{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T10:23:38Z","timestamp":1760955818655},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,5,18]],"date-time":"2018-05-18T00:00:00Z","timestamp":1526601600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Janssen Scientific Affairs, LLC"},{"name":"Valeant Pharmaceuticals International Inc"},{"name":"Cipher Pharmaceuticals Inc"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18\u201055\u00a0years) in a randomized, phase I, double\u2010blind, placebo\u2010 and positive\u2010controlled, multiple\u2010dose, 4\u2010way crossover study. Participants were randomized to receive 1 of 4 treatments (A\u2010D), 1 each in 4 treatment periods (1\u20104), separated by a washout period (7\u201015\u00a0days). Treatment A comprised tramadol 400\u00a0mg (therapeutic dose) on days 1 through 3, tramadol 100\u00a0mg and moxifloxacin\u2010matched placebo on day 4, and placebo on all 4\u00a0days. Treatment B comprised tramadol 600\u00a0mg (supratherapeutic dose) on days 1 through 3, and tramadol 150\u00a0mg and moxifloxacin\u2010matched placebo on day 4. Treatment C comprised placebo on days 1 through 4 and moxifloxacin\u2010matched placebo on day 4. Treatment D comprised placebo on days 1 through 4 and moxifloxacin 400\u00a0mg on day 4. Of 68 participants enrolled, 57 (83.8%) completed the study. Both therapeutic and supratherapeutic doses of tramadol were shown to be noninferior to placebo regarding their effect on QTc prolongation. Sixty\u2010one of 68 (89.7%) participants reported at least 1 treatment\u2010emergent adverse event (mild); nausea was the most frequently reported treatment\u2010emergent adverse event. Summarizing, tramadol at doses up to 600\u00a0mg\/day did not cause clinically relevant QTc interval prolongation in healthy adults.<\/jats:p>","DOI":"10.1002\/cpdd.473","type":"journal-article","created":{"date-parts":[[2018,5,18]],"date-time":"2018-05-18T13:46:26Z","timestamp":1526651186000},"page":"95-106","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Tramadol Hydrochloride at Steady State Lacks Clinically Relevant QTc Interval Increases in Healthy Adults"],"prefix":"10.1002","volume":"8","author":[{"given":"Joseph","family":"Massarella","sequence":"first","affiliation":[{"name":"Janssen Research &amp; Development LLC  Raritan NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Ariyawansa","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development LLC  Raritan NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaya","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development LLC  Raritan NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Francke","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development LLC  Spring House PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Murtaugh","sequence":"additional","affiliation":[{"name":"Quintiles Phase I Services  Overland Park KS USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byron","family":"DeLemos","sequence":"additional","affiliation":[{"name":"Janssen Scientific Affairs LLC  Titusville NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subusola","family":"Vaughan","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development LLC  Titusville NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development LLC  Titusville NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,5,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2004.11.055"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00380-013-0456-5"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/pme.12915"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.89.11.1363"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1185\/03007995.2013.840568"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2008.05.009"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.038240"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03327.x"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2011.576250"},{"issue":"4","key":"e_1_2_11_11_1","first-page":"395","article-title":"Tramadol, pharmacology, side effects, and serotonin syndrome: a review","volume":"18","author":"Beakley BD","year":"2015","journal-title":"Pain Physician"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2015.01.022"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/MJT.0b013e31815b035b"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200443130-00004"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498250110113230"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.584"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002100000266"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03256239"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2044.2007.05360_1.x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1213\/01.ane.0000189613.61910.32"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1734-1140(09)70159-8"},{"issue":"3","key":"e_1_2_11_22_1","first-page":"152","article-title":"Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms","volume":"113","author":"Slanar O","year":"2012","journal-title":"Bratisl Lek Listy"},{"issue":"3","key":"e_1_2_11_23_1","first-page":"391","article-title":"The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects","volume":"76","author":"Lynch T","year":"2007","journal-title":"Am Fam Physician"},{"key":"e_1_2_11_24_1","unstructured":"Guidance for industry. 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