{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:57:22Z","timestamp":1785308242238,"version":"3.55.0"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pain Practice"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Celecoxib\u2010tramadol co\u2010crystal (CTC) is a first\u2010in\u2010class analgesic co\u2010crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co\u2010crystal structure, compared with its active constituents administered alone\/concomitantly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>We evaluated CTC in moderate\u2010to\u2010severe acute postoperative pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>This randomized, double\u2010blind, factorial, active\u2010 and placebo\u2010controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate\u2010to\u2010severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib\/88 mg rac\u2010tramadol hydrochloride] every 12\u00a0h), tramadol (50 mg every 6\u00a0h), celecoxib (100 mg every 12\u00a0h), or placebo for 48\u00a0h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0\u201348\u00a0h sum of pain intensity differences (SPID0\u201348) in all randomized patients. Pain intensity was assessed on a 0\u201310 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n\u00a0=\u00a0184), tramadol (n\u00a0=\u00a0183), celecoxib (n\u00a0=\u00a0181), or placebo (n\u00a0=\u00a089). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0\u201348 (least\u2010squares mean: \u2212139.1 [95% confidence interval: \u2212151.8, \u2212126.5]) than tramadol (\u2212109.1 [\u2212121.7, \u221296.4]; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001), celecoxib (\u2212103.7 [\u2212116.4, \u221291.0]; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001), or placebo (\u221274.6 [\u221292.5, \u221256.6]; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001). Total treatment\u2010emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug\u2010related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs\/deaths.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.<\/jats:p><\/jats:sec>","DOI":"10.1111\/papr.13136","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T07:19:06Z","timestamp":1654845546000},"page":"8-22","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Celecoxib\u2010tramadol co\u2010crystal in patients with moderate\u2010to\u2010severe pain following bunionectomy with osteotomy: A phase 3, randomized, double\u2010blind, factorial, active\u2010 and placebo\u2010controlled trial"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0260-4396","authenticated-orcid":false,"given":"Eugene R.","family":"Viscusi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Sidney Kimmel Medical College, Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0837-9196","authenticated-orcid":false,"given":"Oscar","family":"de Leon\u2010Casasola","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Buffalo\/Roswell Park Cancer Institute  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0238-8638","authenticated-orcid":false,"given":"Jes\u00fas","family":"Cebrecos","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2792-3166","authenticated-orcid":false,"given":"Adam","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Premier Research  Reading UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3897-8966","authenticated-orcid":false,"given":"Adelaida","family":"Morte","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7271-1141","authenticated-orcid":false,"given":"Esther","family":"Ortiz","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1908-9271","authenticated-orcid":false,"given":"Mariano","family":"Sust","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9799-4619","authenticated-orcid":false,"given":"Anna","family":"Vaqu\u00e9","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira","family":"Gottlieb","sequence":"additional","affiliation":[{"name":"Chesapeake Research Group LLC  Pasadena Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Daniels","sequence":"additional","affiliation":[{"name":"Optimal Research LLC  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Gimbel","sequence":"additional","affiliation":[{"name":"Arizona Research Center  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Muse","sequence":"additional","affiliation":[{"name":"JBR Clinical Research  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Winkle","sequence":"additional","affiliation":[{"name":"Anaheim Clinical Trials LLC  Anaheim California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael\u00a0E.","family":"Kuss","sequence":"additional","affiliation":[{"name":"Premier Research  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5049-1379","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Videla","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7694-1796","authenticated-orcid":false,"given":"Neus","family":"Gasc\u00f3n","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Plata\u2010Salam\u00e1n","sequence":"additional","affiliation":[{"name":"ESTEVE Pharmaceuticals S.A  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"FDA.US Food and Drug Administration. Prescribing information SEGLENTIS.2021. Available at:https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/213426s000lbl.pdf. Accessed November 9 2021."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S208082"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2019.1612557"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.cgd.6b01848"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.cgd.9b00008"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2021.04.002"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13395"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13428"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-018-0672-y"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-018-0491-9"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2019.00704"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/1178221820930006"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-8180(97)00147-5"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2346.1998.0233a.x"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.5812\/aapm.119156"},{"key":"e_1_2_10_17_1","unstructured":"United States Drug Enforcement Administration.Drug scheduling. Available at:https:\/\/www.dea.gov\/drug\u2010scheduling. Accessed January 19 2021."},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-018-0235-y"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.09.002"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000375"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/PR9.0000000000000647"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2017.0504"},{"key":"e_1_2_10_23_1","unstructured":"World Health Organization.Tramadol: update review report. 2014. Available at:https:\/\/www.who.int\/medicines\/areas\/quality_safety\/6_1_Update.pdf. Accessed December 18 2020."},{"key":"e_1_2_10_24_1","unstructured":"Centers for Disease Control and Prevention.Calculating total daily dose of opioids for safer dosage. 2016. Available at:https:\/\/www.cdc.gov\/drugoverdose\/pdf\/calculating_total_daily_dose\u2010a.pdf. Accessed January 19 2021."},{"key":"e_1_2_10_25_1","unstructured":"Centers for Disease Control and Prevention National Center for Injury Prevention and Control.Compilation of benzodiazepines muscle relaxants stimulants zolpidem and opioid analgesics with oral morphine milligram equivalent conversion factors 2016 version.2016. Available at:https:\/\/www.cdc.gov\/drugoverdose\/resources\/data.html. Accessed January 19 2021."},{"issue":"1382","key":"e_1_2_10_26_1","first-page":"e1","article-title":"Tramadol: understanding the risk of serotonin syndrome and seizures","volume":"131","author":"Hassamal S","year":"2018","journal-title":"Am J Med"},{"key":"e_1_2_10_27_1","unstructured":"FDA.US Food and Drug Administration. Prescribing information CELEBREX.2021. Available at:https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/020998s056lbl.pdf. Accessed June 23 2022."},{"key":"e_1_2_10_28_1","unstructured":"FDA.US Food and Drug Administration. Prescribing information ULTRAM.2021. Available at:https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/020281s049lbl.pdf. Accessed June 23 2022."},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050405"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611593"}],"updated-by":[{"DOI":"10.1111\/papr.13376","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,4,21]],"date-time":"2024-04-21T00:00:00Z","timestamp":1713657600000}}],"container-title":["Pain Practice"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/papr.13136","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/papr.13136","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/papr.13136","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T09:44:53Z","timestamp":1692438293000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/papr.13136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":29,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1]]}},"alternative-id":["10.1111\/papr.13136"],"URL":"https:\/\/doi.org\/10.1111\/papr.13136","archive":["Portico"],"relation":{"correction":[{"id-type":"doi","id":"10.1111\/papr.13376","asserted-by":"object"}]},"ISSN":["1530-7085","1533-2500"],"issn-type":[{"value":"1530-7085","type":"print"},{"value":"1533-2500","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,8]]},"assertion":[{"value":"2022-07-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}