***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: Abstract  Variability  in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size & NA ; There is uncertainty over whether the patient group in which acute pain studies are conducted ( pain model ) has any influence on the estimate of analgesic efficacy . Data from four recently up date d systematic review s of aspirin 600/650 mg , paracetamol 600/650 mg , paracetamol 1000 mg and ibuprofen 400 mg were used to investigate the influence of pain model . Area under the pain relief versus time curve equivalent to at least 50 % maximum pain relief over 6 h was used as the outcome measure . Event rates with treatment and placebo , and relative benefit ( RB ) and number needed to treat ( NNT ) were used as outputs from the meta‐analyses . The event rate with  placebo was systematic ally statistically lower for dental than postsurgical pain for all four treatments . Event rates with analgesics , RB and NNT were infrequently different between the pain models . Systematic difference in the estimate of analgesic efficacy between dental and postsurgical pain models remains unproven , and , on balance , no major difference is likely BACKGROUND The combination of ibuprofen and paracetamol may confer analgesic benefits over monotherapy with either agent . In a previous study , an ibuprofen/paracetamol combination provided significantly better analgesic efficacy than comparable doses of ibuprofen or paracetamol alone in patients experiencing moderate to severe acute postoperative pain after extraction of impacted third molars . OBJECTIVE This study compared the efficacy and tolerability of 3 doses of a single-tablet fixed-dose combination ( FDC ) of ibuprofen and paracetamol ( ibuprofen/paracetamol doses of 100 mg/250 mg , 200 mg/500 mg , and 400 mg/1000 mg ) with comparable doses of ibuprofen ( 200 or 400 mg ) monotherapy , paracetamol ( 500 or 1000 mg ) monotherapy , and placebo in the 8 hours after surgical removal of 3 to 4 impacted third molars ( stage 1 ) and with placebo over the next 72 hours ( stage 2 ) . METHODS This was a multicenter , 2-stage , r and omized , double-blind , parallel-group , placebo-controlled , factorial study . Male or female out patients were eligible for the study if they were aged > or=16 years , were referred for surgical removal of at least 3 impacted third molars ( 2 of which had to be m and ibular impacted molars ) , and gave written informed consent . In stage 1 , patients were r and omly assigned to ibuprofen 200 mg , ibuprofen 400 mg , paracetamol 500 mg , paracetamol 1000 mg , FDC ibuprofen 100 mg/paracetamol 250 mg , FDC ibuprofen 200 mg/paracetamol 500 mg , FDC ibuprofen 400 mg/paracetamol 1000 mg , or placebo . In stage 2 , patients who had been taking FDC therapy or placebo continued the same treatment , whereas those taking monotherapy received FDC therapy , incorporating the same dose of active monotherapy from stage 1 . First-line rescue medication ( hydrocodone 7.5 mg and paracetamol 500 mg ) was available at any time after dosing ; however , in stage 1 , any patient who required rescue medication within 60 minutes of receipt of study medication was considered a " dropout " from therapy , and , in stage 2 , patients who required > 2 doses of first-line rescue medication in a 24-hour period were considered treatment failures . In stage 1 , the primary efficacy end points were the sum of pain relief and pain intensity differences over an 8-hour follow-up period ( SPRID8 ) and the pain relief and pain intensity difference scores at each time point ( 15 , 30 , 45 , 60 , 90 , 120 , 180 , 240 , 300 , 360 , 420 , and 480 minutes after dosing ) . Several secondary variables were also measured , including the patient 's global assessment of the study medication . The 2-stopwatch method was used for measures of perceptible and meaningful pain relief . In stage 2 , the primary efficacy end point was the number of completed 24-hour periods ( as 0 , 1 , 2 , or 3 ) in which the patient required no more than one dose of rescue medication and rated the treatment as " good , " " very good , " or " excellent . " The tolerability of study medications was assessed in relation to the frequency , nature , and severity of adverse events ( AEs ) , as well as their relationship to study medication ; vital signs were also measured . AEs were assessed at 8 hours after dosing in stage 1 , at 72 hours after dosing in stage 2 , and at the follow-up visit ( 7 - 10 days after surgery ) ; in addition , patients were instructed to report any AE that occurred between scheduled assessment s. RESULTS Of 735 patients r and omly assigned in stage 1 , a total of 715 ( 97.3 % ) entered and 678 ( 92.2 % ) completed stage 2 . Most patients were female ( 62.6 % [ 460/735 ] ) and white ( 91.3 % [ 671/735 ] ) ; the mean ( SD ) age was 20.3 ( 3.5 ) years and the mean weight was 69.7 ( 15.7 ) kg . The mean total impaction score was 11.1 ( 1.4 ) , and the mean baseline pain score on the visual analog scale was 76.9 ( 12.0 ) . Overall , 422 of 735 patients ( 57.4 % ) reported severe pain at baseline and 313 of 735 ( 42.6 % ) reported moderate pain . For the primary efficacy end point ( SPRID8 ) , FDC ibuprofen 400 mg/paracetamol 1000 mg was significantly more effective than ibuprofen 400 mg ( P = 0.02 ) and paracetamol 1000 mg ( P < 0.001 ) in the immediate postoperative period ( stage 1 ) , and FDC ibuprofen 200 mg/paracetamol 500 mg was significantly more effective than ibuprofen 200 mg ( P < 0.001 ) and paracetamol 500 mg ( P < 0.001 ) . The FDC ibuprofen 200 mg/paracetamol 500 mg was also significantly more effective than paracetamol 1000 mg ( P < 0.001 ) , but failed to reach statistical significance in comparison with ibuprofen 400 mg . Continued postoperative therapy with all 3 FDCs on an as-needed basis was significantly more effective than placebo during the subsequent 72 hours ( all , P < 0.001 ) . During stage 1 , rescue medication was required by 53 of 73 ( 72.6 % ) , 29 of 75 ( 38.7 % ) , 21 of 74 ( 28.4 % ) , 56 of 76 ( 73.7 % ) , and 51 of 74 ( 68.9 % ) patients in the placebo group and the ibuprofen 200-mg , ibuprofen 400-mg , paracetamol 500-mg , and paracetamol 1000-mg treatment groups , respectively . In the FDC treatment groups , the need for rescue medication included 27 of 71 ( 38.0 % ) , 40 of 143 ( 28.0 % ) , and 32 of 149 ( 21.5 % ) patients in the ibuprofen 100-mg/paracetamol 250-mg , ibuprofen 200-mg/paracetamol 500-mg , and ibuprofen 400-mg/paracetamol 1000-mg groups , respectively . The rates of treatment-related AEs between the first and second doses of study medication were significantly lower for FDC ibuprofen 400 mg/paracetamol 1000 mg ( 8/149 patients [ 5.4 % ] ) than for placebo ( 14/73 [ 19.2 % ] ; P < 0.01 ) and paracetamol 1000 mg ( 10/74 [ 13.5 % ] ; P < 0.05 ) ; and also lower for FDC ibuprofen 200 mg/paracetamol 500 mg ( 9/143 [ 6.3 % ] ) compared with ibuprofen 200 mg ( 12/75 [ 16.0 % ] ; P < 0.05 ) and paracetamol 500 mg ( 17/76 [ 22.4 % ] ; P < 0.001 ) . CONCLUSION FDC ibuprofen 200 mg/paracetamol 500 mg and ibuprofen 400 mg/paracetamol 1000 mg were significantly more effective in this population than were comparable doses of ibuprofen or paracetamol alone in moderate to severe acute dental pain and were significantly more effective than placebo in providing sustained pain relief BACKGROUND Combination analgesics may offer improved analgesic efficacy , particularly for moderate to severe pain . OBJECTIVE This study evaluated the analgesic benefits of concurrent ibuprofen and paracetamol compared with each drug used alone in the management of acute postoperative dental pain .  METHODS Healthy patients aged 16 to 40 years undergoing surgical removal of 3 to 4 impacted molars ( total impaction score > or = 9 ) were enrolled in this r and omized , double-blind , placebo-controlled , parallel-group , single-dose , 2-center , modified factorial US study . Patients were r and omly assigned in a ratio of 2:1:2:1:1 to ibuprofen 400 mg/paracetamol 1000 mg , ibuprofen 200 mg/paracetamol 500 mg , ibuprofen 400 mg , paracetamol 1000 mg , or placebo when postoperative pain reached moderate to severe intensity . The primary efficacy end point was the sum of pain relief and pain intensity differences from 0 to 8 hours ( SPRID8 ) . Several secondary end points were also measured , including total pain relief ( TOTPAR ) , sum of pain intensity differences ( SPID ) , and SPID on the visual analog scale ( SPID VAS ) at various time points . Other analgesic efficacy measures included peak effect , onset and duration of effect , and patients ' overall assessment of treatment . The tolerability of study medications was assessed in terms of the frequency and nature of adverse events , which were assessed with st and ard questions , as well as changes from baseline in vital signs . RESULTS A total of 234 patients were r and omly assigned to treatment and included in the intent-to- treat population . The patients were predominantly female ( 74.4 % [ 174/234 ] ) and white ( 76.5 % [ 179/234 ] ) ; mean ( SD ) age was 20.8 ( 3.1 ) years and weight was 
    Output:
    
Ibuprofen plus paracetamol combinations provided better analgesia than either drug alone ( at the same dose ) , with a smaller chance of needing additional analgesia over about eight hours , and with a smaller chance of experiencing an adverse event