{"markup":"\u003C?xml version=\u00221.0\u0022 encoding=\u0022UTF-8\u0022 ?\u003E\n    \u003Chtml version=\u0022HTML+RDFa+MathML 1.1\u0022\n    xmlns:content=\u0022http:\/\/purl.org\/rss\/1.0\/modules\/content\/\u0022\n    xmlns:dc=\u0022http:\/\/purl.org\/dc\/terms\/\u0022\n    xmlns:foaf=\u0022http:\/\/xmlns.com\/foaf\/0.1\/\u0022\n    xmlns:og=\u0022http:\/\/ogp.me\/ns#\u0022\n    xmlns:rdfs=\u0022http:\/\/www.w3.org\/2000\/01\/rdf-schema#\u0022\n    xmlns:sioc=\u0022http:\/\/rdfs.org\/sioc\/ns#\u0022\n    xmlns:sioct=\u0022http:\/\/rdfs.org\/sioc\/types#\u0022\n    xmlns:skos=\u0022http:\/\/www.w3.org\/2004\/02\/skos\/core#\u0022\n    xmlns:xsd=\u0022http:\/\/www.w3.org\/2001\/XMLSchema#\u0022\n    xmlns:mml=\u0022http:\/\/www.w3.org\/1998\/Math\/MathML\u0022\u003E\n  \u003Chead\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_itu2PgFdrjV-docKmLK8Jn5oXe_05RgvQh73eOhI_mE.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_at_symbol.js?nzlhap\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_article_reference_popup.js?nzlhap\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_I8yX6RYPZb7AtMcDUA3QKDZqVkvEn35ED11_1i7vVpc.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\n(function(i,s,o,g,r,a,m){i[\u0022GoogleAnalyticsObject\u0022]=r;i[r]=i[r]||function(){(i[r].q=i[r].q||[]).push(arguments)},i[r].l=1*new Date();a=s.createElement(o),m=s.getElementsByTagName(o)[0];a.async=1;a.src=g;m.parentNode.insertBefore(a,m)})(window,document,\u0022script\u0022,\u0022\/\/www.google-analytics.com\/analytics.js\u0022,\u0022ga\u0022);ga(\u0022create\u0022, \u0022UA-15605596-27\u0022, {\u0022cookieDomain\u0022:\u0022auto\u0022});ga(\u0022set\u0022, \u0022page\u0022, location.pathname + location.search + location.hash);ga(\u0022send\u0022, \u0022pageview\u0022);ga(\u0027create\u0027, \u0027UA-189672-26\u0027, \u0027auto\u0027, {\u0027name\u0027: \u0027hwTracker\u0027});\r\nga(\u0027hwTracker.send\u0027, \u0027pageview\u0027);\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\njQuery.extend(Drupal.settings, {\u0022basePath\u0022:\u0022\\\/\u0022,\u0022pathPrefix\u0022:\u0022\u0022,\u0022highwire\u0022:{\u0022markup\u0022:[{\u0022requested\u0022:\u0022full-text\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;15\\\/14\\\/11\u0022},{\u0022requested\u0022:\u0022long\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;15\\\/14\\\/11\u0022}],\u0022ac\u0022:{\u0022spmdc;15\\\/14\\\/11\u0022:{\u0022access\u0022:{\u0022reprint\u0022:true,\u0022full\u0022:true},\u0022pisa_id\u0022:\u0022spmdc;15\\\/14\\\/11\u0022,\u0022atom_uri\u0022:\u0022\u0022,\u0022jcode\u0022:\u0022spmdc\u0022}}},\u0022googleanalytics\u0022:{\u0022trackOutbound\u0022:1,\u0022trackMailto\u0022:1,\u0022trackDownload\u0022:1,\u0022trackDownloadExtensions\u0022:\u00227z|aac|arc|arj|asf|asx|avi|bin|csv|doc(x|m)?|dot(x|m)?|exe|flv|gif|gz|gzip|hqx|jar|jpe?g|js|mp(2|3|4|e?g)|mov(ie)?|msi|msp|pdf|phps|png|ppt(x|m)?|pot(x|m)?|pps(x|m)?|ppam|sld(x|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip\u0022,\u0022trackUrlFragments\u0022:1},\u0022ajaxPageState\u0022:{\u0022js\u0022:{\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/jquery.cluetip.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.hoverIntent.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.bgiframe.min.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_at_symbol.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_article_reference_popup.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/contrib\\\/google_analytics\\\/googleanalytics.js\u0022:1,\u00220\u0022:1}}});\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\u003Cp id=\u0022p-1\u0022\u003EA phase 2b randomized, double-blind, placebo-controlled study shows that naldemedine, a peripherally acting \u00b5-opioid receptor antagonist, is effective in easing opioid-induced constipation compared to placebo. Phase 3 development is expected for the 0.2 mg\/day naldemedine dose.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Enaldemedine\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Econstipation\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eopioids\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Enoncancer pain\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Espontaneous bowel movements\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Egastroenterology clinical trials\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Cp id=\u0022p-2\u0022\u003EAs described by Lynn Webster, MD, PRA Health Sciences, Salt Lake City, Utah, USA, a phase 2b, randomized, double-blind, placebo-controlled study revealed the benefit of naldemedine in easing constipation due to opioids given for relief of chronic noncancer pain.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe use of opioids for relief of noncancer pain has increased substantially over the last 20 years [Chou R et al. \u003Cem\u003EJ Pain\u003C\/em\u003E. 2009], but opioids can often result in constipation. Laxatives are a common recourse, but evidence for their effectiveness is scant and, in many patients, they do not provide satisfactory relief [Camilleri M et al. \u003Cem\u003ENeurogastroenterol Motil\u003C\/em\u003E. 2014].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThis trial evaluated naldemedine, a peripherally acting \u00b5-opioid receptor antagonist that has been developed specifically for the relief of opioid-induced constipation. Patients meeting the enrollment criteria (n\u2005=\u2005244) were randomized 1:1:1:1 (n\u2005=\u200561 for each group) to placebo or naldemedine 0.1, 0.2, or 0.4 mg\/day. The primary efficacy end point was the mean change in the frequency of spontaneous bowel movements (SBMs) from the last 2 weeks of screening to the last 2 weeks of the up-to 28-day treatment period. Safety was also assessed.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EReported results represented patients in the modified intention-to-treat population who were assessed at least once (naldemedine 0.1 mg\/d [n\u2005=\u200561], 0.2 mg\/d [n\u2005=\u200559], and 0.4 mg\/d [n\u2005=\u200557]). Patients in each of the 4 study arms were comparable at baseline in terms of age, sex, body mass index, weekly frequency of SBMs, and daily opioid dose. Naldemedine was rapidly absorbed and displayed a half-life that was compatible with once-daily use.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EIn the primary efficacy end point, naldemedine 0.2 and 0.4 mg\/d produced significant differences in SBMs (3.37 and 3.64) compared with placebo (1.42; \u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.0014 and \u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.0003, respectively). Improvement was also evident for naldemedine 0.1 mg\/d (1.98), but it was not significantly different from the placebo arm (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/14\/11\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Primary Efficacy End PointModified intention-to-treat population: all randomized patients who received study drug had \u0026#x2265;\u0026#x2005;1 postdose primary efficacy assessment completed.LS, least squares; SBM, spontaneous bowel movement.*P\u0026#x2005;=\u0026#x2005;.0014 vs placebo; **P\u0026#x2005;=\u0026#x2005;.0003 vs placebo and P\u0026#x2005;=\u0026#x2005;.6657 vs 0.2 mg (analysis of covariance with treatment group as a term and baseline value as a covariate).Reproduced with permission from L Webster, MD.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1631797530\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Primary Efficacy End PointModified intention-to-treat population: all randomized patients who received study drug had \u0026#x2265;\u0026#x2005;1 postdose primary efficacy assessment completed.LS, least squares; SBM, spontaneous bowel movement.*\u0026amp;lt;em\u0026amp;gt;P\u0026amp;lt;\/em\u0026amp;gt;\u0026#x2005;=\u0026#x2005;.0014 vs placebo; **\u0026amp;lt;em\u0026amp;gt;P\u0026amp;lt;\/em\u0026amp;gt;\u0026#x2005;=\u0026#x2005;.0003 vs placebo and \u0026amp;lt;em\u0026amp;gt;P\u0026amp;lt;\/em\u0026amp;gt;\u0026#x2005;=\u0026#x2005;.6657 vs 0.2 mg (analysis of covariance with treatment group as a term and baseline value as a covariate).Reproduced with permission from L Webster, MD.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/14\/11\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/14\/11\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/15\/14\/11\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/16779\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003EPrimary Efficacy End Point\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EModified intention-to-treat population: all randomized patients who received study drug had \u2265\u20051 postdose primary efficacy assessment completed.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003ELS, least squares; SBM, spontaneous bowel movement.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003E*\u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.0014 vs placebo; **\u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.0003 vs placebo and \u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.6657 vs 0.2 mg (analysis of covariance with treatment group as a term and baseline value as a covariate).\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EReproduced with permission from L Webster, MD.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EA similar pattern was apparent for the secondary end point of SBM response rate (39.3%, 52.5%, 71.2%, and 66.7% for placebo, naldemedine 0.1, 0.2, and 0.4 mg\/day, respectively; \u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.0005 and \u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.003 for naldemedine 0.2 and 0.4 mg\/d, respectively). SBM frequency was significantly increased by naldemedine 0.2 and 0.4 mg\/d by the first week of treatment and maintained through week 4 (\u003Cem\u003EP\u003C\/em\u003E\u2005\u0026lt;\u2005.005 for both doses). Analyses of other secondary end points, such as relief of abdominal bloating and abdominal discomfort, as well as patient satisfaction, favored naldemedine, especially at 0.2 and 0.4 mg\/d.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003ETreatment-emergent adverse events that developed occurred with similar frequency in the 4 trial arms. The incidence of gastrointestinal adverse events was greater in patients who were randomized to naldemedine (13.1%, 21.3%, 25.0%, and 34.4% in placebo and naldemedine 0.1, 0.2, and 0.4 mg\/d, respectively).\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003ENaldemedine treatment did not compromise the effectiveness of opioid pain relief, with no changes evident in pain scores or evidence of opioid withdrawal. The patterns over the 4-week trial were very similar in all 4 trial arms.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/15\/14\/11.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzlhap\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzlhap\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}