impairments.Aversion to manual contact.Neuromuscular diseases.Previous trauma to the elbow region.Elbow pain.Previous surgery to the elbow region.Peripheral nerve entrapment.Cervical radiculopathy.Corticosteroid injection within 6 months.Previous therapy for elbow joint (minimizing expectation bias).All patients signed the written consent form prior to participation. The recruited patients had also completed a standard health questionnaire which encompassed details relating to patient demographics, duration of symptoms, any previous treatment undertaken, and job status.Patients assigned to Group A received supervised therapeutic exercise program which included static stretching of the Extensor Carpi Radialis Brevis followed by eccentric strengthening of the wrist extensors. Static stretching was performed in the seated position with elbow extension, forearm pronation, and wrist flexion with ulnar deviation. According to the patient tolerance stretch force was applied. This stretch position was held for duration of 30–45 seconds and was performed 3 times before and 3 times after the eccentric exercise portion of the treatment for a total of 6 repetitions . There wEccentric strengthening exercise was performed in the seated position with full elbow extension, forearm pronation, and maximum wrist extension. From this position, the patient slowly lowered wrist into flexion for a count of 30, using the contralateral hand to return the wrist to maximum extension. Patients were instructed to continue the exercise even when they experience mild discomfort and to stop the exercise if the pain worsens and becomes disabling. For whom the eccentric exercise could be performed without minor discomfort or pain, the load was increased using free weights based on the patients 10 RM (Repetition Maximum). Three sets of ten repetitions were performed during each treatment, with a one-minute rest interval between each set. Patients were also provided with education manual regarding ergonomics and activity modification technique to avoid aggravation of symptoms.Patients in Group B received Cyriax physiotherapy, which consists of 10 minutes of deep transverse friction massage immediately followed by a single application of Mill's manipulation. The hand placement is shown in For the technique of Mills manipulation, patients were positioned comfortably in the seating position with the affected extremity in 90° of abduction with internal rotation enough so that the olecranon faced up. The therapist stabilized the patient's wrist in full flexion and pronation with one hand, while other hand was placed over the olecranon . While aOutcome measures used in the study includes pain intensity and functional status which were recorded at base line (pretest) and at the end of 4 weeks. An independent observer, who was blinded to the patient group allocation, assessed the outcome measures. Pain intensity was measured using the visual analogue scale (VAS). The VAS consists of a 10 cm horizontal line with two ends labelled as 0 cm representing the “least pain imaginable” and 10 cm the “worst pain imaginable”. Patients were given instructions to intersect this VAS scale with a vertical line depending on their current level of pain. The VAS assessment tool has been found to be a valid and also a reliable method of measuring patients perceived pain , 41.Patients functional status was assessed by completion of the Tennis Elbow Function Scale (TEFS) . In TEFSn = 7), declined to participate (n = 7), and other reason (n = 1). The remaining 20 patients  randomly allocated into 2 groups. Participant flow through the study is illustrated in Thirty-five patients, 20 male and 15 female, were initially assessed for eligibility for this study. 15 patients were excluded for the following reasons: not meeting inclusion criteria  and Group B (Cyriax physiotherapy).t test. For Group A, the age of the subjects ranged between 30 and 45, while for Group B it ranged between 31 and 45. The mean age for Group A was 37.40 ± 4.881 and Group B was 38.20 ± 4.341 as shown in Statistical tool used is the two sample n = 10), with a gender distribution of 4 males (40%) and 6 females (60%). Group B also consisted of 10 patients (n = 10) and a gender distribution of 6 males (60%) and 4 females (40%). These data were presented in Group A consisted of 10 patients (The mean duration of symptoms (in weeks) for Group A was 9.1 ± 0.88 and for Group B was 8.8 ± 0.91 weeks. There is no significant difference between the duration of symptom of the two groups at 5% level of significance as shown in U test. There is no significant difference between the pre-VAS scores of the two groups at 5% level of significance (VAS scores were found to be similar between groups at baseline (Pretest). Statistical tool used is the Mann-Whitney ificance .U test. There is no significant difference between the pre-TEFS scores of the two groups at 5% level of significance (TEFS scores were found to be similar between groups at baseline (Pre Test). Statistical tool used is the Mann-Whitney ificance .The intragroup comparison of pain intensity as measured by VAS at the end of treatment intervention in Group A, presented in Tables The intragroup comparison of pain intensity as measured by VAS at the end of treatment intervention in Group B, presented in Tables U test  and Cyriax physiotherapy treatment (Group B) groups experienced significant improvements in pain and function following 4 weeks treatment sessions. The supervised exercise and static stretching group experienced greater outcomes for all variables in comparison to those receiving Cyriax physiotherapy treatment. The reported success of supervised exercise program in this study is consistent with previously published research studies , 36, 37.The early return of functional status is very useful for a sports person, as it will facilitate his/her return to sports in less duration. This improvement in functional status will also prevent disuse atrophy or muscle weakness resulting from less or no activity due to pain and disability caused by tennis elbow. It has been assumed that the underlying mechanism of pain relief secondary to friction massage may be due to modulation of pain impulses at the spinal cord level . At presNo follow-up data was collected; therefore, the long-term effects of the interventions in the present study remain unknown.Absence of true control group affects the internal validity of the study.We rejected the null hypothesis that no difference would be seen in pain intensity and functional status after 4 weeks as compared with Cyriax physiotherapy treatment. The groups that performed supervised exercise program for 4 weeks showed significantly greater improvement in reduction of pain and functional status than the Cyriax physiotherapy treatment. The favorable results in the present study indicate the need for future research examining the incorporation of supervised exercise program into multimodal treatment regimens.