***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE To evaluate the efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg combination tablets ( tramadol/APAP ) as add-on therapy for subjects with osteoarthritis ( OA ) pain inadequately controlled by COX-2 nonsteroidal antiinflammatory drugs ( NSAID ) . METHODS This 91-day , multicenter , r and omized , double-blind , placebo-controlled trial enrolled subjects with symptomatic OA for > /= 1 year who experienced at least moderate pain [ visual analog scale ( VAS ) score > /= 50/100 mm ] despite treatment with stable doses of celecoxib ( > /= 200 mg/day ) or rofecoxib ( > /= 25 mg/day ) . Tramadol/APAP or matching placebo was titrated to 4 tablets/day on Day 10 and thereafter as needed up to 8 tablets/day . The primary efficacy measure was final VAS score ; secondary measures included final pain relief rating scores , subject/investigator overall medication assessment s , rate and time to discontinuation due to lack of efficacy , and selected quality -of-life/physical functioning scores . RESULTS Of 307 subjects r and omized , 306 taking celecoxib ( 56.5 % ) or rofecoxib ( 43.5 % ) were included in the intent-to-treat population ( n = 153 tramadol/APAP , 153 placebo ) . Mean final VAS scores for tramadol/APAP plus COX-2 NSAID were significantly lower than placebo plus COX-2 NSAID ( 41.5 vs 48.3 ; p = 0.025 ) and mean final pain relief rating scores were significantly higher ( p = 0.002 ) . Subjects taking tramadol/APAP showed significant improvements compared with placebo in subject/investigator medication assessment s , as well as in the WOMAC Physical Function and the Medical Outcome Study Short Form-36 Role-Physical measures . The most common treatment-related adverse events for tramadol/APAP were somnolence ( 6.5 % ) , nausea ( 4.6 % ) , and constipation ( 3.3 % ) . Mean tramadol/APAP dose was 4.1 tablets ( 154 mg tramadol/ 1332 mg APAP ) . CONCLUSION Tramadol 37.5 mg/APAP 325 mg combination tablets were effective and safe as add-on therapy with COX-2 NSAID for treatment of OA pain BACKGROUND In a flare of osteoarthritis ( OA ) pain , increasing the dose of st and ard anti-inflammatory or routine analgesic drugs may not be practical because of an increased incidence of side effects . In patients achieving inadequate pain relief from traditional non-steroidal anti-inflammatory drugs ( NSAIDs ) or cyclooxygenase (COX)-2-selective inhibitors , it may be appropriate to add an analgesic agent with a different mechanism of action , thereby targeting multiple components of the pain pathway . OBJECTIVE The addition of tramadol/acetaminophen tablets to existing therapy was compared with the addition of placebo in the treatment of OA flare pain . METHODS This was a multicenter , outpatient , r and omized , double-blind , placebo-controlled , parallel-group , add-on study . Patients received 1 or 2 tramadol/acetaminophen ( 37.5 mg/325 mg ) tablets QID or matching placebo for 10 days in addition to ongoing NSAID or COX-2-selective inhibitor therapy . The primary outcome measures were average daily pain intensity and average daily pain relief scores from days 1 through 5 . RESULTS Three hundred eight patients were r and omized to tramadoUacetaminophen ( n = 197 ) or placebo ( n = 111 ) and were followed for up to 10 days . Patients had a mean ( + /-SD ) age of 60.1 + /- 9.87 years , and were predominantly female ( 71.8 % ) and white ( 87.7 % ) . Their mean ( + /- SD ) pain visual analog score at baseline was 73.2 + /- 11.8 mm , and their mean pain intensity score was 2.4 + /- 0.5 ( on a scale from 0 = none to 3 = severe ) . Average daily pain intensity and pain relief scores were significantly improved with tramadol/acetaminophen compared with placebo on the primary assessment of efficacy from days 1 through 5 ( both , P < 0.001 ) and on the assessment of efficacy from days I through 10 ( both , P < 0.001 ) Tramadol/acetaminophen was significantly superior to placebo on the patients ' and physicians ' overall assessment s of medication ( both , P < 0.001 ) and on 3 of 4 subscales ( pain [ P = 0.004 ] , physical function [ P = 0.013 ] , and overall [ P = 0.008 ] ) of the Western Ontario and McMaster Universities Osteoarthritis Index Question naire . The most common treatment-emergent adverse events with tramadol/acetaminophen were nausea , vomiting , and dizziness . No serious adverse events were reported in the tramadol/acetaminophen group . CONCLUSION In this study , addition of tramadol/acetaminophen to NSAID or COX-2-selective inhibitor therapy was well tolerated and effective in the treatment of OA flare pain The efficacy and safety of a once-daily extended-release formulation of tramadol hydrochloride ( tramadol ER ) was evaluated in patients with moderate to severe chronic pain of osteoarthritis ( OA ) . This was a r and omized , double-blind , placebo-controlled , parallel-group , 12-week study . Eligible patients with radiographically confirmed OA of the knee meeting the American College of Rheumatology diagnostic criteria , defined by knee pain and presence of osteophytes , plus at least age > 50 years , morning stiffness < 30 minutes in duration , and /or crepitus , entered a 2 - 7 day washout period during which all analgesics were discontinued . When pain at the index knee joint reached > or = 40 mm ( 0 - 100 mm VAS ) , patients were r and omized to tramadol ER or placebo . Tramadol ER was initiated at 100 mg QD and increased to 200 mg QD by the end of 1 week of treatment . After the first week , further increases to tramadol ER 300 mg or 400 mg QD were allowed . Outcome measures included Arthritis Pain Intensity Visual Analogue Scale ( VAS ) , Western Ontario and McMaster Universities Arthritis Scale ( WOMAC ) Pain , Stiffness , Physical Function VAS subscales , Patient and Physician Global Assessment of Therapy , Sleep , dropouts due to insufficient therapeutic effect , and adverse events .  Two hundred forty-six patients were r and omized ( tramadol ER 124 , placebo 122 ) . There were no baseline differences between the two treatments . The mean age was 61 years , mean duration of OA 12.9 years , and the mean tramadol ER dose was 276 mg QD . All efficacy outcome measures favored tramadol ER over placebo . On the primary outcome variable of average change from baseline in Arthritis Pain Intensity VAS over 12 weeks , tramadol ER was superior to placebo ( least squares mean change from baseline : 30.4 mm vs. 17.7 mm , P < 0.001 ) . Significant differences from placebo were evident at week 1 , the first post-treatment visit . Similarly , outcomes on the WOMAC Pain , Stiffness and Physical Function subscales , the WOMAC Composite Scale , dropouts due to insufficient therapeutic effect , Patient and Physician Global Assessment of Therapy , and Sleep were all significantly better with tramadol ER than placebo ( P < 0.001 to < 0.05 ) . Treatment with tramadol ER results in statistically significant and clinical ly important and sustained improvements in pain , stiffness , physical function , global status , and sleep in patients with chronic pain . A once-a-day formulation of tramadol has the potential to provide patients increased control over the management of their pain , fewer interruptions in sleep and improved compliance BACKGROUND Osteoarthritis ( OA ) is the most common joint disease encountered throughout Europe . A task force for the EULAR St and ing Committee for Clinical Trials met in 1998 to determine the method ological and logistical approach required for the development of evidence based guidelines for treatment of knee OA . The guidelines were restricted to cover all currently available treatments for knee OA diagnosed either clinical ly and /or radiographically affecting any compartment of the knee . METHODS The first stage was the selection of treatment modalities to be considered . The second stage comprised a search of the electronic data bases Medline and Embase using a combination of subject headings and keywords . All European language publications in the form of systematic review s , meta-analyses , r and omised controlled trials , controlled trials , and observational studies were included . During stage three all the relevant studies were quality scored . The summary statistics for vali date d outcome measures , when available , were recorded and , where practical , the numbers needed to treat and the effect size for each treatment were calculated . In the fourth stage key clinical propositions were determined by expert consensus employing a Delphi approach . The final stage ranked these propositions according to the available evidence . A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach . RESULTS Over 2400 English language publications and 400 non-English language publications were identified . Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA . Quantitative analysis of treatment effect was possible in only 61 studies . Recommendations for the management of knee OA based on currently available data and expert opinion are presented . Proposals for a future research agenda are highlighted . CONCLUSIONS These are the first clinical guidelines on knee OA to combine an evidence based approach and a consensus approach across a wide range of treatment modalities . It is apparent that certain clinical propositions are supported by substantial research based evidence , while others are not . There is thus an urgent need for future well design ed trials to consider key clinical questions Objective To compare the 24-hour sustained efficacy and safety of a new tramadol once-daily formulation ( tramadol OAD ) using Contramid ® controlled-release technology with a marketed twice-daily formulation ( tramadol BID ) . Patients , design and setting 431 patients with osteoarthritis of the knee were enrolled in this r and omised , double-blind , multicentre , parallel study . After titration to optimum dose ( range 100–400 mg ) , patients received medication for 12 weeks . Main outcome measures and results Efficacy evaluations included : Western Ontario and McMaster University Osteoarthritis Index ( WOMAC ) scores ( pain , stiffness , physical function and global ) , daily efficacy ratings ( post-dose : tramadol OAD 24 hours ; tramadol BID 12 hours ) , pain ratings over 24 hours , and patient and investigator overall ratings . Non-inferiority was demonstrated for the primary endpoint , mean percentage change in WOMAC pain score from baseline to week 12 ( tramadol OAD 58 % ; tramadol BID 59 % ) [ 95 % CI −7.67 , 3.82 ] . The median optimum dose received was 200 mg ( both treatments ) . In 73 % of patients , pain was mild to absent at the end of the dosing interval for both treatments ( tramadol OAD 24 hours ; tramadol BID 12 hours ) . Pain ratings over 24 hours were similar between groups , indicating 24-hour sustained efficacy for tramadol OAD . More tramadol BID patients reported dizziness/vertigo ( 37 % vs 26 % ) , vomiting ( 14 % vs 8 % ) and headache ( 18 % vs 13 % ) while tramadol OAD patients reported more somnolence ( 30 % vs 21 % ) . Conclusions This study demonstrated that this novel tramadol OAD formulation provides sustained analgesic efficacy over the entire 24-hour dosing interval and a clinical ly favourable safety profile , both of which will provide a clear clinical benefit & NA ; Opioids are increasingly used in the treatment of chronic non‐malignant pain . The aim of this open‐label , r and omised , parallel group study was to compare analgesia and side‐effects of two commonly used opioid analgesics , tramadol and dihydrocodeine , in long‐acting formulations in 60 osteoarthritis patients with strong pain despite NSAID 's . Dose titration based on effect was performed with the respective immediate release solutions given additionally to tramadol 100 mg bid and dihydrocodeine 60 mg bid during the first 4 days of the 1 month treatment . Electrical sensation and pain thresholds over the osteoarthritic joint and at a distant location and gastrointestinal transit times were performed before and during treatment . Thirty patients with pain controlled by NSAID 's alone formed the comparator group . Pain intensities at rest and during movement decreased highly significantly with tramadol and dihydrocodeine from median pre‐treatment verbal ratings of over 3 ( 0=none , 4=unbearable ) to 1 and below from the second treatment day onwards ( ANOVA P< 
    Output:
    
No conclusion could be drawn on how tramadol or tramadol/paracetamol compared with available pharmacological treatments because of the limited number of studies that evaluated such therapies .
Tramadol or tramadol/paracetamol decreases pain intensity , produces symptom relief and improves function , but these benefits are small .
Adverse events , although reversible and not life threatening , often cause participants to stop taking the medication and could limit tramadol or tramadol plus paracetamol usefulness