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Participants undertook an incremental symptom-limited treadmill test followed by five endurance treadmill tests at 75% of their maximal work rate; two tests for familiarisation and three tests 30\u2005min after intravenous injection of either methylnaltrexone 0.3\u2005mg\u00b7kg<jats:sup>\u22121<\/jats:sup>(blocking peripheral opioid receptors only) or naloxone 0.1\u2005mg\u00b7kg<jats:sup>\u22121<\/jats:sup>(blocking both central and peripheral opioid receptors) or normal saline, in randomised order. The primary end-point was the regression slope between breathlessness intensity (0\u201310 numerical rating scale) and oxygen consumption (<jats:italic>V<\/jats:italic>\u2032<jats:sub>O<jats:sub>2<\/jats:sub><\/jats:sub>) during the walk tests, comparing methylnaltrexone and placebo using a paired t-test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>17 participants completed the trial: median (range) 66 (55\u201382) years; 15 males; mean\u00b1<jats:sc>sd<\/jats:sc>forced expiratory volume (FEV<jats:sub>1<\/jats:sub>) 53.8\u00b117.6% predicted; FEV<jats:sub>1<\/jats:sub>\/forced vital capacity ratio 0.55\u00b115.9. There was no statistically or clinically significant difference in the primary end-point (regression slope of breathlessness intensity and<jats:italic>V<\/jats:italic>\u2032<jats:sub>O<jats:sub>2<\/jats:sub><\/jats:sub>) for methylnaltrexone (p=0.498) or naloxone (p=0.804), compared to placebo. Secondary outcomes were similar between the three treatment groups, including peak and mean breathlessness intensity and unpleasantness, exercise capacity, endurance time and leg fatigue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Answer to the question<\/jats:title><jats:p>Blocking peripheral opioid receptors (methylnaltrexone) or peripheral and central opioid receptors (naloxone) did not appear to modulate breathlessness intensity nor exercise capacity when compared with placebo (no blockade).<\/jats:p><\/jats:sec>","DOI":"10.1183\/23120541.00153-2019","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T13:55:15Z","timestamp":1577109315000},"page":"00153-2019","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Isolating peripheral effects of endogenous opioids in modulating exertional breathlessness in people with moderate or severe COPD: a randomised controlled trial"],"prefix":"10.1183","volume":"5","author":[{"given":"David C.","family":"Currow","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toby","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Louw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3503-2363","authenticated-orcid":false,"given":"Danny","family":"Eckert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Allcroft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim H.M.","family":"To","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aine","family":"Greene","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malgorzata","family":"Krajnik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Don","family":"Mahler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magnus","family":"Ekstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"81","published-online":{"date-parts":[[2019,12,23]]},"reference":[{"key":"2024101707274361000_5.4.00153-2019.1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02277-2016"},{"key":"2024101707274361000_5.4.00153-2019.2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00092613"},{"key":"2024101707274361000_5.4.00153-2019.3","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00079-2018"},{"key":"2024101707274361000_5.4.00153-2019.4","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201501-034OC"},{"key":"2024101707274361000_5.4.00153-2019.5","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2016-209868"},{"key":"2024101707274361000_5.4.00153-2019.6","doi-asserted-by":"publisher","DOI":"10.1378\/chest.12-1541"},{"key":"2024101707274361000_5.4.00153-2019.7","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00145208"},{"key":"2024101707274361000_5.4.00153-2019.8","doi-asserted-by":"publisher","DOI":"10.3109\/15412555.2011.560132"},{"key":"2024101707274361000_5.4.00153-2019.9","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100164"},{"key":"2024101707274361000_5.4.00153-2019.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(97)00050-9"},{"key":"2024101707274361000_5.4.00153-2019.11","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-152-11-201006010-00232"},{"key":"2024101707274361000_5.4.00153-2019.12","unstructured":"Global Initiative for Chronic Obstructive Lung Disease (GOLD). 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