***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 BACKGROUND Traditional and largely qualitative review s of evidence are now giving way to much more structured systematic overviews that use a quantitative method to calculate the overall effect of treatment . The latter approach is dependent on the quality of primary studies , which may introduce bias if they are of poor method ologic quality . OBJECTIVE To test the hypothesis that the inclusion of poor- quality trials in meta-analyses would bias the conclusions and produce incorrect estimates of treatment effect . METHODS An overview of r and omized trials of antiestrogen therapy in subfertile men with oligospermia was performed to test the hypothesis . Data sources included online search ing of MEDLINE and Science Citation Index data bases between 1966 and 1994 , scanning the bibliography of known primary studies and review articles , and contacting experts in the field . After independent , blind assessment , nine of 149 originally identified studies met the inclusion criteria and were selected . We assessed study quality independently . Outcome data from each study were pooled and statistically summarized . RESULTS There was a marginal improvement in pregnancy rate with antiestrogen treatment ( odds ratio , 1.6 ; 95 % confidence interval , 0.9 to 2.6 ) . Sensitivity analyses on the basis of method ologic quality demonstrated that poor- quality studies produced a positive effect with treatment , whereas no benefit was observed with high- quality studies . CONCLUSION The results of a meta- analysis are influenced by the quality of the primary studies included . Method ologically , poor studies tend to exaggerate the overall estimate of treatment effect and may lead to incorrect inferences UNLABELLED The aim of this r and omized double-blind , placebo-controlled , parallel-group study was to evaluate the efficacy , safety , and tolerability of pregabalin in combination with oxycodone or placebo , in patients with either postherpetic neuralgia ( PHN ) or painful diabetic neuropathy ( PDN ) . After a 7-day washout period , 62 patients were r and omized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week . Patients were then started on open-label pregabalin ( 75 , 150 , 300 and 600 mg/day ) according to a forced titration dosing regimen , while continuing the same dosage of oxycodone or placebo for 4 weeks . The primary efficacy measure was a decrease in the pain-intensity score of at least 2 cm and a pain score < 4 cm measured using a 10-cm visual analogue scale ( VAS ) following pregabalin dosage escalation and treatment for 4 weeks . Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale . There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain . PERSPECTIVE Peripheral neuropathic pain presents commonly in clinical practice , and 2 of its most prevalent types are PHN and PDN . Currently available treatments provide some degree of pain relief in approximately 40 - 60 % of patients , leaving the remainder with unremitting pain . Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN , it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin UNLABELLED Physical dependence or withdrawal is an expected effect of prolonged opioid therapy . Oxytrex ( oxycodone + ultralow-dose naltrexone ) is an investigational drug shown here to minimize physical dependence while providing strong analgesia with twice-daily dosing . In this 719-patient , double-blind , placebo- and active-controlled Phase III clinical trial in chronic low back pain , patients were r and omized to receive placebo , oxycodone qid , or oxytrex qid or bid . Each oxytrex tablet contains 1 microg naltrexone ; oxytrex bid and qid treatments provide 2 and 4 microg naltrexone/day , respectively . Following a washout , patients with pain > or=5 on a 0 - 10 scale were dose-escalated weekly from 10 up to 80 mg/day until reaching adequate pain relief ( < or=2 ) or a tolerable level of side effects . Following titration , the dose was fixed for 12 weeks . Active treatment groups attained comparable analgesia despite significantly lower drug use ( P = .03 ) by oxytrex patients . Patients taking  oxytrex bid reported 55 % less physical dependence than patients on oxycodone ( P = .01 ) by the Short Opiate Withdrawal Scale 24 h after treatment cessation . Oxytrex bid patients also reported decreased moderate-to-severe constipation ( by 44 % , P = .01 ) , somnolence ( by 33 % , P = .03 ) , and pruritus ( by 51 % , P < .001 ) . This is the first large well controlled study to show strong analgesia with minimal withdrawal symptoms and better safety compared with oxycodone . PERSPECTIVE Previous clinical data have shown ultralow-dose naltrexone enhances and prolongs oxycodone analgesia , and pre clinical data also show a suppression of opioid tolerance and dependence . A cellular mechanism of action has been demonstrated to be the prevention of aberrant G protein signaling by mu opioid receptors caused by chronic opioid administration Background : Painful neuropathy is one of the most common long‐term complications of diabetes mellitus and often proves difficult to relieve . Methods : Patients with diabetic neuropathy with moderate or greater pain for at least 3 months , were evaluated for efficacy , safety and health‐related quality of life ( QOL ) while receiving controlled‐release ( CR ) oxycodone ( OxyContin ® ) or active placebo . Patients underwent washout from all opioids 2–7 days before r and omization to 10 mg CR oxycodone or active placebo ( 0.25 mg benztropine ) q12h . The dose was increased , approximately weekly , to a maximum of 40 mg q12h CR oxycodone or 1 mg q12h benztropine , with crossover to the alternate treatment after a maximum of 4 weeks . Acetaminophen , 325–650 mg q4‐6h prn was provided as rescue . Results : Thirty‐six patients were evaluable for efficacy ( 21 men , 15 women , mean age 63.0±9.4 years )  . CR oxycodone result ed in significantly lower ( P=0.0001 ) mean daily pain ( 21.8±20.7 vs. 48.6±26.6 mm VAS ) , steady pain ( 23.5±23.0 vs. 47.6±30.7 mm VAS ) , brief pain ( 21.8±23.5 vs. 46.7±30.8 mm VAS ) , skin pain ( 14.3±20.4 vs. 43.2±31.3 mm VAS ) , and total pain and disability ( 16.8±15.6 vs. 25.2±16.7 ; P=0.004 ) . Scores from 6 of the 8 SF‐36 domains and both summary scales , St and ardized Physical Component ( P=0.0002 ) and St and ardized Mental Component ( P=0.0338 ) were significantly better during CR oxycodone treatment . The number needed to treat to obtain one patient with at least 50 % pain relief is 2.6 and clinical effectiveness scores favoured treatment with CR oxycodone over placebo ( P=0.0001 ) . Conclusion : CR oxycodone  is effective and safe for the management of painful diabetic neuropathy and improves QOL Background and objective : Opioid treatment has played a limited role in the management of diabetic neuropathy , in part because of concerns about the responsiveness of neuropathic pain to opioid treatment . This controlled study evaluated the efficacy and safety of controlled-release ( CR ) oxycodone in subjects with moderate to severe pain due to diabetic neuropathy . Methods : This multicenter , r and omized , double-blind , placebo-controlled , parallel-group study included 159 subjects with moderate to severe pain due to diabetic neuropathy . Treatment began with either one 10-mg tablet of CR oxycodone ( n = 82 ) or identical placebo ( n = 77 ) every 12 hours . Doses could be increased every 3 days to a maximum of 6 tablets ( 60 mg CR oxycodone ) every 12 hours . Treatment lasted up to 6 weeks . The primary efficacy variable was overall average daily pain intensity during study days 28 to 42 . Results : At an average ( SD ) dose of 37 ( 21 ) mg per day ( range 10 to 99 mg/d ) , CR oxycodone provided more analgesia  than placebo ( p= 0.002 ) in the intent-to-treat cohort . From days 28 to 42 , overall average daily pain intensity ( least squares mean ±SE ) , rated in subject diaries on a numeric scale of 0 ( no pain ) to 10 ( pain as bad as you can imagine ) , was 4.1 ± 0.3 in subjects given CR oxycodone and 5.3 ± 0.3 in placebo-treated subjects . Overall , 80 ( 96 % ) of 82 subjects given CR oxycodone and 52 ( 68 % ) of 77 subjects who received placebo  reported adverse events . The most common adverse events in the CR oxycodone group were opioid related . Conclusions : In this 6-week trial , CR oxycodone was effective for the treatment of moderate to severe pain due to diabetic neuropathy . Adverse events were typical of opioid-related side effects UNLABELLED This multicenter , r and omized , double-blind , placebo- and active-controlled trial was conducted to compare the analgesic efficacy and safety of oxymorphone extended release ( ER ) with placebo and oxycodone controlled release ( CR ) in ambulatory patients with moderate to severe chronic low back pain requiring opioid therapy . Patients ( N = 213 ) aged 18 to 75 years were r and omized to receive oxymorphone ER ( 10 to 110 mg ) or oxycodone CR ( 20 to 220 mg ) every 12 hours during a 7- to 14-day dose-titration phase . Patients achieving effective analgesia at a stable opioid dose entered an 18-day double-blind treatment phase and either continued opioid therapy or received placebo . With stable dosing throughout the treatment phase , oxymorphone ER ( 79.4 mg/day ) and oxycodone CR ( 155 mg/day ) were superior to placebo for change from baseline in pain intensity as measured on a visual analog scale ; the LS mean differences were -18.21 and 18.55 ( 95 % CI , -25.83 to -10.58 and -26.12 to -10.98 , respectively ; P = .0001 ) . Use of rescue medication was 20 mg per day . Adverse events for the active drugs were similar ; the most frequent were constipation and sedation . Oxymorphone ER and oxycodone CR were generally safe and effective for controlling low back pain . Oxymorphone ER was equianalgesic to oxycodone CR at half the milligram daily dosage , with comparable safety . PERSPECTIVE Definitive studies of long-acting opioids in patients with chronic low back pain are lacking . We report the results of a multicenter , r and omized , placebo-controlled , double 
    Output:
    
Third tier evidence indicated greater pain intensity reduction and better patient satisfaction with oxycodone than with placebo in all three studies , but such evidence was derived mainly from group mean data , with last observation carried forward ( LOCF ) imputation or completer analysis , in small studies lasting less than eight weeks ( very low quality evidence ) .Adverse events were more common with oxycodone CR than with placebo .
Withdrawals due to lack of efficacy were less frequent with oxycodone CR ( 1.1 % ) than placebo ( 11 % ) , with an NNT to prevent one withdrawal of 10 ( RR 0.12 ( 0.03 to 0.45 ) ; very low quality evidence ) .We found no relevant studies in chronic neuropathic pain conditions other than painful diabetic neuropathy or postherpetic neuralgia , or in fibromyalgia .
No convincing , unbiased evidence suggests that oxycodone ( as oxycodone CR ) is of value in treating people with painful diabetic neuropathy or postherpetic neuralgia .
There is no evidence at all for other neuropathic pain conditions , or for fibromyalgia .
Adverse events typical of opioids appear to be common