{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:11:39Z","timestamp":1790194299961,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small\u2010peptidic structure limits CNS entry, minimizing potential CNS\u2010mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single\u2010center, randomized, double\u2010blind, placebo\u2010controlled, three\u2010way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg\/kg i.v.) or placebo on sequential days with an intervening 24 (\u00b12) h washout period. The primary end points included incidence of increased end\u2010tidal carbon dioxide (ETCO<jats:sub>2<\/jats:sub>) greater than or equal to 10\u00a0mm Hg versus baseline or a level greater than 50\u00a0mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO<jats:sub>2<\/jats:sub>) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO<jats:sub>2<\/jats:sub>or reduced SpO<jats:sub>2<\/jats:sub>primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4\u2010h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO<jats:sub>2<\/jats:sub>, SpO<jats:sub>2<\/jats:sub>, or respiratory rate. The most commonly reported treatment\u2010emergent AEs (TEAEs; \u226520% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg\/kg i.v. did not produce respiratory depression.<\/jats:p>","DOI":"10.1111\/cts.13042","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T08:27:15Z","timestamp":1620894435000},"page":"1886-1893","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Effect of difelikefalin, a selective kappa opioid receptor agonist, on respiratory depression<b>:<\/b>A randomized, double\u2010blind, placebo\u2010controlled trial"],"prefix":"10.1111","volume":"14","author":[{"given":"Eugene R.","family":"Viscusi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc C.","family":"Torjman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Munera","sequence":"additional","affiliation":[{"name":"Cara Therapeutics Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph W.","family":"Stauffer","sequence":"additional","affiliation":[{"name":"Cara Therapeutics Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice S.","family":"Setnik","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Toronto Toronto Ontario Canada"},{"name":"Altasciences Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukirti N.","family":"Bagal","sequence":"additional","affiliation":[{"name":"Cara Therapeutics Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(95)80024-V"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0168-0102(95)00933-K"},{"key":"e_1_2_10_4_1","first-page":"69","article-title":"Opioid receptors on peripheral sensory neurons","volume":"521","author":"Stein C","year":"2003","journal-title":"Adv Exp Med Biol"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2340\/00015555-1353"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318238bba6"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-010-1819-6"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161212803582469"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.2217\/pmt.14.19"},{"key":"e_1_2_10_10_1","volume-title":"Drug Poisoning Deaths in the United States, 1980\u20102008","author":"Warner M","year":"2011"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/AJP.0b013e3181c49e3a"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002130100788"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2011.07.007"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12404"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2015.01.340"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2015.01.341"},{"key":"e_1_2_10_17_1","unstructured":"JonesJB MenzaghiF O\u2019ConnorSJ SpencerRH ChalmersDT.Analgesic and morphine\u2010sparing effects of the peripherally\u2010restricted kappa opioid agonist CR845 after intravenous administration in women undergoing a laparoscopic hysterectomy [poster PT 426]. Presented at: Biennial World Congress on Pain; August 27\u201031 2012; Milan Italy."},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1197\/j.aem.2005.12.017"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912770"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2020.01.006"},{"key":"e_1_2_10_21_1","unstructured":"SpencerRH MathurVS TumlinJA StaufferJW MenzaghiF.CR845 a novel kappa opioid receptor agonist reduces moderate\u2010to\u2010severe pruritus and improves quality of life in chronic kidney disease patients undergoing hemodialysis [poster SA\u2010PO1117]. Presented at: Annual Meeting of the American Society of Nephrology; November 5\u20108 2015; San Diego CA."},{"key":"e_1_2_10_22_1","unstructured":"O\u2019ConnorS.CR845: Novel peripherally acting kappa opioid receptor agonist for the treatment of pain and pruritus [oral presentation]. Presented at: Boulder Peptide Symposium; September 27 2016; Boulder CO."},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1481803500012549"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.4187\/respcare.04919"},{"key":"e_1_2_10_25_1","unstructured":"O\u2019ConnorS LabissiereG SpencerR ChalmersD MenzaghiF.Safety pharmacokinetic and pharmacodynamic profile of CR845 a novel peptidergic kappa opioid agonist in development for the treatment of acute pain and itch [poster PT371]. Presented at: Biennial World Congress on Pain; August 28\u2010September 2 2010;Montreal QC Canada."},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03012664"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1213\/00000539-199212000-00015"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aeh180"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1213\/01.ane.0000269489.26048.63"},{"issue":"3","key":"e_1_2_10_30_1","first-page":"126","article-title":"Clinical perspectives on capnography during sedation and general anesthesia in dentistry","volume":"42","author":"Kaneko Y","year":"1995","journal-title":"Anesth Prog"},{"key":"e_1_2_10_31_1","first-page":"S96","article-title":"CR845, a peripheral kappa opioid, provides better pain relief with less nausea and vomiting than placebo in patients after bunionectomy [abstract]","volume":"127","author":"Stauffer JW","year":"2015","journal-title":"Postgrad Med"},{"key":"e_1_2_10_32_1","first-page":"S97","article-title":"Analgesic efficacy of the peripheral kappa\u2010opioid agonist CR845 in laparoscopic hysterectomy [abstract]","volume":"127","author":"Stauffer JW","year":"2015","journal-title":"Postgrad Med"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1681\/ASN.20203110S122d","article-title":"Efficacy and safety of difelikefalin for moderate\u2010to\u2010severe CKD\u2013associated pruritus: a global phase 3 study in hemodialysis patients (KALM\u20102) [abstract FR\u2010OR24]","volume":"31","author":"Wooldridge TD","year":"2020","journal-title":"J Am Soc Nephrol"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13042","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.13042","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13042","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T20:14:52Z","timestamp":1725048892000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":32,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["10.1111\/cts.13042"],"URL":"https:\/\/doi.org\/10.1111\/cts.13042","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,21]]},"assertion":[{"value":"2020-11-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}