***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 CONTEXT R and omized trials with adequate sample size offer an opportunity to assess the safety of new medications in a controlled setting ; however , generalizable data on drug safety reporting are sparse . OBJECTIVE To scrutinize the completeness of safety reporting in r and omized trials .  DESIGN , SETTING , AND PATIENTS Survey of safety reporting in 192 r and omized drug trials 7 diverse topics with sample sizes of at least 100 patients and at least 50 patients in a study arm ( N = 130074 patients ) . Trial reports were identified from comprehensive meta-analyses in 7 medical areas . MAIN OUTCOME MEASURES Adequate reporting of specific adverse effects and frequency and reasons for withdrawals due to toxic effects ; article space allocated to safety reporting and predictors of such reporting . RESULTS Severity of clinical adverse effects and laboratory-determined toxicity was adequately defined in only 39 % and 29 % of trial reports , respectively . Only 46 % of trials stated the frequency of specific reasons for discontinuation of study treatment due to toxicity . For these 3 parameters , there was significant heterogeneity in rates of adequate reporting across topics ( P = .003 , P<.001 , and P = .02 , respectively ) . Overall , the median space allocated to safety results was 0.3 page . A similar amount of space was devoted to contributor names and affiliations ( P = .16 ) . On average , the percentage of space devoted to safety in the results section was 9.3 % larger in trials involving dose comparisons than in those that did not ( P<.001 ) and 3.8 % smaller in trials reporting statistically significant results for efficacy outcomes ( P = .047 ) . CONCLUSIONS The quality and quantity of safety reporting vary across medical areas , study design s , and setting s but they are largely inadequate . Current st and ards for safety reporting in r and omized trials should be revised to address this inadequacy We assessed the quality of assessment and reporting of adverse effects in r and omized , double-blind clinical trials of single-dose acetaminophen or ibuprofen compared with placebo in moderate to severe postoperative pain . Reports were identified by systematic search ing of a number of bibliographic data bases ( e.g. , MEDLINE ) . Information on adverse effect assessment , severity and reporting , patient withdrawals , and anesthetic used was extracted . Compliance with former guidelines for adverse effect reporting was noted . Fifty-two studies were included ; two made no mention of adverse effects . No method of assessment was given in 19 studies . Twenty trials failed to report the type of anesthetic used , eight made no mention of patient withdrawals , and nine did not state the severity of reported adverse effects . Only two studies described the method of assessment of adverse effect severity . When all adverse effect data were pooled , significantly more adverse effects were reported with active treatment than with placebo . For individual adverse effects , there was no difference between active ( acetaminophen 1000 mg or ibuprofen 400 mg ) and placebo ; the exception was significantly more somnolence/drowsiness with ibuprofen 400 mg . Ninety percent of trials reporting somnolence/drowsiness with ibuprofen 400 mg were in dental pain . All studies published after 1994 complied with former guidelines for adverse effect reporting . Different methods of assessing adverse effects produce different reported incidence : patient diaries yielded significantly more adverse effects than other forms of assessment . We recommend guidelines for reporting adverse effect information in clinical trials There is controversy about whether the lack of response of some chronic pain to opioid treatment is absolute or relative . It is widely believed that nociceptive pain is responsive to opioids whereas neuropathic pain tends not to be . We have used a method of patient-controlled analgesia ( PCA ) with simultaneous nurse-observer measurement of analgesia , mood , and adverse effects to address these issues . Ten patients with chronic pain were given morphine at two concentrations ( 10 and 30 mg/ml ) by PCA in two separate sessions in a double-blind r and omised crossover study . Before the study a clinical judgment was made as to whether each pain was nociceptive or neuropathic . Seven patients showed good analgesic responses ( more than 70 mm pain relief on a visual-analogue scale ) of pain at rest , two patients poor responses ( less than 30 mm pain relief ) , and one a moderate response with both concentrations ( 30 - 70 mm pain relief ) . The response to  morphine  was consistent ( greater and faster relief with the higher concentration ) in nine patients . Two patients had pain on movement that responded moderately to low-concentration morphine and well to the higher concentration . All patients with pains judged to be nociceptive showed good analgesic responses compared with half of those with neuropathic pain . There was no evidence that analgesic responses in patients with neuropathic pain were due to changes in mood . This PCA method is a quick and efficient tool to determine the consistency of the analgesic response . Such consistency can guide the clinician as to whether continued or higher-dose opioid treatment will produce good analgesia . An inconsistent response points to the use of other pain-relieving strategies & NA ; The aim of the present study has been to assess the responsiveness of various types of chronic pain  to opioids given i.v . and tested against placebo in a double‐blind , r and omized fashion . Pain classified as primary nociceptive was effectively alleviated ( P > 0.001 ) while neuropathic deafferentation pain was not significantly influenced by morphine or equivalent doses of other opioids . Also ‘ idiopathic ’ pain , defined as chronic pain with no or little demonstrable pathology , failed to respond . The results were not related to whether the patients were regular users of narcotic analgesics or not . The outcome of our double‐blind opioid test has proved useful to justify a continued , or discontinued , use of narcotic medication in individual patients . It may also support the indication and choice of invasive stimulation procedures ( spinal cord or brain ) . The results of the study illustrate the misconception of chronic pain as an entity and highlight the importance of recognizing different neurobiological mechanisms and differences in responsiveness to analgesic drugs as well as to non‐pharmacological modes of treatment . The opioid test has thus become a valuable tool in pain analysis and helpful as a guide for further treatment & NA ; A data base of r and omised  clinical trials ( RCTs ) in pain research published from 1950 to 1990 was created following an extensive literature search . By applying a refined MEDLINE search strategy from 1966 to 1990 and by h and ‐ search ing more than 1 000 000 pages of a total of 40 biomedical journals published during the period 1950–1990 , more than 8000 RCTs were identified . The RCTs were published in more than 800 journals and over 85 % appeared between 1976 and 1990 . If the trend of the last 15 years persists , a total of more than 15 000 RCTs will be published in pain relief by the year 2000 . A detailed description of methods to ensure efficient use of re sources during the identification , retrieval and management of the information in pain relief and other fields is given . Emphasis is made on the importance of refining MEDLINE search strategies , on the use of volunteers to h and ‐ search journals and on careful monitoring of each of the steps of the process . The potential uses of the data base to guide clinical and research decisions are discussed Abstract Healthy university students and hospital staff taking no medications  were surveyed by question naire to obtain data on the occurrence of many symptoms often listed as side effects of drugs 
    Output:
    
Use of any oral opioid produced higher rates of adverse events than did placebo .
Because most trials were short , less than four weeks , and because few titrated the dose , these results have limited applicability to longer-term use of opioids in clinical practice .