***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 1 In a double-blind study , 108 postpartum patients received single oral doses of either placebo , acetaminophen ( paracetamol ) 1000 mg , hydrocodone 10 mg , the combination of acetaminophen plus hydrocodone , or codeine 60 mg . 2 In the 2X2 factorial analysis , both the acetaminophen and hydrocodone effects were statistically significant , whereas the interaction contrast was not . This indicates that the analgesic effect of the combination represents the additive effect of its constituents and is consistent with the assumption that these constituents are producing analgesia by different mechanisms . 3 Although significantly superior to placebo , codeine seemed to be inferior to the other treatments . 4 Compared with placebo , both codeine and hydrocodone ( central ly acting narcotics ) seemed relatively more effective in uterine cramp than episiotomy pain ; the reverse seemed true with acetaminophen ( a peripherally acting analgesic ) . 5 Some method ological implication s for the evaluation of analgesic combinations are discussed This study was conducted to compare the analgesic efficacy of four commonly used analgesics namely ibuprofen , analgin , paracetamol and aspirin in post-episiotomy pain . The subjects were healthy postpartum women on the obstetric service of Goa Medical College , each of whom received only one experimental medication .  Subjective reports were used as indices of pain intensity or relief .  Ibuprofen was found to be the most effective analgesic in post-episiotomy pain followed by analgin and paracetamol in that order . Surprisingly , aspirin was found to be no better than placebo The results of a r and omized clinical trial can be reported using relative and /or absolute estimators of treatment effect . These various measures convey different information , and the choice can influence the physician 's appreciation of the size of treatment effect and , subsequently , treatment decisions . We compare the estimators with respect to the clinical ly relevant information conveyed to physicians , and identify which clinical questions can and can not be answered directly by each . We also identify opportunities for misinterpretation when one estimator is substituted for another , or when an estimator is mislabeled . Clinical ly important questions are addressed most directly by reporting both relative and absolute effects using relative risk and its complement , relative risk reduction , and risk difference and its reciprocal , number needed to treat . This is true of estimates of treatment effect derived from a single trial and also from meta- analysis of a group of trials . Because the control group 's risk affects the numerical value of the odds ratio , the odds ratio can not substitute for the risk ratio in conveying clinical ly important information to physicians . This is especially important when large treatment effects are shown in trials carried out in population s at high baseline risk 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 The aims of this study were to test the hypotheses that the type of 3rd molar removal determines baseline pain and that baseline pain influences analgesic assay sensitivity . Three groups of patients were studied : ( i ) 100 patients that had one fully erupted maxillary 3rd molar extracted ; ( ii ) 95 patients that had one lower impacted 3rd molar surgically removed ; and ( iii ) 98 patients that had two ipsilateral impacted 3rd molars surgically removed . In a r and omized , double-blind fashion , the patients received ( every third hour , three times ) either : ( i ) paracetamol 1 g ; ( ii ) paracetamol 1 g plus codeine 60 mg ; or ( iii ) placebo .  Baseline pain intensity ( 100 mm Visual Analogue Scale ) was significantly lower after extraction ( 8 mm ( 2 - 20 ) ) ( = median ( 25th -75th percentile ) than after surgical removal of one 3rd molar ( 35 mm ( 15 - 57 ) ) , which was significantly lower than pain intensity after surgical removal of two 3rd molars ( 49 mm ( 24 - 82 ) ) . Analgesic effects of the active test drugs were superior to placebo . Paracetamol with and without codeine  could be distinguished in patients after surgical removal of one 3rd molar . In conclusion , baseline pain was related to the degree of surgical trauma , but large inter-individual variation in baseline pain intensity reduced the ability to distinguish between paracetamol with and without codeine & 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 & NA ; The purpose of this study was to determine the levels of change on st and ard pain scales that represent clinical ly important differences to patients . Data from analgesic studies are often difficult to interpret because the clinical importance of the results is not obvious . Differences between groups , as summarized by a change in mean values over time , can be difficult to apply to clinical care . Baseline scores vary widely and group mean differences could reflect large changes in a few patients , small changes in many patients , or any combination of these outcomes . Determination of the proportion of patients who have a clinical ly important improvement in their pain would provide a more interpretable result with direct clinical implication s. However , determining a clinical ly important outcome requires information about the degree of change over time that is clinical ly important . Data from the titration phase of a multiple cross‐over r and omized clinical trial of oral transmucosal fentanyl citrate ( OTFC )  for the treatment of cancer‐related breakthrough pain were re‐analyzed to examine the differences in pain scores between treatment episodes that did and did not yield adequate pain relief . The scales evaluated were absolute pain intensity difference ( PID , 0–10 scale ) , percentage pain intensity difference ( PID% , 0–100 % scale ) , pain relief ( PR , 0 ( none ) , 1 ( slight ) , 2 ( moderate ) , 3 ( lots ) , 4 ( complete ) ) , sum of the pain intensity difference ( SPID over 60 min ) , percentage of maximum total pain relief ( % Max TOTPAR over 60 min ) , and global medication performance ( 0 ( poor ) , 1 ( fair ) , 2 ( good ) , 3 ( very good ) , 4 ( excellent ) ) . Adequate relief was defined by the patient 's decision not to use another dose of opioid medication as a rescue , in addition to the study medication , to treat each painful episode . One hundred thirty OTFC naive patients contributed data on 1268 episodes of breakthrough pain . The scales that were converted to a percentage change yielded the best accuracy in predicting adequate relief , with balanced sensitivity and specificity . The best cut‐off point for both the % Max TOTPAR and the PID% was 33 % . The best cut‐off points for the absolute scales were absolute pain intensity difference of 2 , pain relief of 2 ( moderate ) , and SPID of 2 . The global medication performance of 2 ( good ) had excellent values as well . This study presents data ‐derived cut‐off points for the changes in several pain scales , each reflecting the clinical ly important improvement for patients treating breakthrough cancer pain episodes with OTFC . Confirmation in other patient population s and different pain syndromes will be needed . The use of consistent clinical ly important cut‐off points as the primary outcome in future pain therapy clinical trials will enhance their validity , comparability , and clinical applicability This r and omized , double-blind , placebo-controlled study compared the time to onset of analgesia and the analgesic efficacy of two formulations of acetaminophen 1000 mg -- an effervescent solution and tablet -- in 242 patients with moderate or severe pain following dental surgery . Onset of analgesia was determined using a two-stopwatch procedure . Analgesia was assessed over a 4-hour period . Treatments were compared using st and ard indexes of pain intensity and pain relief and summary measures . Both acetaminophen formulations were significantly more effective than their corresponding placebo for all efficacy assessment s. The median time to onset of analgesia was significantly shorter with effervescent acetaminophen ( 20 minutes ) compared to tablet acetaminophen ( 45 minutes ) . During the first 45 minutes after administration , effervescent acetaminophen was significantly more effective at each scheduled assessment time than tablet acetaminophen . The median time to meaningful pain relief was significantly shorter with effervescent acetaminophen ( 45 minutes ) compared to tablet acetaminophen ( 60 minutes ) . At 4 hours after administration , the pain relief was significantly better with tablet acetaminophen than with effervescent acetaminophen . No other significant differences were observed between the active treatments . In conclusion , effervescent acetaminophen produces a significantly faster onset of analgesia than tablet acetaminophen Our objective was to determine the value of caffeine in combination with acetaminophen in the relief of pain from uterine cramping , episiotomy , and third molar extraction . In the dental study , 173 patients received two or four tablets of 500 mg acet 
    Output:
    
When there are at least 500 patients studied in trials of high quality , credible efficacy estimates for effective drugs can be derived ; more patients are needed for less effective drugs .