***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: Tolfenamic acid is a fenamate which inhibits prostagl and in ( PG ) bio synthesis and may act as a PG antagonist as well . Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks , but controlled clinical studies on fixed combinations with analgesics are rare . The effects of orally given tolfenamic acid ( 200 mg ) , caffeine ( 100 mg ) , metoclopramide ( 10 mg ) , tolfenamic acid + caffeine ( 200 mg + 100 mg ) , tolfenamic acid + metoclopramide ( 200 mg + 10 mg ) and placebo were studied in 49 migraine patients ( 3 men , 46 women ) in a double-blind r and omized cross-over study comprising 482 migraine attacks . The patients were allowed to take either one or two capsules of each preparation for an attack . Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered . Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine , but caffeine and metoclopramide alone did not differ from placebo . Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack . Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences 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 Three hundred fifty out patients with postoperative pain after the surgical removal of impacted third molars were r and omly assigned , on a double-blind basis , to receive a single oral dose of aspirin 650 or 1000 mg , caffeine 65 mg , a combination of aspirin 650 mg with caffeine 65 mg , or placebo . Using a self-rating record , subjects rated their pain and its relief hourly for 6 hours after medicating . Estimates of summed pain intensity difference , peak pain intensity difference , total relief , peak relief , and hours of 50 % relief were derived from these subjective reports . All active treatments except caffeine were significantly superior to placebo . Pairwise comparisons indicated the aspirin-caffeine combination was statistically superior to aspirin 650 mg alone for hours of 50 % relief among patients who had severe baseline pain . Adverse effects were transitory and none were serious OBJECTIVE A phase II , r and omized , double-blind , crossover study was design ed to evaluate the efficacy of 100-mg diclofenac sodium softgel ( formulated using ProSorb technology ) with or without 100-mg caffeine versus placebo in migraineurs during migraine attacks . BACKGROUND Diclofenac has been demonstrated to be an effective migraine treatment in several placebo-controlled studies . A rapidly absorbed softgel of diclofenac has been shown to be effective in the rapid relief of acute pain , and may have advantages in migraine treatment . In addition , caffeine has consistently been shown to increase both the efficacy and speed of onset of concurrently administered analgesics . The ability of caffeine to both enhance and accelerate analgesic effects has been documented with a variety of different medications ( ie , aspirin , acetaminophen , ibuprofen , and ergotamine ) . METHODS The 3-period crossover study was design ed to compare diclofenac softgel 100 mg , diclofenac softgel 100 mg plus caffeine 100 mg , and placebo in the acute treatment of migraine . Subjects treated one moderate or severe attack with each study medication . The primary efficacy parameter was the percentage of subjects with headache relief at 60 minutes as defined by a reduction of headache severity from moderate or severe at baseline to absent or mild compared with placebo . Though the sample size estimate required that 72 subjects treat 3 separate attacks , 51 subjects treated 1 migraine attack , 44 treated 2 attacks , and 39 treated 3 attacks . Results .-In the placebo group , 6 ( 14 % ) of 43 subjects reported headache relief at 60 minutes versus 12 ( 27 % ) of 45 subjects in the diclofenac softgel group , and 19 ( 41 % ) of 46 subjects in the diclofenac softgel plus caffeine group . Differences were statistically significant for the diclofenac softgel plus caffeine group versus placebo ( odds ratio , 4.2 ; 95 % confidence interval , 1.3 to 13.7 ) . Rescue medication was used by 27 ( 63 % ) of 43 subjects treated with placebo , 15 ( 33 % ) of 45 subjects treated with diclofenac softgel , and 14 ( 30 % ) of 46 subjects treated with diclofenac softgel plus caffeine . This result is highly statistically significant ( chi22= 11.56 , P=.003 ) . Both the diclofenac plus caffeine ( P < .03 ) and diclofenac only ( P < .03 ) groups were significantly different from the placebo group in terms of the visual analog scale score at 60 minutes . CONCLUSIONS The major finding of the present study is that diclofenac softgel plus caffeine produces statistically significant benefits relative to placebo at 60 minutes . Diclofenac softgel alone did not differ significantly from placebo , perhaps due to limits in sample size . Nonsignificant trends support the analgesic adjuvant benefit of caffeine when added to diclofenac softgels A double-blind , cross-over trial was made of three analgesic preparations -- paracetamol , paracetamol with caffeine ( Finimal ) and aspirin in the relief of  postoperative pain  in 72 orthopedic in patients and in 144 ambulatory out patients suffering form common idiopathic headache . The combination of paracetamol and caffeine ( Finimal ) in this study shows the greatest pain relief in both groups of patients . This evaluation supports the results of BOOY3 demonstrating the superiority of the paracetamol-caffeine combination to paracetamol alone or aspirin To refine the assessment of over‐the‐counter analgesic agents in the treatment of muscle‐contraction headache , we design ed a single‐dose model with attention to specific method ologic features and two relevant assessment s — the percentage of subjects who achieve complete relief and the time until pain is no longer experienced . Subjects were r and omly assigned to receive a single dose of 1000 mg acetaminophen , 1000 mg aspirin with 64 mg caffeine , or placebo . Under double‐blind conditions , subjects rated headache pain intensity and relief over 4 hours and provided a Comparative Evaluation at the end of the trial . Both active agents were significantly distinguished from placebo on the time‐point analyses ( p < 0.05 ) and summary end point measurements ( sum of pain intensity difference [ SPID ] , total of pain relief , percentage of patients with complete relief , percentage of treatment failures , and the Comparative Evaluation ) , as well as causing a faster elimination of headache ( p < 0.05 ) . The aspirin‐caffeine combination was rated higher than acetaminophen on all summary measurements , particularly SPID ( p < 0.05 ) , with significantly more patients obtaining complete relief with aspirin‐caffeine ( p < 0.01 ) than with acetaminophen . We conclude that this headache pain model can be used to demonstrate the efficacy of over‐the‐counter analgesic agents and to assess their relative efficacy Objective .— To compare the superior efficacy of the fixed combination of acetylsalicylic acid , paracetamol , and caffeine over the single substances , which was observed in the r and omized , double‐blind phase of the clinical trial , with the efficacy of the respective usual nonprescription medication taken by the patients in the open‐label pre‐phase of the same study 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 ; Caffeine is frequently added to mild analgesic preparations but its effect when used alone on pain has never been studied in humans . Using a double‐blind placebo‐controlled multiple crossover design , 53 patients with non‐migrainous headaches were given placebo , acetaminophen , 2 doses of caffeine and 2 combinations of caffeine with acetaminophen . Caffeine appeared to have independent analgesic effects that were equivalent to acetaminophen and were still significant when statistical adjustments were made for prior caffeine consumption and caffeine 's effects on mood & 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 BACKGROUND Narcotics are used extens 
    Output:
    
About 5 % to 10 % more participants achieve a good level of pain relief ( at least 50 % of the maximum over four to six hours ) with the addition of caffeine , giving a NNT of about 14 ( high quality evidence ) .Most comparisons individually demonstrated numerical superiority with caffeine , but not statistical superiority .
The addition of caffeine ( ≥ 100 mg ) to a st and ard dose of commonly used analgesics provides a small but important increase in the proportion of participants who experience a good level of pain relief