Applicability and Clinical Relevance of Results in Randomized Controlled Trials: The Cochrane Review on Exercise Therapy for Low Back Pain as an Example A nurse-initiated pain protocol in the ED improves pain treatment in patients with acute musculoskeletal pain. Factors That Can Affect the External Validity of Randomised Controlled Trials Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Better outcome from arthroscopic partial meniscectomy than skin incisions only? A sham-controlled randomised trial in patients aged 35–55 years with knee pain and an MRI-verified meniscal tear Acupuncture for infantile colic: A blinding-validated, randomized controlled multicentre trial in general practice SWISSspine: a nationwide registry for health technology assessment of lumbar disc prostheses Clinically meaningful measurement of pain in children with sickle cell disease. Skeletal muscle contractility, self-reported pain and tissue sensitivity in females with neck/shoulder pain and upper Trapezius myofascial trigger points– a randomized intervention study [Laparoscopic or classical appendectomy? A prospective randomized study]. Changes in Pain, Disability, and Muscle Activation Patterns in Chronic Whiplash Patients After Ambulant Myofeedback Training Benign Adverse Events Following Chiropractic Care for Neck Pain Are Associated With Worse Short-term Outcomes but Not Worse Outcomes at Three Months Topical formulation of heparin is effective in reducing the symptoms of superficial venous thrombosis: a monocenter, observer-blind, placebo-controlled randomized study. Effects of denosumab on pain and analgesic use in giant cell tumor of bone: Interim results from a phase II study Acupuncture for chronic headaches--an epidemiological study. A Comparison of Change in the 0–10 Numeric Rating Scale to a Pain Relief Scale and Global Medication Performance Scale in a Short-term Clinical Trial of Breakthrough Pain Intensity The Effects of Dynamic Isolated Lumbar Extensor Training on Lumbar Multifidus Functional Cross-Sectional Area and Functional Status of Patients With Chronic Nonspecific Low Back Pain Drug-related problems and pharmacotherapeutic advisory intervention at a medicine clinic A double-blind study to compare the efficacy, tolerance and safety of two doses of the angiotensin converting enzyme inhibitor ramipril with placebo. Active rehabilitation for chronic low back pain: Cognitive-behavioral, physical, or both? First direct post-treatment results from a randomized controlled trial [ISRCTN22714229] Placebo response in asthma: a robust and objective phenomenon. A clinical decision support system algorithm for intravenous to oral antibiotic switch therapy: validity, clinical relevance and usefulness in a three-step evaluation study Pain-relieving properties of topically applied morphine on arterial leg ulcers: a pilot study.
Study Design . A critical appraisal of the literature . Objectives . To increase awareness of the importance of applicability and clinical relevance of the results of r and omized controlled trials ( RCTs ) in the field of spinal disorders by formulating a list of items for assessment of applicability and clinical relevance of results of RCTs . Summary of Background Data . In systematic review s of r and omized controlled trials ( RCTs ) , critical appraisal of method ologic quality is considered important . Less attention has been paid to the assessment of the applicability and the clinical relevance of the results . Methods . RCTs in an up date of the Cochrane review on  exercise therapy for low back pain were used . Most of the trials did not score positively on the five Cochrane Back Review Group basic items describing patients : intervention and setting , outcome , effect size , and benefits related to adverse effects . Item 1 was met by 88 % of the trials , but item 2 only by 51 % , item 3 by 67 % , item 4 by 35 % , and item 5 by 0 % . Subsequently , a more comprehensive list of items for the assessment of applicability and clinical relevance of results of RCTs was developed . These criteria were pilot tested on the RCTs . After pilot testing and a subsequent consensus meeting , the list of items was drafted and circulated among the members of the Editorial Board of the Cochrane Back Review Group . Changes were made in response to comments . Results . The final list consists of 40 items . The items are ordered on two headings : Does the report enable the assessment of applicability ? Are the study results clinical ly relevant ? We present examples of informative and noninformative reporting of RCTs in order to illustrate how information on applicability and clinical relevance of results can be assessed . Conclusions . Authors of RCTs should adequately report on items that are essential to assess the applicability and clinical relevance of results . The presented list of items may help clinicians reading RCTs and authors of systematic review s to draw more balanced conclusions on applicability and clinical relevance of results While acute musculoskeletal pain is a frequent complaint , its management is often neglected . An implementation of a nurse-initiated pain protocol based on the algorithm of a Dutch pain management guideline in the emergency department might improve this . A pre-post intervention study was performed as part of the prospect i ve PROTACT follow-up study . During the pre- ( 15 months , n = 504 ) and post-period ( 6 months , n = 156 ) patients ' self-reported pain intensity and pain treatment were registered . Analgesic provision in patients with moderate to severe pain ( NRS ≥4 ) improved from 46.8 % to 68.0 % . Over 10 % of the patients refused analgesics , result ing into an actual analgesic administration increase from 36.3 % to 46.1 % . Median time to analgesic decreased from 10 to 7 min ( P < 0.05 ) , whereas time to opioids decreased from 37 to 15 min ( P < 0.01 ) . Mean pain relief significantly increased to 1.56 NRS-points , in patients who received analgesic treatment even up to 2.02 points . The protocol appeared to lead to an increase in analgesic administration , shorter time to analgesics and a higher clinical ly relevant pain relief . Despite improvements , suffering moderate to severe pain at ED discharge was still common . Protocol adherence needs to be studied in order to optimize pain management R and omised controlled trials ( RCTs ) must be internally valid ( i.e. , design and conduct must eliminate the possibility of bias ) , but to be clinical ly useful , the result must also be relevant to a definable group of patients in a particular clinical setting ( i.e. , they must be externally valid ) . Lack of external validity is the most frequent criticism by clinicians of RCTs , systematic review s , and guidelines , and is one explanation for the widespread underuse in routine practice of many treatments that have been shown to be beneficial in trials and are recommended in guidelines [ 1 ] . Yet medical journals , funding agencies , ethics committees , the pharmaceutical industry , and governmental regulators seem to give external validity a low priority . Admittedly , whereas the determinants of internal validity are intuitive and can generally be worked out from first principles , underst and ing of the determinants of the external validity of an RCT requires clinical rather than statistical expertise , and often depends on a detailed underst and ing of the particular clinical condition under study and its management in routine clinical practice . However , reliable judgments about the external validity of RCTs are essential if treatments are to be used correctly in as many patients as possible in routine clinical practice . The results of RCTs or systematic review s will never be relevant to all patients and all setting s , but they should be design ed and reported in a way that allows clinicians to judge to whom the results can reasonably be applied . Table 1 lists some of the important potential determinants of external validity , each of which is review ed briefly below . Many of the considerations will only be relevant in certain types of trials , for certain interventions , or in certain clinical setting s , but they can each sometimes undermine external validity . Moreover , the list is not exhaustive and requires more detailed annotation and explanation than is possible in this short review . Table 1 Main Issues That Can Affect External Validity and Should Be Addressed in Reports of the Results of R and omised Controlled Trials or Systematic Review s and Considered by Clinicians Some of the issues that determine external validity are relevant to the distinction between pragmatic trials and explanatory trials [ 2 ] , but it would be wrong to assume that pragmatic trials necessarily have greater external validity than explanatory trials . For example , broad eligibility criteria , limited collection of baseline data , and inclusion of centres with a range of expertise and differing patient population s have many advantages , but they can also make it very difficult to generalise the overall average effect of treatment to a particular clinical setting OBJECTIVE This trial investigated the efficacy and long-term tolerability of intranasal fentanyl spray ( INFS ) 50 to 200 microg in the treatment of breakthrough pain in opioid-tolerant patients with cancer . METHODS This Phase III , double-blind , r and omized , placebo-controlled , crossover trial was conducted at pain centers , anesthesiology departments , palliative care units , and oncology clinics in Austria , Denmark , France , Germany , and Pol and . Eligible patients were adults with cancer receiving a stable dose of long-term opioid treatment for the control of background pain . Patients were treated at home with their effective dose of INFS ( 50 , 100 , or 200 microg ) or inactive spray ( placebo ) in a r and omized sequence for 3 weeks , followed by a 10-month , open-label tolerability phase during which they received their effective dose of INFS . Throughout the study , patients were allowed to use their usual rescue medication , which was recorded in patient diaries . The primary efficacy end point was the pain intensity difference at 10 minutes after study drug administration ( PID(10 ) ) , as assessed using an 11-point numeric rating scale ( 0 = no pain to 10 = worst pain imaginable ) . An effect size of 0.5 for PID was considered clinical ly relevant . The rate of response , defined as PID(10 ) > 2 , was also assessed . Adverse events ( AEs ) were recorded in patient diaries during the efficacy period and reported in monthly clinic visits and follow-up weekly telephone contacts during the extension period . RESULTS In all , 120 patients were enrolled and achieved an effective dose ; 113 were r and omized and 111 were included in the intent-to-treat analysis set ( 56 men , 55 women ; mean [ SD ] age , 60.6 [ 9.45 ] years ; mean weight , 70.3 kg [ men ] and 65.3 kg [ women ] ; white race , 107 [ 96.4 % ] ; INFS 50 microg , 18 ; INFS 100 microg , 48 ; INFS 200 microg , 45 ; placebo , 110 ) . PID(10 ) with INFS was 2-fold that with placebo ( adjusted means , 2.36 vs 1.10 ; adjusted difference , 1.26 [ greater than the clinical ly relevant difference of 0.5 ] ; P < 0.001 ) . Additional analysis revealed that the mean response rate with all 3 doses of INFS was 51.1 % versus 20.9 % with placebo . The prevalence of AEs was 22/111 ( 19.8 % ) during the efficacy period , during which the most frequently reported AEs were nausea ( 5 [ 4.5 % ] ) and vertigo ( 2 [ 1.8 % ] ) . No serious AEs were considered related to the study drugs . In all , 108 patients entered the extension period , with a mean duration of exposure to INFS of 134.9 days . Progression of underlying malignant disease was the most common AE reported during this period ( 55 [ 50.9 % ] ) ; this event was not considered treatment related . CONCLUSIONS In these opioid-tolerant patients with cancer , INFS at doses of 50 , 100 , and 200 microg was associated with an onset of activity at 10 minutes and effective treatment of breakthrough pain compared with placebo . All doses were generally well tolerated and clinical ly efficacious Objective Compare arthroscopic partial meniscectomy to a true sham intervention . Methods Sham-controlled superiority trial performed in three county hospitals in Denmark comparing  arthroscopic partial meniscectomy to skin incisions only  in patients aged 35–55 years with persistent knee pain and an MRI-confirmed medial meniscus lesion . A computer-generated table of r and om numbers generated two comparison groups . Participants and outcome assessors were blinded to group allocation . Exclusions were locking knees , high-energy trauma or severe osteoarthritis . Outcomes were collected at baseline , 3 and 24 months . We hypothesised no difference between groups . The primary outcome was the between-group difference in change from baseline to 2 years in the mean score across all five normalised Knee injury and Osteoarthritis Outcome Score ( KOOS ) subscales ( KOOS5 ) . Results Forty-four patients ( of the estimated 72 ) underwent r and omisation ; 22 in each group . Sixteen participants ( 36 % ) were non-blinded and eight participants ( 36 % ) from the sham group crossed over to the surgery group prior to the 2-year follow-up . At 2 years , both groups reported clinical ly relevant improvements ( surgery 21.8 , skin incisions only 13.6 ) , the mean difference between groups was 8.2 in favour of surgery , which is slightly less than the cut-off of 10 prespecified to represent a clinical ly relevant difference ; judged by the 95 % CI ( −3.4 to 19.8 ) , a possibility of clinical ly relevant difference could not be excluded . In total , nine participants experienced 11 adverse events ; six in the surgery group and three in the skin-incisions-only group . Conclusion We found greater improvement from arthroscopic partial meniscectomy compared with skin incisions only at 2 years , with the statistical uncertainty of the between-group difference including what could be considered clinical ly relevant . Because of the study being underpowered , nearly half in the sham group being non-blinded and one-third crossing over to surgery , the results can not be generalised to the greater patient population . Trial registration number NCT01264991 Abstract Objective . Infantile colic is a painful condition in the first months of infancy . Acupuncture is used in Sc and inavia as a treatment for infantile colic . A r and omized controlled trial was carried out with the aim of testing the hypothesis that acupuncture treatment has a clinical ly relevant effect for this condition . Design . A prospect i ve , blinding-vali date d , r and omized controlled multicentre trial in general practice . Research assistants and parents were blinded . Setting . 13 GPs ’ offices in Southern Norway . Intervention . Three days of bilateral needling of the acupuncture point ST36 , with no treatment as control . Subjects . 113 patients were recruited ; 23 patients were excluded , and 90 r and omized ; 79 diaries and 84 interviews were analysed . Main outcome measures . Difference in changes in crying time during the trial period between the intervention and control group . Results . The blinding validation questions showed a r and om distribution with p = 0.41 and 0.60 , indicating true blinding . We found no statistically significant difference in crying time reduction between acupuncture and control group at any of the measured intervals , nor in the main analysis of differences in changes over time ( p = 0.26 ) . There was a tendency in favour of the acupuncture group , with a non-significant total baseline-corrected mean of 13 minutes ( 95 % CI –24 to + 51 ) difference in crying time between the groups . This was not considered clinical ly relevant , according to protocol . Conclusion . This trial of acupuncture treatment for infantile colic showed no statistically significant or clinical ly relevant effect . With the current evidence , the authors suggest that acupuncture for infantile colic should be restricted to clinical trials SWISSspine is a so-called pragmatic trial for assessment of safety and efficiency of  total disc arthroplasty ( TDA ) .  It follows the new health technology assessment ( HTA ) principle of “ coverage with evidence development ” . It is the first m and atory HTA registry of its kind in the history of Swiss orthopaedic surgery . Its goal is the generation of evidence for a decision by the Swiss federal office of health about reimbursement of the concerned technologies and treatments by the basic health insurance of Switzerl and . During the time between March 2005 and 2008 , 427 interventions with implantation of 497 lumbar total disc arthroplasties have been documented . Data was collected in a prospect i ve , observational multicenter mode . The preliminary timeframe for the registry was 3 years and has already been extended . Data collection happens pre- and perioperatively , at the 3 months and 1-year follow-up and annually thereafter . Surgery , implant and follow-up case report forms are administered by spinal surgeons . Comorbidity question naires , NASS and EQ-5D forms are completed by the patients . Significant and clinical ly relevant reduction of low back pain VAS ( 70.3–29.4 points preop to 1-year postop , p < 0.0001 ) leg pain VAS ( 55.5–19.1 points preop to 1-year postop , p < 0.001 ) , improvement of quality of life ( EQ-5D , 0.32–0.73 points preop to 1-year postop , p < 0.001 ) and reduction of pain killer consumption was revealed at the 1-year follow-up . There were 14 ( 3.9 % ) complications and 7 ( 2.0 % ) revisions within the same hospitalization reported for monosegmental TDA ; there were 6 ( 8.6 % ) complications and 8 ( 11.4 % ) revisions for bisegmental surgery . There were 35 patients ( 9.8 % ) with complications during followup in monosegmental and 9 ( 12.9 % ) in bisegmental surgery and 11 ( 3.1 % ) revisions with new hospitalization in monosegmental and 1 ( 1.4 % ) in bisegmental surgery . Regression analysis suggested a preoperative VAS “ threshold value ” of about 44 points for increased likelihood of a minimum clinical ly relevant back pain improvement . In a short-term perspective , lumbar TDA appears as a relatively safe and efficient procedure concerning pain reduction and improvement of quality of life . Nevertheless , no prediction about the long-term goals of TDA can be made yet . The SWISSspine registry proofs to be an excellent tool for collection of observational data in a nationwide framework whereby advantages and deficits of its design must be considered . It can act as a model for similar projects in other health-care domains BACKGROUND Limited underst and ing of the interpretability of patient-reported pain scores may impact pain management . The current study assessed the minimal clinical ly significant improvement in pain and pain scores signifying patient-reported need for medication and treatment satisfaction in patients with sickle cell disease ( SCD ) . PROCEDURE Patients , 8 - 18-years-old , with SCD were recruited while receiving treatment for pain .  Patients completed initial pain severity ratings using the Visual Analog Scale ( VAS ) and the Numeric Rating Scale ( NRS ) . Serial assessment s of pain severity , pain relief , perceived need for medication , and treatment satisfaction were completed in the emergency department and the hospitalization . Data were used to calculate the minimal clinical ly significant improvement in pain and pain scores associated with perceived need for pain medication and treatment satisfaction . RESULTS Twenty-eight patients completed 305 assessment s during 37 total visits . A decrease in pain severity score of 0.97 cm for the VAS and 0.9 for the NRS was found to be the minimum clinical ly significant improvement in pain . Pain scores > 7.45 cm on the VAS or 7.5 on the NRS were suggestive of patient-reported need for pain medication . Pain scores < 7.35 cm on the VAS or 8.5 on the NRS were suggestive of patient-reported treatment satisfaction discrimination . CONCLUSIONS The minimal clinical significant improvement was defined for the VAS and NRS and both scales were able to discriminate between important clinical findings including pain relief , need for pain medication , and treatment satisfaction . Collectively , this study provides data to improve our underst and ing of pain ratings of pediatric patients with SCD Background In relation to Myofascial Triggerpoints ( MFTrPs ) of the upper Trapezius , this study explored muscle contractility characteristics , the occurrence of post-intervention muscle soreness and the effect of dry needling on muscle contractile characteristics and clinical outcomes . Methods Seventy-seven female office workers ( 25 - 46yrs ) with and without neck/shoulder pain were observed with respect to self-reported pain ( NRS-101 ) , pressure-pain threshold ( PPT ) , maximum voluntary contraction ( Fmax ) and rate of force development ( RFD ) at baseline ( pre-intervention ) , immediately post-intervention and 48 hours post-intervention . Symptomatic and asymptomatic participant groups were each r and omized into two treatment sub-groups ( superficial ( SDN ) and deep dry needling ( DDN ) ) after baseline testing . At 48 hours post-intervention participants were asked whether delayed onset muscle soreness ( DOMS ) and /or post-needling soreness had developed . Results Muscle contractile characteristics did not differ between groups at baseline . Forty-six individuals developed muscle soreness ( 39 from mechanical testing and seven from needling ) . No inter-group differences were observed post-intervention for Fmax or RFD for the four sub-groups . Over the observation period , symptomatic participants reported less pain from both SDN ( p= 0.003 ) and DDN ( p=0.011 ) . However , PPT levels were reduced for all participants ( p=0.029 ) . Those reporting DOMS experienced significant decreases in PPT , irrespective of symptom state or intervention ( p=0.001 ) . Conclusions In selected female neck/shoulder pain sufferers , maximum voluntary contraction and rapid force generation of the upper Trapezius was not influenced by clinical ly relevant self-reported pain or the presence of diagnostically relevant MFTrPs . Dry needling , deep or superficial , did not affect measured functional outcomes over the 48-hour observation period . DOMS affected participants uniformly irrespective of pain , MFTrP status or intervention type and therefore is like to act as a modifier . Trial registration Clinical Trials.gov- NCT01710735 Significance and InnovationsThe present investigation is one of the first to examine the hypothesis of gross muscle contractile inhibition due to the presence of diagnostically relevant MFTrPs . Individuals suffering from clinical ly relevant levels of self-reported pain are able to tolerate maximum voluntary contraction testing , but delayed onset muscle soreness ( DOMS ) is a likely side-effect irrespective of symptom status . As a consequence , its confounding effect during subsequent testing must be taken into account Though laparoscopic appendectomy started endoscopic surgery in general surgery , it has yet not reached the acceptance as is the case with cholecystectomy . The application of this technique in possibly bl and appendices and reports that the technique was accompanied by severe complications , increases the scepticism about it . This made us decide to start a r and omized controlled trial : laparoscopic vs. conventional appendectomy . More than 1000 endoscopic interventions mainly performed at the gallbladder and the stomach and 165 prospect ively documented and partly treated patients with acute appendicitis were the basis to start this trial . " Acute Appendicitis " was diagnosed on the basis of clinical symptoms by means of the computer-aided question naire of the EC- study " Acute Abdominal Pain " , a self-developed vali date d diagnostic score , the macroscopic findings and the careful assessment of the histology of the resected appendix . Beside the technical feasibility , principle end-points were mainly intensity and course of postoperative pain measured by means of the Visual Analogue Scale ( VAS ) in lying , st and ing and moving position and the postoperative consumption of analgesics . We assessed a difference of 15 points on the VAS as clinical ly relevant . Of 57 patients with acute appendicitis we performed open appendectomy in 23 and laparoscopy in 34 patients according to r and omization . In 9 patients of the laparoscopy group it was necessary to change over to open appendectomy for different reasons result ing in a direct comparison of 25 laparoscopies versus 23 open appendectomies . There were no differences between sociodemographic and pre clinical data in both groups . ( ABSTRACT TRUNCATED AT 250 WORDS Objective The aim of this exploratory study was to investigate changes in pain , disability , and muscle activation patterns in patients with chronic whiplash-associated disorder ( WAD ) after 4 weeks of myofeedback training . Methods Eleven WAD patients received ambulatory myofeedback training  , during which upper trapezius muscle activation and relaxation were continuously recorded and processed for 4 weeks . Feedback was provided when muscle relaxation was insufficient . Pain in neck , shoulders , and upper back ( Visual Analogue Scale ) , disability ( Neck Disability Index ) , and muscle activation patterns during rest , typing , and stress tasks ( surface electromyography ) were assessed before and after the 4 weeks of training . Results Pain intensity decreased after 4 weeks of training . Clinical ly relevant changes were found with regard to pain in the neck and upper back region ( 55 % of the patients ) , right shoulder ( 64 % ) , and left shoulder ( 18 % ) . A trend for decreased disability was found which was clinical ly relevant in 36 % of the patients . A remarkable reduction was found in the Neck Disability Index items concerning headache and lifting weights . Overall , muscle activation was lower and muscle relaxation was higher after the training period with the largest differences during rest . Clinical ly relevant changes in surface electromyography parameters were found in a minority of patients . Conclusion Four weeks of ambulant training may be beneficial in reducing pain and disability levels and normalizing muscle activation patterns in chronic WAD patients . A r and omized-controlled study is recommended to further explore the effects of myofeedback training Study Design . A prospect i ve cohort study on chiropractic patients with neck pain . Objective . To examine the association between self-reported benign adverse events after chiropractic care for neck pain and the outcome measures namely , perceived recovery , neck pain , and neck disability . Summary of Background Data . Only 1 study has examined the association between adverse events and outcome in subjects with neck pain treated by chiropractors , which concluded that those receiving cervical spinal manipulation were more likely to report an adverse event compared to cervical mobilization , and those reporting an adverse event were less likely to have improved outcomes at all follow-up measurements . Methods . This was a prospect i ve , multicenter , observational cohort study conducted in the private clinics of chiropractors throughout The Netherl and s. All new , consecutive patients , between 18 and 65 years of age with neck pain of any duration , who had not undergone chiropractic or manual therapy in the prior 3 months , were eligible for recruitment .  Self-reported question naires were administered at the first 3 visits and at 3 months . Multivariate multilevel logistic and linear regression analyses were used to evaluate the association between adverse events and recovery , neck pain , and neck disability . Outcomes were measured at the fourth visit and at 3 months . Results . In total , 529 patients were recruited who fulfilled the inclusion criteria . The response rate at 3 months was 90 % . At the fourth visit , subjects who reported a benign adverse event or “ intense ” adverse event after any of the first 3 visits were less likely to be recovered , and had slightly worse levels of neck pain . However , the differences in neck pain were too small to be clinical ly meaningful . Intense adverse events , on the other h and , were not only associated with more neck disability but also clinical ly relevant differences . At 3 months , adverse events were not associated with better or worse outcomes for any of the three outcome measures examined . Conclusion . Self-reported benign adverse events after chiropractic care for neck pain are associated with worse short-term outcomes . Intense adverse events are associated with more neck disability and clinical ly relevant differences at the short-term only . However , there is no association between adverse events and worse outcomes at 3 months AIM The aim of the present , r and omized , placebo controlled study was to assess the dose-dependent symptom reduction efficacy , safety and tolerability of heparin-spraygel ( Viatromb 2.400 IU/g heparin spraygel ) in patients with superficial vein thrombosis ( SVT ) of the lower limbs . METHODS A number of clinical ly relevant objectives ; time to onset and intensity of symptoms ' reduction reflected also by rescue medication consumption were considered and assessed . RESULTS Pain reduction between the two time-points ( days 0 and 7 ) was significant within both treatment groups ( active drug and placebo ) . However , subjects treated with active drug reported a mean pain reduction ( VAS ) of 76.21 mm ( 93.13 % decrease ) ; in subjects treated with placebo it was 50.36 ( 61.35 % ) mm ( P<0.0001 ) . The difference in pain reduction between the active drug and placebo groups was significant ( P<0.05 ) . The proportion of responders ( subjects with at least 50%reduction in pain ( VAS ) on day 7 and day 14 ) was higher within subjects treated with Viatromb ( P<0.05 ) . The extension of erythema , evaluated by planimetry indicated a significantly higher reduction ( day 0 to 7 and 0 to 14 ) in Viatromb-treated subjects in comparison with placebo . In the Viatromb group , the reduction in thrombus size was remarkable towards placebo ( P<0.05 ) . Reduction of edema and pain ( VRS ) had comparable time courses . Both investigator 's and subject 's global assessment of efficacy were significantly better with Viatromb . No adverse events or reactions were reported during the study and the follow up period . CONCLUSION Viatromb was significantly more effective than placebo in the symptomatic treatment of SVT Abstract Background . Giant cell tumor of bone ( GCTB ) is an aggressive primary osteolytic tumor . GCTB often involves the epiphysis , usually causing substantial pain and functional disability .  Denosumab , a fully human monoclonal antibody against receptor activator of nuclear factor κΒ lig and ( RANKL ) , is an effective treatment option for patients with advanced GCTB . This analysis of data from an ongoing , open-label study describes denosumab 's effects on pain and analgesic use in patients with GCTB . Material and methods . Patients with unresectable disease ( e.g. sacral or spinal GCTB , or multiple lesions including pulmonary metastases ) were enrolled into Cohort 1 ( N = 170 ) , and patients with resectable disease whose planned surgery was associated with severe morbidity ( e.g. joint resection , limb amputation , or hemipelvectomy ) were enrolled into Cohort 2 ( N = 101 ) . Patients received denosumab ( 120 mg ) subcutaneously every four weeks , with additional doses on study days 8 and 15 . Patients assessed worst pain severity with the Brief Pain Inventory – Short Form ( BPI-SF ) at baseline , at each visit for the first six months , and every three months thereafter . Results . Clinical ly relevant pain improvement was reported by 29 % of patients in Cohort 1 and 35 % in Cohort 2 during week 1 and by ≥ 50 % of patients in each cohort at each study visit from months 2–30 . Median time to clinical ly relevant improvement was 30 ( 95 % CI 16 , 57 ) days in Cohort 1 and 15 ( 95 % CI 15 , 29 ) days in Cohort 2 . Results in patients with moderate/severe pain at baseline were similar . Fewer than 30 % of patients in Cohort 1 and 10 % in Cohort 2 experienced clinical ly relevant pain worsening at any visit through 27 months . Most patients had no/low analgesic use during the study . Conclusion . Most patients treated with denosumab experienced clinical ly relevant decreases in pain within two months OBJECTIVE To investigate the characteristics and outcomes of patients undergoing acupuncture treatment for chronic headaches under conditions of routine care provided within the framework of statutory health insurance in Germany . Furthermore , we investigated correlations between different outcomes . PATIENTS AND METHODS Patients with migraine , episodic or chronic tension-type headache ( TTH ) , or several other forms of chronic headache ( cluster , vascular , drug-induced headache ; other specific headaches ) treated with acupuncture ( mean number of sessions 8.6 + /- 3.0 ) were included into an observational study . Detailed question naires including questions on headache days and instruments measuring disability ( Pain Disability Index ) and quality of life ( SF-36 ) were completed before treatment , after treatment , and at 6 months after inclusion . RESULTS A total of 2,022 patients ( 732 with migraine , 351 with episodic and 440 with chronic TTHs , and 499 with other diagnoses ) treated by 1,418 physicians were included in the main analysis . Sociodemographic and baseline characteristics differed considerably in the four diagnostic groups . Statistically highly significant and clinical ly relevant improvements were seen for all clinical outcome measures in all diagnostic groups . In 52.6 % of patients headache frequency decreased by at least 50 % compared to baseline . The comparison of headache frequency , pain intensity , and generic outcome measures showed that some of these outcomes correlate only weakly . CONCLUSIONS In this epidemiological study , headache patients reported clinical ly relevant improvements after receiving acupuncture . R and omized trials performed in parallel to this study confirm the relevant overall effect , however , the effect may largely be due to potent unspecific needling and placebo effects Background : Pain intensity is commonly reported using a 0–10 Numeric Rating Scale in pain clinical trials . Analysis of the change on the Pain Intensity Numerical Rating Scale as a proportion has most consistently correlated with clinical ly important differences reported on the patient 's global impression of change . The correlation of data from patients with breakthrough pain with a Pain Relief Scale and a different global outcome measures will extend our underst and ing of these measures . Methods : Data were obtained from the open titration phase of a multiple crossover , r and omized , double-blind clinical trial comparing oral transmucosal fentanyl citrate with immediate-release oral morphine sulfate for the treatment of cancer-related breakthrough pain . Raw and percentage changes in the pain intensity scores from 1,307 episodes of pain in 134 oral transmucosal fentanyl citrate-naïve patients were correlated with the clinical ly relevant secondary outcomes of Pain Relief Verbal Response Scale and the global medication performance scale . The changes in raw and percentage change were assessed over time and compared with the ordinal Pain Relief Verbal Response Scale and Global Medication Performance Scale . Results : The P value of the interaction between the raw pain intensity difference was significant ( P = 0.034 ) for four 15-min time periods but not for the percentage pain intensity difference score ( P = 0.26 ) . We found similar results in comparison with the ordinal Pain Relief Verbal Response Scale ( P = 0.0048 and P = 0.36 respectively ) and global medication performance categories ( P = 0.048 and P = 0.45 , respectively ) . Conclusion : The change in pain intensity in breakthrough pain was more consistent over time and when compared with both the Pain Relief Verbal Response Scale and the Global Medication Performance Scale when the percentage change is used rather than raw pain intensity difference Study Design . A prospect i ve single-arm trial . Objective . To investigate whether dynamic isolated resistance training of global lumbar extensor muscles leads to changes in lumbar multifidus ( LM ) morphology in terms of cross-sectional muscle , and , if so , whether these changes are associated with observed changes in self-experienced functional status of chronic nonspecific low back pain ( CNSLBP ) . Summary of Background Data . LM morphology is associated with the recurrence of CNSLBP . Methods . Sixteen male patients underwent a dynamic isolated resistance-training program for the lower back muscles of approximately 10 sessions in 12 weeks . In the next 12 weeks , frequency of training was tailored to the patients ' need . Participants underwent lumbar magnetic resonance imaging at baseline ( T0 ) , after 12 weeks ( T12 ) , and after 24 weeks ( T24 ) . Functional cross-sectional area was obtained by analyzing the magnetic resonance images . Functional status was assessed using the patient-specific functional scale , Rol and -Morris disability question naire , and global perceived effect scale . Results . Rol and -Morris disability question naire and patient-specific functional scale scores showed significant and clinical ly relevant improvements between baseline and T12 , with 44 % and 39 % , respectively . Between T12 and T24 , these scores did not change significantly . Seven participants ( 44 % ) reported clinical ly relevant improvements in global perceived effect at T12 . At T24 , 1 more participant reported a relevant global perceived effect improvement , whereas 2 participants ( 13 % ) reported worsening of their condition . The magnetic resonance imaging analysis showed minor nonsignificant changes in functional cross-sectional area . Conclusion . Our study shows that 10 weeks of dynamic isolated training of the lumbar extensors , once a week , leads to clinical ly relevant improvements in functional status of men with CNSLBP , without accompanying improvements in functional cross-sectional area of LM . These findings suggest that improvement in LM morphology is not a critical success factor in restoring functional status of patients with CNSLBP , at least in the short term ( 6 mo ) Objective To describe the scenario and frequency of drug-related problems ( DRPs ) in in- patients and to determine whether a pharmacotherapeutic advisory intervention aim ing at reducing DRPs could affect rates of re-hospitalisation and /or death within 6 months . Methods This prospect i ve , r and omised , controlled advisory intervention study was carried out at the Clinic of Internal Medicine at Stockholm Söder Hospital . Three hundred patients from four wards took part in the study . Patients taking two drugs or more were included . In the intervention arm , potential drug interactions were found using a computer system .  Medical symptoms were estimated by a nurse together with the patient .  Creatinine clearance was calculated . Thereafter a clinical pharmacologist scrutinised the patient´s medical record for DRPs together with the nurse . DRPs judged to be clinical ly relevant result ed in written advice to the physician in charge of the patient . The control group received usual care . Results In the intervention group , a total of 299 DRPs were found among 71 % of the patients ( 106/150 ) . The number of written letters of advice to the physicians in charge was 106 . Of these , 63 % were accepted . After 6 months , the proportion of re-hospitalisations or death in the intervention group was 49 % ( 73/150 ) compared to 46 % ( 69/150 ) in the control group . The difference was not significant . Conclusions DRPs were common . Potential drug interactions and adverse drug reactions dominated . Hospital-based medication review by a clinical pharmacologist was not associated with reduced rates of re-hospitalisation and /or death . The clinical relevancy of DRPs might be overestimated as a risk for re-hospitalisation or death . It is of great importance to clarify if and how drug-related problems can be prevented . In design ing such studies , one should consider choosing inclusion criteria that accumulate risk In a r and omized , double-blind trial , 2 doses of ramipril ( 2.5 and 5 mg once daily ) were compared with placebo in patients with mild to moderate essential hypertension . A 2-week placebo run-in phase was followed by 4 weeks of treatment . Eighty-six patients entered the study and 17 withdrew during the course of the study . Both doses of ramipril appeared to be more effective than placebo in reducing blood pressure , but significant differences between 2.5 mg of ramipril and placebo were not found in any statistical analyses . In the endpoint analyses ( taking the last measurement from each patient ) , the patients receiving 5 mg of ramipril had significantly larger decreases in blood pressure than the patients receiving placebo ( t tests : st and ing systolic , p less than 0.001 ; supine diastolic , p less than 0.05 ; st and ing diastolic , p less than 0.05 ) and also than the patients receiving 2.5 mg of ramipril ( st and ing systolic , p less than 0.05 ) . It appears from the results of this study that the minimum effective dosage of ramipril is 5 mg once daily . No clinical ly relevant side effects or clinical ly relevant changes in laboratory values were observed Background The treatment of non-specific chronic low back pain is often based on three different models regarding the development and maintenance of pain and especially functional limitations : the deconditioning model , the cognitive behavioral model and the biopsychosocial model . There is evidence that rehabilitation of patients with chronic low back pain is more effective than no treatment , but information is lacking about the differential effectiveness of different kinds of rehabilitation . A direct comparison of a physical , a cognitive-behavioral treatment and a combination of both has never been carried out so far . Methods The effectiveness of active physical , cognitive-behavioral and combined treatment for  chronic non-specific low back pain compared with a waiting list control group was determined by performing a r and omized controlled trial in three rehabilitation centers . Two hundred and twenty three patients were r and omized , using concealed block r and omization to one of the following treatments , which they attended three times a week for 10 weeks : Active Physical Treatment ( APT ) , Cognitive-Behavioral Treatment ( CBT ) , Combined Treatment of APT and CBT ( CT ) , or Waiting List ( WL ) . The outcome variables were self-reported functional limitations , patient 's main complaints , pain , mood , self-rated treatment effectiveness , treatment satisfaction and physical performance including walking , st and ing up , reaching forward , stair climbing and lifting . Assessment s were carried out by blinded research assistants at baseline and immediately post-treatment . The data were analyzed using the intention-to-treat principle . Results For 212 patients , data were available for analysis . After treatment , significant reductions were observed in functional limitations , patient 's main complaints and pain intensity for all three active treatments compared to the WL . Also , the self-rated treatment effectiveness and satisfaction appeared to be higher in the three active treatments . Several physical performance tasks improved in APT and CT but not in CBT . No clinical ly relevant differences were found between the CT and APT , or between CT and CBT . Conclusion All three active treatments were effective in comparison to no treatment , but no clinical ly relevant differences between the combined and the single component treatments were found BACKGROUND Placebos are hypothesized to exert positive effects on medical conditions by enhancing patient expectancies . Recent review s suggest that placebo benefits are restricted to subjective responses , like pain , but might be ineffective for objective physiologic outcomes . Nevertheless , mind-body links and placebo responsivity in asthma are widely believed to exist . OBJECTIVE We carried out a r and omized , double-blind investigation to ( 1 ) determine whether placebo can suppress airway hyperreactivity in asthmatic subjects , ( 2 ) quantify the placebo effect , ( 3 ) identify predictors of the placebo response , and ( 4 ) determine whether physician interventions modify the placebo response . METHODS In a double-blind , crossover design investigation , 55 subjects with mild intermittent and persistent asthma with stable airway hyperreactivity were r and omized to placebo or salmeterol before serial methacholine challenges . Subjects were additionally r and omized to physician interactions that communicated either positive or neutral expectancies regarding drug effect . RESULTS Placebo bronchodilator administration significantly reduced bronchial hyperreactivity compared with baseline ( the calculated concentration of methacholine required to induce a 20 % decrease in FEV(1 ) nearly doubled ) ; 18 % of subjects were placebo responders by using conservative definitions . Experimental manipulation of physician behavior altered perceptions of the physician but not the magnitude or frequency of the placebo response . CONCLUSIONS Objective placebo effects exist in asthma . These responses are of significant magnitude and likely to be meaningful clinical ly . The placebo response was not modulated by alterations in physician behavior in this study . CLINICAL IMPLICATION S The placebo response in patients with asthma is important in underst and ing the limitations of clinical research studies and in maximizing safe and effective therapies . This article confirms the existence of a strong placebo response in an objective and clinical ly relevant measure of disease activity Objectives To evaluate a clinical decision support system ( CDSS ) based on consensus-based intravenous to oral switch criteria , which identifies intravenous to oral switch c and i date s. Methods A three-step evaluation study of a st and -alone CDSS with electronic health record interoperability was performed at the Erasmus University Medical Centre in the Netherl and s. During the first step , we performed a technical validation . During the second step , we determined the sensitivity , specificity , negative predictive value and positive predictive value in a retrospective cohort of all hospitalized adult patients starting at least one therapeutic antibacterial drug between 1 and 16 May 2013 . ICU , paediatric and psychiatric wards were excluded . During the last step the clinical relevance and usefulness was prospect ively assessed by reports to infectious disease specialists . An alert was considered clinical ly relevant if antibiotics could be discontinued or switched to oral therapy at the time of the alert . Results During the first step , one technical error was found . The second step yielded a positive predictive value of 76.6 % and a negative predictive value of 99.1 % . The third step showed that alerts were clinical ly relevant in 53.5 % of patients . For 43.4 % it had already been decided to discontinue or switch the intravenous antibiotics by the treating physician . In 10.1 % , the alert result ed in advice to change antibiotic policy and was considered useful . Conclusions This prospect i ve cohort study shows that the alerts were clinical ly relevant in > 50 % ( n = 449 ) and useful in 10 % ( n = 85 ) . The CDSS needs to be evaluated in hospitals with varying activity of infectious disease consultancy services as this probably influences usefulness OBJECTIVE To assess whether topical morphine is pharmacologically effective in relieving pain from ulcers caused by arterial insufficiency and identify whether this effect is central ly or peripherally mediated . METHOD The analgesic effect of a topically applied hydrogel containing 0.5 % of morphine was evaluated in a double-blind , placebo-controlled , three-way crossover pilot study involving nine patients with painful arterial leg ulcers . All patients had a baseline pain intensity of at least 5 on a 10-point numeric rating scale . They received the following three treatments in r and om order : morphine hydrogel plus a subcutaneous ( SC ) placebo infusion ; placebo gel plus a SC infusion of 5 mg morphine over six hours and a placebo gel plus a SC placebo infusion . Each treatment lasted one day . Pain was assessed during the first 24 hours after application of the hydrogel and the start of the subcutaneous infusion . RESULTS There was a statistically significant difference between average baseline pain scores and those reported during treatment , but this difference was not clinical ly relevant . The three treatments did not differ in terms of the pain relief provided . CONCLUSION Topical morphine does not have a clinical ly relevant analgesic effect in patients with painful arterial leg ulcers . Further research should focus on ulcers of other aetiology
Our review revealed a great heterogeneity in definition , format , and values of what is considered a clinical ly relevant difference in pain in RCTs of analgesics , and st and ardizations are advisable
OBJECTIVE To describe the  pain decrease considered as clinical ly relevant when design ing a trial and reporting its results .