***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: Background Dexketoprofen trometamol plus tramadol hydrochloride is a new oral combination of two analgesics , which have different mechanisms of action for the treatment of moderate to severe acute pain . Methods R and omised , double-blind , parallel , placebo and active-controlled , single and multiple-dose study to evaluate the analgesic efficacy and safety of dexketoprofen/tramadol 25 mg/75 mg in comparison with the single agents ( dexketoprofen 25 mg and tramadol 100 mg ) in moderate to severe acute pain after abdominal hysterectomy . Patients received seven consecutive doses of study drug within a 3-day period , each dose separated by an 8-hour interval . A placebo arm was included during the single-dose phase to vali date the pain model . Efficacy assessment s included pain intensity , pain relief , patient global evaluation and use of rescue medication . The primary endpoint was the mean sum of pain intensity differences over the first 8 h ( SPID8 ) . Results The efficacy analysis included 606 patients , with a mean age of 48 years ( range 25–73 ) . The study results confirmed the superiority of the combination over the single agents in terms of the primary endpoint ( p < 0.001 ) . Secondary endpoints were generally supportive of the superiority of the combination for both single and multiple doses . Most common adverse drug reactions ( ADRs ) were nausea ( 4.6 % ) and vomiting ( 2.3 % ) . All other ADRs were experienced by less than 2 % of patients . Conclusions The study results provided robust evidence of the superiority of dexketoprofen/tramadol 25 mg/75 mg over the single components in the management of moderate to severe acute pain , as confirmed by the single-dose efficacy , repeated-dose sustained effect and good safety profile observed . Trial registration EU Clinical Trials Register ( EudraCT number 2012 - 004545 - 32 , registered 04 October 2012 ) ; Clinical trials.gov ( NCT01904149 , registered 17 July 2013 ) 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 Background . The aim was to evaluate the analgesic efficacy and safety of the dexketoprofen/tramadol 25 mg/75 mg fixed-dose combination vs dexketoprofen ( 25 mg ) and tramadol ( 100 mg ) in moderate-to-severe acute pain after total hip arthroplasty . Methods . This was a r and omized , double-blind , parallel-group study in patients experiencing pain of at least moderate intensity on the day after surgery , compared with placebo  at first administration to vali date the pain model . The study drug was administered orally every 8 h throughout a 5 day period . Rescue medication , metamizole 500 mg , was available during the treatment period . The evaluation of efficacy was based on patient assessment s of pain intensity and pain relief . The primary end point was the mean sum of the pain intensity difference values throughout the first 8 h ( SPID8 ) . Results . Overall , 641 patients , mean age 62 ( range 29–80 ) yr , were analysed ; mean ( sd ) values of SPID8 were 247 ( 157 ) for dexketoprofen/tramadol , 209 ( 155 ) for dexketoprofen , 205 ( 146 ) for tramadol , and 151 ( 159 ) for placebo . The primary analysis confirmed the superiority of the combination over dexketoprofen 25 mg ( P=0.019 ; 95 % confidence interval 6.4–73 ) and tramadol 100 mg ( P=0.012 ; 95 % confidence interval 9.5–76 ) . The single components were superior to placebo ( P<0.05 ) , confirming model sensitivity . Most secondary analyses supported the superiority of the combination . The incidence of adverse drug reactions was low and similar among active treatment groups . Conclusion . The efficacy results confirmed the superiority of dexketoprofen/tramadol over its single components , even at higher doses ( tramadol ) , with a safety profile fully in line with that previously known for these agents in monotherapy . Clinical trial registration . EudraCT 2012 - 004548 - 31 ( https://www . clinical trialsregister.eu/ctr- search / search ? query = eudract_number:2012 - 004548 - 31 ) ; Clinical Trials.gov NCT01902134 ( https://www . clinical trials.gov/ct2/show/NCT01902134?term=NCT01902134&rank=1 ) Background Combination analgesics are effective in acute pain , and a theoretical framework predicts efficacy for combinations . The combination of dexketoprofen and tramadol is untested , but predicted to be highly effective . Methods This was a r and omised , double-blind , double-dummy , parallel-group , placebo-controlled , single-dose trial in patients with moderate or severe pain following third molar extraction . There were ten treatment arms , including dexketoprofen trometamol ( 12.5 mg and 25 mg ) and tramadol hydrochloride ( 37.5 mg and 75 mg ) , given as four different fixed combinations and single components , with ibuprofen 400 mg as active control as well as a placebo control . The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo . The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours . Results 606 patients were r and omised and provided at least one post-dose assessment . All combinations were significantly better than placebo . The highest percentage of responders ( 72 % ) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group ( NNT 1.6 , 95 % confidence interval 1.3 to 2.1 ) . Addition of tramadol to dexketoprofen result ed in greater peak pain relief and greater pain relief over the longer term , particularly at times longer than six hours ( median duration of 8.1 h ) . Adverse events were unremarkable . Conclusions Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain . The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae . Trial registration EudraCT ( 2010 - 022798 - 32 ) ; Clinical trials.gov ( NCT01307020 ) & 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 Abstract A previously established relationship for deriving dichotomous from continuous information in r and omised controlled trials ( RCTs ) of analgesics has been tested using an independent data set . Individual patient information from 18 RCTs of parallel‐group design in acute postoperative pain ( after abdominal , gynaecological and oral surgery ) was used to calculate the percentage of the maximum possible pain relief score  ( % maxTOTPAR ) and the proportion of patients with > 50%maxTOTPAR for the different treatments . The relationship between the measures was investigated in 85 treatments with over 3400 patients . In 80 of 85 treatments ( 94 % ) agreement between calculated and actual number of patients with > 50%maxTOTPAR was within four patients per treatment and in 72 ( 85 % ) was within three ( average of 40 patients per treatment , range 21–58 patients ) . Summing the positive and negative differences between actual and calculated numbers of patients with > 50%maxTOTPAR gave an average difference of 0.30 patients per treatment arm . Reports of RCTs of analgesics frequently describe results of studies in the form of mean derived indices , rather than using discontinuous events , such as number or proportion of patients with 50 % pain relief . Because mean data inadequately describe information with a non‐normal distribution , combining mean data in systematic review s may compromise the results . Showing that dichotomous data can reliably be derived from mean data in acute pain studies enables data published as means to be used for quantitative systematic review s which require data in dichotomous form & NA ; Reports of RCTs of analgesics frequently describe results of studies in the form of mean derived indices , rather than using discontinuous events — such as number or proportion of patients with 50 % pain relief . Because mean data inadequately describe information with a non‐normal distribution , combining mean data in systematic review s may compromise the results . Showing that dichotomous data can reliably be derived from mean data , at least in acute pain models , indicates that more meaningful overviews or meta‐ analysis may be possible . This study investigated the relationship between continuous and dichotomous analgesic measures in a set of individual patient data , and then used that relationship to derive dichotomous from continuous information in r and omised controlled trials ( RCTs ) of analgesics .  Individual patient information from 13 RCTs of parallel‐group and crossover design in acute postoperative pain was used to calculate the percentage of the maximum possible pain relief score ( % maxTOTPAR ) and the proportion of patients with greater than 50 % pain relief ( > 50%maxTOTPAR ) for the different treatments . The relationship between the measures was investigated in 45 actual treatments and 10 000 treatments simulated using the underlying actual distribution ; 1283 patients had 45 separate treatments . Mean % maxTOTPAR correlated with the proportion of patients with > 50%maxTOTPAR ( r2 = 0.90 ) . The relationship calculated from all the 45 treatments predicted to within three patients the number of patients with more than 50 % pain relief in 42 of 45 treatments , and 98.8 % of 10 000 simulated treatments . For seven effective treatments , actual numbers‐needed‐to‐treat ( NNT ) to achieve > 50%maxTOTPAR compared with placebo were very similar to those derived from calculated data Abstract One way to ensure adequate sensitivity for analgesic trials is to test the intervention on patients who have established pain of moderate to severe intensity . The usual criterion is at least moderate pain on a categorical pain intensity scale . When visual analogue scales ( VAS ) are the only pain measure in trials we need to know what point on a VAS represents moderate pain , so that these trials can be included in meta‐ analysis when baseline pain of at least moderate intensity is an inclusion criterion . To investigate this we used individual patient data from 1080 patients from r and omised controlled trials of various analgesics .  Baseline pain was measured using a 4‐point categorical pain intensity scale and a pain intensity VAS under identical conditions . The distribution of the VAS scores was examined for 736 patients reporting moderate pain and for 
    Output:
    
We down grade d the evidence because it was not possible to estimate the effect exactly in the two multiple dose studies , result ing in imprecision .
Adverse events and serious adverse events were not reported consistently for the single dose phase of the studies .
Rates were lower with placebo and lower doses ( very low quality evidence ) .
Information on multiple dosing over three and five days supported a low event rate with the combination .
Overall , rates were generally low in all treatment arms , as they were for withdrawals for adverse events or other reasons .
A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief with long duration of action to more people than placebo or the same dose of dexketoprofen or tramadol alone .
The magnitude of the effect was similar to other good analgesics .
Adverse event rates were low .
There is modest uncertainty about the precision of the point estimate for efficacy , but the NNT of 3 is consistent with other analgesics considered effective and commonly used