***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: Oral controlled-release oxycodone has been available for the treatment of  chronic pain in Germany since 1998 . Controlled trials have shown good clinical efficacy and tolerability . This survey reports results from six open prospect i ve multicenter trials . In these trials 4196 patients suffering from cancer pain and non-cancer-related pain with inadequate pain relief were treated with oral controlled-release oxycodone for 3 - 4 weeks . Only a few participating physicians were pain specialists . A total of 356 patients suffering from pain of the musculoskeletal system and receiving oxycodone therapy were monitored for 6 months . Exclusion from the studies was due mainly to inadequate analgesia , side effects , and noncompliance . The efficacy of oxycodone  was rated to be better than moderate by most of the patients , quality of life parameters increased significantly , and patient satisfaction was high . The treatment with oral controlled-release oxycodone was a safe and effective option even when used by nonspecialized physicians BACKGROUND : Current clinical guidelines have identified the need for studies comparing the effect of different short-acting or rapid-onset opioids for the treatment of breakthrough pain ( BTP ) . In this study we evaluated the efficacy and safety of treatment with fentanyl buccal tablet ( FBT ) in comparison with immediate-release oxycodone in alleviating BTP in opioid-tolerant patients with chronic pain . METHODS : In this cross-over design study , opioid-tolerant patients were r and omized to open-label titration with FBT ( 200 , 400 , 600 , 800 & mgr;g ) followed by oxycodone ( 15 , 30 , 45 , 60 mg ) or vice versa for the management of BTP . After titration to a successful dose of both study drugs , patients were rer and omized to double-blind treatment for 10 BTP episodes with 1 of the already identified successful doses of study drug followed by cross-over to double-blind treatment for 10 BTP episodes with the other study drug . The primary efficacy measure was the difference in pain intensity ( based on an 11-point numerical scale ) 15 minutes after administration of study drug ( PID15 ) . Other efficacy measures included PID at other time points postdose ( 5 through 60 minutes ) , the sum of pain intensity differences ( SPID ) at 30 and 60 minutes postdose , pain relief ( 5 through 60 minutes ) , proportion of BTP episodes for which patients experienced meaningful reduction in pain intensity , and patient preference for BTP medication . Adverse events were also recorded . RESULTS : Of the 323 patients enrolled , 203 achieved a successful dose of both study drugs , 191 completed the titration phase , and 180 completed the double-blind phase . PID15 was significantly greater after FBT versus oxycodone ( mean [ SD ] , 0.82 [ 1.12 ] vs. 0.60 [ 0.88 ] ; 95 % confidence interval [ CI ] = 0.18 , 0.29 ; P < 0.0001 ) . Secondary efficacy measures favored FBT and showed differences versus oxycodone from 5 minutes postdose for PID and 10 minutes postdose for pain relief . SPID30 and SPID60 were greater with FBT than with oxycodone ( P < 0.0001 for both measures ) . A ≥33 % improvement in pain intensity occurred in a larger proportion of FBT-treated episodes versus oxycodone beginning 15 through 45 minutes postdose ( P < 0.05 ) . FBT was preferred by 52 % of patients , oxycodone by 33 % . Adverse events with both study drugs were generally typical of opioids , and the majority occurred during titration . Two serious adverse events ( pneumonia ) were reported in 1 patient ; both occurrences were considered unrelated to study drug . CONCLUSION : FBT result ed in more rapid onset of analgesia and was generally well tolerated in comparison with oxycodone for the treatment of BTP in opioid-tolerant patients Opioid use has been reported to be associated with increased fracture risks . In a nested case-control study using the United Kingdom-based General Practice Research Data base , we tested the hypotheses that fracture risk was associated with 1 ) an elevated risk of falls caused by the acute central nervous system effects of opioids including sedation and dizziness , and 2 ) osteoporosis caused by chronic opioid-induced hypogonadism . Among a cohort of adults aged 18 - 80 years without cancer who received ≥1 opioid prescription during 1990 - 2008 , we selected cases with a first diagnosed fracture of the hip , humerus , or wrist ; up to 4 controls , matched by age , sex , index date ( date of the first diagnosed fracture ) , and general practice , were r and omly selected for each case . Adjusted odds ratios and 95 % confidence intervals were estimated by using conditional logistic regression . Current use of 1 prescription was associated with a strong risk of fracture ( adjusted odds ratio = 2.70 , 95 % confidence interval : 2.34 , 3.13 ) . The risk decreased with increasing use . There was no association with current use of > 20 opioid prescriptions . The findings were consistent for all study fractures and for most common opioids , suggesting that acute central nervous system effects of opioids rather than chronic opioid-induced hypogonadism play a key role in fracture risk BACKGROUND S With increasing use of opioids for chronic noncancer pain comes concern about safety of this class of drugs . Opioid-induced hypogonadism , which could increase the risk for myocardial infa rct ion ( MI ) , has recently come to the attention of clinicians . To evaluate this concern we examined the association between  opioid use for noncancer pain and risk of MI amongst adults . METHODS We conducted a nested case-control study using the UK General Practice Research Data base . Amongst 1.7 million opioid users during 1990 - 2008 , we identified 11 693 incident MI cases aged 18 - 80 years , and r and omly selected up to four controls matched by age , gender , index date ( date of onset symptoms or diagnosis of first-ever MI ) and general practice via risk-set sampling . Cases and controls were required to have no cancer and no major risk factors for MI before the index date .  Adjusted odds ratios ( ORs ) and 95 % confidence intervals ( CIs ) were estimated from conditional logistic regression . RESULTS Compared with nonuse , current use of opioids was associated with a 1.28-fold ( 95 % CI 1.19 - 1.37 ) risk of MI . Cumulative use of opioids with 11 - 50 ( OR = 1.38 , 95 % CI : 1.28 - 1.49 ) or > 50 ( OR = 1.25 , 95 % CI : 1.11 - 1.40 ) prescriptions , was also marginally associated with increased risk of MI . The risk was particularly increased in users of morphine ( OR = 1.71 , 95 % CI : 1.09 - 2.68 ) , meperidine ( OR = 2.15 , 95 % CI : 1.24 - 3.74 ) and polytherapy ( OR = 1.46 , 95 % CI : 1.22 - 1.76 ) . CONCLUSIONS Current use of any opioids and cumulative use of 11 or more prescriptions are associated with a small increased risk for MI compared to nonuse and the risk was greater in morphine , meperidine and polytherapy users . Residual confounding , particularly confounding by indication , should be considered in interpreting our results & NA ; Data on comparative safety of opioid analgesics are limited , but some reports suggest disproportionate mortality risk associated with methadone . Our objective was to compare mortality rates among patients who received prescribed methadone or long‐acting morphine for pain . This is a retrospective observational cohort drawn from Department of Veterans Affairs ( VA ) health care data bases , January 1 , 2000 , to December 31 , 2007 . We included 28,554 patients who received methadone and 79,938 who received long‐acting morphine from VA pharmacies . Compared with those who received long‐acting morphine , patients who received methadone were younger , less likely to have some medical comorbidities , and more likely to have psychiatric and substance use disorders . Patients were stratified into quintiles according to propensity score ; the probability of receiving methadone was conditional on demographic , clinical , and VA service area variables . Overall propensity‐adjusted mortality was lower for methadone than for morphine .  Hazard ratios varied across propensity score quintiles ; the magnitude of the between‐drug difference in mortality decreased as the propensity to receive methadone increased . Mortality was significantly lower for methadone in all but the last quintile , in which there was no between‐drug difference in mortality ( hazard ratio = 0.92 , 95 % confidence interval = 0.74 , 1.16 ) . Multiple sensitivity analyses found either no difference in mortality between methadone and long‐acting morphine or lower mortality rates among patients who received methadone . In summary , we found no evidence of excess all‐cause mortality among VA patients who received methadone  compared with those who received long‐acting morphine . R and omized trials and prospect i ve observational research are needed to better underst and the relative safety of long‐acting opioids . Among patients who received methadone or long‐acting morphine for pain from Department of Veterans Affairs pharmacies in 2000–2007 , no evidence of excess all‐cause mortality associated with methadone was found Driving has been regarded as an activity of daily living that is important in maintaining a person 's independence in the community , access to employment , and social activities . Many patients , however , using opioid medications on a regular basis ( Chronic Opioid Analgesic Therapy : COAT ) to ameliorate their intractable pain have been restricted from driving out of concern that skills would be impaired and driving safety compromised by these medications . Yet there are no driving studies which have explored the effects of using opioid analgesics for an extended period of time . This pilot study was design ed to determine the effects of medically prescribed , stable opioid use on the driving abilities of patients with persistent , nonmalignant pain . Sixteen patients with chronic nonmalignant pain on COAT , who met criteria for participation in the study , underwent a comprehensive off-road driving evaluation using measures which have been shown to be sensitive in predicting on-road driving performance . The evaluation consisted of a pre-driver evaluation ( PDE ) , a simulator evaluation ( SDE ) , and behavioral observation during simulator performance .  Patients in the COAT group were compared to a historical control group of 327 cerebrally compromised patients ( CComp ) who had undergone the same evaluation and then passed an on-road , behind-the-wheel evaluation ( BTW Pass ; n = 162 ) or failed ( BTW Fail ; n = 165 ) . Results revealed that COAT patients generally outperformed the CComp patients as a group by equaling or exceeding PDE and SDE scores of the BTW Fail patients as well as the BTW Pass patients on all measures that differentiated the groups . Notably , COAT patients had a relatively poorer performance than CComp patients on specific neuropsychometric tests in the PDE ; however , the differences were not statistically significant and did not imply a systematic pattern of scores that reflected domain-specific deficits . Behaviorally , COAT patients were generally superior to CComp patients , also ; however , COAT patients had greater difficulty in following instructions and as well as a tendency toward impulsivity , like the BTW fail group . While there was general support for the notion that COAT did not significantly impair the perception , cognition , coordination , and behavior measured in off-road tests that have been regarded as requisite for on-road driving , method ological problems may limit the generalizability of results and recommendations are made for research beyond a pilot study Prer and omization run-in periods are being used to select or exclude patients in an increasing number of clinical trials , but the implication s of run-in periods for interpreting the results of clinical trials and applying these results in clinical practice have not been systematic ally examined . We analyzed illustrative examples of reports of clinical trials in which run-in periods were used to exclude noncompliant subjects , placebo responders , or subjects who could not tolerate or did not respond to active drug . The Physicians ' Health Study exemplifies the use of a prer and omization run-in period to exclude subjects who are nonadherent , while recent trials of tacrine for Alzheimer disease and carvedilol for congestive heart failure typify the use of run-in periods to exclude patients who do not tolerate or do not respond to the study drug . The reported results of these studies are valid . However , because the reported results apply to subgroups of patients who can not be defined readily based on demographic or clinical characteristics , the applicability of the results in clinical practice is diluted . Compared with results that would have been observed without the run-in period , the reported results overestimate the benefits and underestimate the risks of treatment , underestimate the number needed to treat , and yield a smaller P value . The Cardiac Arrhythmia Suppression Trial exemplifies the use of an active-drug run-in period that enhances clinical applicability by selecting a group of study subjects who closely resembled patients undergoing active clinical management for this problem . Run-in periods can dilute or enhance the clinical applicability of the results of a clinical trial , depending on the patient group to whom the results will be applied . Reports of clinical trials using run-in periods should indicate how this aspect of their design affects the application of the results to clinical practice 
    Output:
    
Evidence on long-term opioid therapy for chronic pain is very limited but suggests an increased risk of serious harms that appears to be dose-dependent .