***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 PURPOSE The WHO guidelines on cancer pain management recommend a sequential three-step analgesic ladder . However , conclusive data are lacking as to whether moderate pain should be treated with either step II weak opioids or low-dose step III strong opioids . PATIENTS AND METHODS In a multicenter , 28-day , open-label r and omized controlled study , adults with moderate cancer pain were assigned to receive either a weak opioid or low-dose morphine . The primary outcome was the number of responder patients , defined as patients with a 20 % reduction in pain intensity on the numerical rating scale . RESULTS A total of 240 patients with cancer ( 118 in the low-dose morphine and 122 in the weak-opioid group ) were included in the study . The primary outcome occurred in 88.2 % of the low-dose morphine and in 57.7 % of the weak-opioid group ( odds risk , 6.18 ; 95 % CI , 3.12 to 12.24 ; P < .001 ) . The percentage of responder patients was higher in the low-dose morphine group , as early as at 1 week . Clinical ly meaningful ( ≥ 30 % ) and highly meaningful ( ≥ 50 % ) pain reduction from baseline was significantly higher in the low-dose morphine group ( P < .001 ) . A change in the assigned treatment occurred more frequently in the weak-opioid group , because of inadequate analgesia . The general condition of patients , which was based on the Edmonton Symptom Assessment System overall symptom score , was better in the morphine group . Adverse effects were similar in both groups . CONCLUSION In patients with cancer and moderate pain , low-dose morphine  reduced pain intensity significantly compared with weak opioids , with a similarly good tolerability and an earlier effect In this multicentre trial tramadol and buprenorphine were compared for the treatment of neoplastic pain no longer responsive to non-steroidal antiinflammatory drugs . A total of 131 adults ( 86 M , 45F ) were treated with tramadol ( one 100-mg slow-release tablet every 8 - 12 h ) , or buprenorphine ( one sublingual 0.2-mg tablet every 6 - 8 h ) . The trial was to continue for up to six months . Most patients started treatment with 2 - 3 tablets/day in both groups , and the mean treatment period was 58 days for tramadol and 51 for buprenorphine . Almost all dose changes needed were made in the first fortnight in both treatment groups , and the largest number of patients dropped out because of inadequate pain relief or progression of the underlying disease . The results achieved in the first two weeks persisted throughout the rest of the trial , and the investigator 's assessment s on each patient 's clinical chart corresponded closely with those that patients made in their own daily diaries . In the four hours after the first dose both drugs virtually halved the severity of pain ( measured using a visual analogue scale ) , and this relief lasted throughout treatment . By the end of the first week the proportion of patients with strong/unbearable pain in the tramadol group had fallen significantly ( from 98.4 % to 48.1 % , p < 0.05 ) , as compared to a drop from 92 % to 66.7 % for buprenorphine . The quality of sleep also tended to improve in the tramadol group , with the proportion of patients enjoying good or deep sleep rising from 37 % to 50 % , as compared to 33 % to 40 - 44 % with buprenorphine .  Karnofsky 's and Spitzer 's indices reflecting the quality of life did not change in the tramadol group ; in the buprenorphine group the Karnofsky index dropped slightly after a fortnight ( p < 0.05 between treatments ) . In the first two months of the trial the number of patients with no/moderate pain rose continuously in the tramadol group ( 71 % and 80 % after one and two months ) ; the rise was less marked in the buprenorphine group ( number of patients with mild/moderate pain , 45 % and 65 % ) . In both the short term and in the longer term , it was found that the levels of efficacy and acceptability were always significantly better in the tramadol group than in the buprenorphine group . General and biological safety in both drugs was good . The most typical side-effects were those characteristic of opioids ( nausea and /or vomiting , drowsiness ) . Adverse reactions were reported in 17 patients taking tramadol  ( 25 % ) and in 16 taking buprenorphine  ( 26 % ) . There were six drop-outs in the first group ( 9 % ) and seven in the second ( 11 % ) . Serious symptoms arose more frequently in the buprenorphine group ( 19 % cf . 10 % ) . No signs of dependence or tolerance were noted Cobrotoxin produces intense analgesia but it has an onset of response of 1 - 3 h which hampers its clinical use in cancer pain . Recently , a compound analgesic formulation combining cobrotoxin , tramadol hydrochloride and ibuprofen ( Compound Keluoqu , CKLQ ) has become available in China . The aim of this study was to evaluate the clinical efficacy of CKLQ for moderate to severe cancer pain . A consecutive series of patients with chronic moderate to severe cancer pain was enrolled into two multicenter trials . Of the 230 eligible patients , 119 were assigned to a r and omized , double-blind , cross-over study , while 111 entered an open-label study . They were all of Han-China nationality and had a mean age of 52.0 and 55.4 years and a mean body weight of 55.6 and 52.9 kg , respectively . A total of 11 patients discontinued the study , 6 ( 54.5 % ) because of insufficient pain relief and 5 due to the occurrence of adverse events . In the cross-over study , 59 patients were r and omized to receive a CKLQ package with 2 CKLQ tablets ( each containing 0.16 mg cobrotoxin , 25 mg tramadol hydrochloride and 50 mg ibuprofen ) and 2 placebo capsules , a placebo package with 2 placebo tablets and 2 placebo capsules , and an active control package with 2 tramadol hydrochloride capsules ( each containing 50 mg tramadol hydrochloride ) and 2 placebo tablets ( arm A ) , and 60 to receive a tramadol hydrochloride package , a placebo package and a CKLQ package ( arm B ) , sequentially and only once . Patients in the open-label study only received CKLQ and were given the option to continue for up to 7 days as long as they had satisfactory pain relief . Pain response was classified as CR , PR and NC . CR was defined as 100 % pain relief , with a pain score of 0 on a 0 - 10 VAS . PR was defined as decreased to mild pain , with a pain score of no more than 4 on a 0 - 10 VAS . NC was defined as pain that either remained unchanged or that was reduced from severe to moderate at baseline , with a VAS pain score of more than 4 after treatment . One hundred and eight patients completed the cross-over study with all the three drug units . The overall rate of pain relief was 93/111 ( 83.7 % ) for CKLQ , 75/110 ( 68.2 % ) for tramadol hydrochloride ( P=0.011 ) and 39/111 ( 35.1 % ) for placebo ( P<0.001 ) . The mean duration of pain relief with CKLQ was significantly longer than that of the other two agents ( P<0.001 ) . Of the 35 patients who did not respond to tramadol hydrochloride , 27 ( 77.1 % ) responded to CKLQ , while of the 18 who did not respond to CKLQ , 8 ( 55.6 % ) achieved satisfactory pain control with tramadol hydrochloride . In the open-label study , the overall relief rate of a single-dose of CKLQ was 99/111 ( 89.2 % ) . A reduction in the percentage of complete relief , an increase in that of PR and a significant decrease in duration of relief were observed after continuous treatment with at least 10 doses of CKLQ . The frequency of adverse events for CKLQ was similar to that of tramadol hydrochloride . The results of the r and omized , double-blind , cross-over study and the open-label study of CKLQ in cancer patients with chronic moderate to severe cancer pain suggest that the CKLQ may be valuable for the treatment of chronic moderate to severe cancer pain . However , the tolerance of CKLQ remains to be further defined BACKGROUND The European Pain in Cancer survey sought to increase underst and ing of cancer-related pain and treatment across Europe . PATIENTS AND METHODS Patients with all stages of cancer participated in a two-phase telephone survey conducted in 11 European countries and Israel in 2006 - 2007 . The survey screened for patients experiencing pain at least weekly , then r and omly selected adult patients with pain of at least moderate intensity occurring several times per week for the last month completed a detailed attitudinal question naire . RESULTS Of 5084 adult patients contacted , 56 % suffered moderate-to-severe pain at least monthly . Of 573 patients r and omly selected for the second survey phase , 77 % were receiving prescription-only analgesics  , with 41 % taking  strong opioids either alone or with other drugs for cancer-related pain . Of those prescribed analgesics , 63 % experienced breakthrough pain . In all , 69 % reported pain-related difficulties with everyday activities ; however , 50 % believed that their quality of life was not considered a priority in their overall care by their health care professional . CONCLUSIONS Across Europe and Israel , treatment of cancer pain is suboptimal . Pain and pain relief should be considered integral to the diagnosis and treatment of cancer ; management guidelines should be revised to improve pain control in patients with cancer BACKGROUND Tramadol and dihydrocodeine ( DHC ) are analgesics of step 2 WHO analgesic ladder ( opioids for mild to moderate pain , weak opioids ) frequently used in the treatment of cancer pain of moderate intensity . The aim of the study was to assess the impact of tramadol and DHC treatment on quality of life ( QL ) and performance status ( PS ) of patients with cancer pain . PATIENTS AND METHODS R and omised , cross-over , clinical study of 40 opioid-naive patients with nociceptive cancer pain who received tramadol or DHC controlled release tablets for 7 days , and then drugs were switched and administered for another 7 days .  Pain was assessed by visual analogue scale ( VAS ) , QL by EORTC QLQ C 30 , and PS by Eastern Cooperative Oncology Group ( ECOG ) and Karnofsky . RESULTS From 40 patients recruited , 30 completed the study .  DHC treatment provided better analgesia ( VAS ) . In QL functional scales , better emotional functioning in tramadol group and better global QL and cognitive functioning in DHC group were observed . In symptom scales , less fatigue , pain and sleep disturbances , less nausea and vomiting and better appetite in DHC group were noted . In tramadol group , less constipation and less financial problems were observed . No differences in dyspnoea and diarrhoea were noted . ECOG and Karnofsky PS were low and did not differ between tramadol and DHC groups . CONCLUSIONS Dihydrocodeine treatment was associated with better global QL , cognitive functioning , 
    Output:
    
There was no useful information for any other outcome of benefit or harm .
There is limited , very low quality , evidence from r and omised controlled trials that tramadol produced pain relief in some adults with pain due to cancer and no evidence at all for children .
There is very low quality evidence that it is not as effective as morphine .