***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: & NA ; Tramadol hydrochloride is a synthetic & mgr;‐opioid agonist with additional monoaminergic activity . Tramadol 's analgesic effect has been equated with that of pethidine , with a more favourable side‐effect profile . Tramadol has been the most‐selling prescription analgesic in Germany for several years , and it is now available in many other European countries , but still there is a lack of adequately controlled clinical studies of its analgesic properties . The purpose of this study was to compare the analgesic efficacy of 50 and 100 mg oral tramadol with our st and ard analgesic for postoperative pain treatment , 1000 mg paracetamol + 60 mg codeine , and placebo . A single‐dose , parallel group , double‐blind design was used . One hundred forty‐four patients were enrolled the day after total hip replacement if they had a pain intensity of 60 mm or more on a 0–100 mm visual analogue scale . Treatments were compared on the basis of pain intensity and derived variables ( pain intensity difference , and summed pain intensity differences ) , the need of rescue medication , and a global evaluation . Serum concentrations confirmed rapid and good absorption comparable with the reported in healthy volunteers . The active drug control , paracetamol + codeine , was significantly superior to placebo for all efficacy variables ( P = 0.0002–0.004 ) , confirming good assay sensitivity .  Paracetamol + codeine  was also significantly superior to both 50 mg tramadol ( P = 0.002–0.03 ) and 100 mg tramadol ( P = 0.002–0.02 ) . There was no difference between placebo and 50 and 100 mg tramadol for any of the efficacy variables . Adverse events were more common with tramadol than with the active control ( P < 0.02 ) , with significantly more emetic episodes after 50 and 100 mg tramadol ( P < 0.05 ) . Thus , this double‐blind , placebo‐ and active drug‐controlled study after orthopaedic surgery shows that 50 and 100 mg oral tramadol is well absorbed but has no significant analgesic effect in doses that are tolerable as single doses by mouth . We emphasize the importance of proper study design with documented assay sensitivity and sufficiently high initial pain intensity for differentiation between analgesics of different potencies 1 In a double-blind crossover study identical oral surgical procedures were performed on two separate occasions in 24 out patients . 2 At one operation they were given tablets containing paracetamol + codeine phosphate ( 400 mg + 30 mg ) , and at the other plain paracetamol ( 400 mg ) . The day of operation 2 tablets were taken 3 , 6 and 9 h after surgery , the following two days 1 tablet four times daily . 3 Several measurements / assessment s were recorded for a paired comparison of the postoperative courses . 4 No increase In the analgesic effect could be demonstrated by addition of codeine to paracetamol . 5 On the day of operation 18 patients reported adverse effects like nausea , dizziness and drowsiness with paracetamol + codeine , while only 3 patients experienced side effects with paracetamol alone ( P less than 0.001 ) . 6 Measurements revealed almost identical swelling after the two operations . 7 Compared with results obtained in previous studies , the present findings indicate that paracetamol may exert anti-inflammatory activity and reduce postoperative swelling , even when given 3 h after surgery . 8 On the day of operation and the following two days 20 patients preferred the treatment with plain paracetamol , while only 4 favoured paracetamol + codeine ( P less than 0.001 ) The purpose of the present investigation was to compare the analgesic efficacy of flurbiprofen , a nonsteroidal anti-inflammatory drug , which is a phenyl propionic acid derivative , with acetaminophen and placebo in 63 adult out patients with moderate to severe dental pain following periodontal surgery . After surgery was completed under local anesthesia , the patients received under double-blind conditions an envelope containing four tablets of either flurbiprofen 100 mg , acetaminophen 500 mg , or placebo and they were instructed to take one tablet every 6 hours when postoperative pain reached moderate to severe intensity . To determine analgesic efficacy and patients recorded pain intensity on a scale of 0 to 3 . Patients were allowed to remedicate after 1 hour if pain was not reduced . Flurbiprofen was shown to possess an adequate analgesic effect superior to either placebo ( P less than 0.005 ) or acetaminophen ( P less than 0.01 ) in the parameters studied . Our results seem to further support earlier data obtained with the drug in dental patients with postoperative pain after the surgical removal of impacted third molars ; therefore , it is concluded that flurbiprofen used as directed is a new alternative for the proper treatment of pain following periodontal surgery 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 In a double‐blind , r and omized , single‐dose trial the analgesic contribution of acetaminophen , 1000 mg , and codeine , 60 mg , was determined . The study was a 2 × 2 factorial experiment in which 120 patients suffering from pain as a result of oral surgery rated their pain intensity and pain relief for up to 5 hours after a single dose of one of : 1000 mg acetaminophen , 60 mg codeine , 1000 mg acetaminophen plus 60 mg codeine , or placebo . The factorial analysis showed that both 1000 mg acetaminophen and 60 mg codeine made a statistically significant ( P < 0.05 ) contribution to the analgesic effectiveness of the combination on all measures of efficacy ( sum of pain intensity differences , largest pain intensity difference , total pain relief , largest pain relief , and time to remedication ) . The incidence of adverse effects did not appear to differ among the treatments , including placebo To determine the relative analgesic efficacy of ibuprofen 400 mg and acetaminophen 1000 mg , we conducted a single-dose , double-blind , placebo-controlled , r and omized clinical trial using a st and ard assay for analgesic agents , the dental pain model . At regular intervals over 6 hours , 184 patients who had undergone dental impaction surgery rated pain intensity and relief on categorical scales and pain half-gone on a dichotomous nominal scale ; a categorical overall evaluation was completed at the end of 6 hours . Both active agents were effective compared to placebo . Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for Sum Pain Intensity Difference ( SPID ) , Total Pain Relief ( TOTPAR ) , sum pain half-gone , and overall evaluation ( P less than .05 to P less than .001 ) . The time-effect curves demonstrated a greater peak effect and longer duration of action for ibuprofen 400 mg compared to acetaminophen 1000 mg . Side effects were reported in five ibuprofen patients , 11 acetaminophen-treated patients , and seven placebo patients . Based on the results of this clinical study , we conclude that ibuprofen 400 mg is a safe and more effective analgesic than acetaminophen 1000 mg for patients with acute pain A double-blind , placebo-controlled trial was carried out in 299 patients suffering from post-episiotomy pain to compare the analgesic effectiveness and tolerance of single doses of 500 mg dipyrone and 500 mg paracetamol . Assessment s of pain relief over a 6-hour period showed that dipyrone produced significantly better results than placebo within half an hour of intake and maintained this superiority throughout the 6 hours . It also afforded consistently better pain relief than paracetamol and was significantly more effective at the 6-hour assessment . Side-effects were few and mild In a double‐blind , single‐dose , parallel‐group study , ketorolac ( 5 , 10 , or 20 mg ) was compared with acetaminophen ( 500 or 1000 mg ) when taken by mouth for postoperative orthopedic pain . Analgesic measurements were made by trained nurse observers who used st and ard verbal rating and visual analog scales . Acetaminophen , 1000 mg , was statistically superior to 500 mg acetaminophen , demonstrating assay sensitivity . Ketorolac , 20 mg , was distinguished from 500 mg acetaminophen , 5 mg ketorolac , and 10 mg ketorolac , but not from 1000 mg acetaminophen . The higher doses of ketorolac induced a longer lasting peak analgesic effect than did acetaminophen , but the magnitude of the peak pain relief was changed little by an increased ketorolac dose . Overall , 10 mg ketorolac appeared equivalent to 1000 mg acetaminophen . Acetaminophen , 500 mg , induced less sedation than the higher doses of ketorolac , but neither drug caused untoward side effects A double-blind r and omized analgesic trial was carried out on 180 patients undergoing surgical removal of an impacted lower wisdom tooth . The patients took their first dose of either 1000 mg paracetamol plus 60 mg codeine or 650 mg paracetamol plus 65 mg dextropropoxyphene when pain appeared after the decline of the local anaesthesia . If needed , another two doses were available during the observation period ( ≤10 h ) . The analgesic efficacy  of paracetamol/codeine was overall superior to paracetamol/dextropropoxyphene in all variables . Sufficient pain relief was obtained in most patients . The pain reduction after the first dose was 64 % in the group receiving paracetamol/codeine compared with 53 % in the group receiving paracetamol/dextropropoxyphene and the mean duration s of effect of the first dose were 6.6 and 5.8 h , respectively . Side-effects appeared in all patient groups but were most frequent in women taking paracetamol/codeine One hundred sixty-one patients with postoperative pain were treated at a single center in a double-blind , r and omized , parallel study design ed to compare the efficacy and safety of single oral doses of ketoprofen ( 50 and 150 mg ) , an acetaminophen ( 650 mg ) plus codeine ( 60 mg ) combination , and placebo . From 1 through 4 hours after administration of the study drugs , the mean summed pain intensity difference ( SPID ) and time-weighted total pain relief ( TOPAR ) scores for the three active treatments generally were significantly ( P less than 0.05 ) higher than those for placebo but not significantly different from each other . At the 6-hour evaluation , the ketoprofen groups , but not the acetaminophen-codeine group , had higher ( P less than 0.05 ) mean SPID and TOPAR scores than the placebo group , as a result of a shorter duration of pain relief in the acetaminophen-codeine group . The 6-hour TOPAR scores were significantly ( P less than 0.05 ) higher for both ketoprofen groups than for the acetaminophen-codeine group ; the ketoprofen 150 mg group also had significantly ( P less than 0.05 ) higher mean 6-hour SPID and global subjective assessment scores . As a result of a higher frequency of somnolence , there was a significantly ( P less than 0.05 
    Output:
    
Drug-related study withdrawals were rarely reported .
Studies reported a variable incidence of adverse effects that were generally mild and transient .
There were no statistically significant differences in the frequency of reported adverse effects between paracetamol 975/1000 mg and placebo .
REVIEW ER 'S CONCLUSIONS Single doses of paracetamol are effective analgesics for acute postoperative pain and give rise to few adverse effects