***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: OBJECTIVES : This multicenter , phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain . METHODS : Adults with opioid-induced constipation ( OIC ; <3 spontaneous bowel movements [ SBMs ] per week ) were r and omized 1:1 to double-blind lubiprostone 24 μg or placebo twice daily for 12 weeks . The primary end point was the overall SBM response rate . Responders had at least moderate response ( ≥1 SBM improvement over baseline frequency ) in all treatment weeks with available observed data , as well as full response ( ≥3 SBMs per week ) for at least 9 of the 12 treatment weeks . RESULTS : In total , 431 patients were r and omized ; 212 each received lubiprostone and placebo , and 7 were not treated . Overall , the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo ( 27.1 vs. 18.9 % , respectively ; P=0.030 ) . Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo ( 3.2 vs. 2.4 , respectively ; P=0.001 ) . The median time to first SBM was significantly shorter with lubiprostone vs. placebo ( 23.5 vs. 37.7 h , respectively ; P=0.004 ) . Compared with placebo , the patients treated with lubiprostone exhibited significant improvements in straining ( P=0.004 ) , stool consistency ( P<0.001 ) , and constipation severity ( P=0.010 ) . No significant differences were observed in quality -of-life measures or the use of rescue medication ; however , the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 ( 34.9 vs. 37.7 % ) , 2 ( 23.4 vs. 26.6 % ) , and 3 ( 20.5 vs. 22.0 % ) . Adverse events ( AEs ) > 5 % were diarrhea , nausea , vomiting , and abdominal pain  ( lubiprostone : 11.3 , 9.9 , 4.2 , and 7.1 % , respectively ; placebo , 3.8 , 4.7 , 5.2 , and 0 % , respectively ) . None of the serious AEs ( lubiprostone , 3.3 % ; placebo , 2.8 % ) were related to lubiprostone . CONCLUSIONS : Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain Background Opioid-induced constipation ( OIC ) has negative effects on quality of life ( QOL ) . Prucalopride is a new , selective 5-HT4 agonist and enterokinetic with strong clinical data in chronic constipation . This study investigated the efficacy , safety , and tolerability of prucalopride in patients with noncancer pain and OIC . Methods A phase II , double-blind , placebo-controlled study of 196 patients r and omized to placebo ( n = 66 ) , prucalopride 2 mg ( n = 66 ) or 4 mg ( n = 64 ) , for 4 weeks , was carried out . The primary endpoint was the proportion of patients with increase from baseline of ≥1 spontaneous complete bowel movement (SCBM)/week . Secondary endpoints [ proportion of patients with ≥3 SCBM/week , weekly frequency of (SC)BM , severity of constipation , and efficacy of treatment ] , adverse events ( AEs ) , and safety parameters were also monitored . Results More patients had an increase from baseline of ≥1 SCBM per week ( weeks 1–4 ) in the prucalopride groups [ 35.9 % ( 2 mg ) and 40.3 % ( 4 mg ) ] versus placebo ( 23.4 % ) , reaching statistical significance in week 1 . Over weeks 1–4 , more patients in the prucalopride groups achieved an average of ≥3 SBM per week versus placebo ( 60.7 % and 69.0 % versus 43.3 % ) , reaching significance at week 1 . Prucalopride 4 mg significantly improved patient-rated severity of constipation and effectiveness of treatment versus placebo . Patient Assessment of Constipation-Symptom ( PAC-SYM ) total scores and Patient Assessment of Constipation- Quality of Life ( PAC-QOL ) total and satisfaction subscale scores were improved . The most common AEs were abdominal pain and nausea . There were no clinical ly relevant differences between groups in vital signs , laboratory measures or electrocardiogram parameters . Conclusion In this population with OIC , prucalopride improved bowel function and was safe and well tolerated BACKGROUND Subcutaneous methylnaltrexone , a peripherally acting μ-opioid receptor antagonist , improves opioid-induced constipation ( OIC ) in patients with chronic noncancer pain . An oral methylnaltrexone formulation has been developed . METHODS In this phase 3 , double-blind trial , adults with chronic noncancer pain receiving opioid doses of ≥ 50 mg/day oral morphine equivalents with OIC were r and omly assigned to oral methylnaltrexone ( 150 , 300 , or 450 mg ) or placebo once daily ( QD ) for 4 weeks followed by as-needed dosing for 8 weeks . Patients who had ≥ 3 rescue-free bowel movements (RFBMs)/week  , with an increase of ≥ 1 RFBM/week from baseline for ≥ 3 of 4 weeks during the QD period , were responders . RESULTS Overall , 803 patients were included in the analyses . A significantly greater percentage of patients had an increase in mean percentage of dosing days result ing in an RFBM within 4 hours of dosing during weeks 1 through 4 ( QD period ; primary endpoint ) with methylnaltrexone ( 300 mg/day [ 24.6 % ; P = 0.002 ] and 450 mg/day [ 27.4 % ; P < 0.0001 ] ) vs. placebo ( 18.2 % ) . The percentage of responders ( 49.3 % for 300 mg [ P = 0.03 ] and 51.5 % for 450 mg [ P = 0.005 ] vs. 38.3 % with placebo ) and change from baseline in mean number of weekly RFBMs ( difference vs. placebo , 0.5 for 300 mg [ P = 0.03 ] and 0.5 for 450 mg [ P = 0.02 ] ) was significantly greater with methylnaltrexone 300 and 450 mg/day vs. placebo during the QD period . All dosages of oral methylnaltrexone were well tolerated . CONCLUSIONS Oral methylnaltrexone was efficacious and well tolerated for OIC in patients with chronic noncancer pain , particularly the 450-mg dose Abstract Objective This study evaluated the efficacy and safety of oral naldemedine 0.1 mg , 0.2 mg , or 0.4 mg once daily in patients who had opioid-induced constipation ( OIC ) and maintained a stable laxative regimen . Methods This four-week , phase 2b , r and omized , double-blind placebo-controlled trial ( clinical trials.gov identifier NCT01443403 ) enrolled patients on long-term opioid therapy for chronic noncancer pain with OIC . The primary efficacy end point was change in weekly spontaneous bowel movement ( SBM ) frequency from baseline to the last two weeks of treatment . Secondary end points included the proportion of SBM responders ( patients with ≥3 SBMs/week and an increase of ≥1 SBM/week from baseline over the last 2 weeks of treatment ) . Safety parameters assessed included adverse events , effects on analgesia , and opioid withdrawal symptoms . Results Overall , 244 patients were r and omized 1:1:1:1  to naldemedine 0.1 mg , 0.2 mg , 0.4 mg , or placebo . Baseline patient characteristics were comparable . Weekly SBM frequency was significantly higher with naldemedine 0.2 mg ( 3.37 , P = 0.0014 ) and 0.4 mg ( 3.64 , P = 0.0003 ) , but not with 0.1 mg ( 1.98 , P = 0.3504 ) , vs placebo ( 1.42 ) . The proportion of SBM responders was significantly higher with naldemedine 0.2 mg ( 71.2 % , P = 0.0005 ) and 0.4 mg ( 66.7 % , P = 0.003 ) , but not with 0.1 mg ( 52.5 % , P = 0.1461 ) , vs placebo ( 39.3 % ) . Treatment-emergent adverse events were generally mild to moderate in severity ; incidences increased with naldemedine dose . No clinical ly meaningful changes in other safety parameters were observed . Conclusion Naldemedine 0.2 mg once daily is the optimal dose for future confirmatory trials in OIC BACKGROUND Opioid-induced constipation is common and debilitating . We investigated the efficacy and safety of naloxegol , an oral , peripherally acting , μ-opioid receptor antagonist , for the treatment of opioid-induced constipation . METHODS In two identical phase 3 , double-blind studies ( study 04 , 652 participants ; study 05 , 700 participants ) , out patients with noncancer pain and opioid-induced constipation were r and omly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo . The primary end point was the 12-week response rate ( ≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks ) in the intention-to-treat population . The key secondary end points were the response rate in the sub population of patients with an inadequate response to laxatives before enrollment , time to first postdose spontaneous bowel movement , and mean number of days per week with one or more spontaneous bowel movements . RESULTS Response rates were significantly higher with 25 mg of naloxegol than with placebo ( intention-to-treat population : study 04 , 44.4 % vs. 29.4 % , P=0.001 ; study 05 , 39.7 % vs. 29.3 % , P=0.02 ; patients with an inadequate response to laxatives : study 04 , 48.7 % vs. 28.8 % , P=0.002 ; study 05 , 46.8 % vs. 31.4 % , P=0.01 ) ; in study 04 , response rates were also higher in the group treated with 12.5 mg of naloxegol ( intention-to-treat population , 40.8 % vs. 29.4 % , P=0.02 ; patients with an inadequate response to laxatives , 42.6 % vs. 28.8 % , P=0.03 ) . A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies ( P<0.001 ) and with 12.5 mg of naloxegol in study 04 ( P<0.001 ) . Pain scores and daily opioid dose were similar among the three groups . Adverse events ( primarily gastrointestinal ) occurred most frequently in the groups treated with 25 mg of naloxegol . CONCLUSIONS Treatment with naloxegol , as compared with placebo , result ed in a significantly higher rate of treatment response , without reducing opioid-mediated analgesia . ( Funded by AstraZeneca ; KODIAC-04 and KODIAC-05 Clinical Trials.gov numbers , NCT01309841 and NCT01323790 , respectively . ) Methylnaltrexone , a peripheral mu-opioid receptor antagonist with restricted ability to cross the blood-brain barrier , may relieve  opioid-induced constipation ( OIC ) without reversing analgesia . A total of 154 patients with advanced illness and OIC enrolled in a double-blind , r and omized , placebo-controlled trial , with optional open-label phases ( up to 4 months ) in hospice and palliative care centers during 2003 - 2005 . They received a single subcutaneous injection of methylnaltrexone ( 0.15 mg/kg or 0.3 mg/kg ) or placebo . Laxation response within 4 hours was 62 % and 58 % for methylnaltrexone 0.15 mg/kg and 0.3 mg/kg , respectively , compared with 14 % for placebo ( P < 0.0001 ; each dose vs placebo ) . Approximately half of 
    Output:
    
In network meta- analysis , naloxone and naldemedine appear to be the most efficacious treatments for OIC .
Naloxone was the safest of these agents