{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T02:03:13Z","timestamp":1775354593774,"version":"3.50.1"},"reference-count":32,"publisher":"BMJ","issue":"2","funder":[{"DOI":"10.13039\/501100014337","name":"Menarini Group","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014337","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100014337","name":"Menarini Group","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014337","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2018,11,5]]},"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>To compare efficacy\/safety of oral tramadol 75\u2009mg\/dexketoprofen 25\u2009mg (TRAM\/DKP) and TRAM 75\u2009mg\/paracetamol 650\u2009mg (TRAM\/paracetamol) in moderate to severe pain following surgical removal of impacted lower third molar.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Multicentre, randomised, double-blind, placebo-controlled, phase IIIb study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>Healthy adult patients scheduled for surgical extraction of at least one fully\/partially impacted lower third molar requiring bone manipulation. 654 patients were randomised and 653 were eligible for analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Surgery was performed under local anaesthetic. No sedation was permitted. Patients rated pain intensity (PI) using an 11-Numerical Rating Scale (NRS) (0 no pain; 10 worst pain). Participants experiencing moderate\/severe pain (\u22654) within 4\u2009hours of surgery were randomised (2:2:1 ratio) to a single oral dose of TRAM\/DKP 75\/25\u2009mg, TRAM\/paracetamol 75\/650\u2009mg or placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main outcome measures<\/jats:title><jats:p>Efficacy was based patients\u2019 electronic diaries. Analgesia and pain were recorded as follows: pain relief (PAR) on a 5-point Verbal Rating Scale (0=\u2018no relief\u2019, 1=\u2018a little (perceptible) relief\u2019, 2=\u2018some (meaningful) relief\u2019, 3=\u2018lot of relief\u2019, 4=\u2018complete relief\u2019) at the predefined postdose time points t15 min, t30 min, t1 hour, t1.5 hour, t2 hour, t4 hour, t6 hour and t8 hour and PI on the 11-point NRS at t0 and at the same predefined postdose time points. Onset of analgesia documented using double stopwatch method over a 2-hour period. Primary endpoint was total pain relief over 6\u2009hours (TOTPAR6). Rescue medication was available during the treatment period.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TRAM\/DKP was superior to TRAM\/paracetamol and placebo at the primary endpoint TOTPAR6 (p&lt;0.0001). Mean (SD) TOTPAR6 in the TRAM\/DKP group was 13 (6.97), while those in the active control and placebo groups were 9.2 (7.65) and 1.9 (3.89), respectively. Superiority of TRAM\/DKP over active comparator and placebo was observed at all secondary endpoints. Incidence of adverse events was comparable between active groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>TRAM\/DKP (75\/25\u2009mg) is effective and superior to TRAM\/paracetamol (75\/650\u2009mg) in relieving moderate to severe acute pain following surgical removal of impacted lower third molar, with a faster onset of action, greater and durable analgesia, together with a favourable safety profile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p>EudraCT 2015-004152-22 and<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"NCT02777970\" ext-link-type=\"clintrialgov\">NCT02777970<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1136\/bmjopen-2018-023715","type":"journal-article","created":{"date-parts":[[2019,2,7]],"date-time":"2019-02-07T09:36:22Z","timestamp":1549532182000},"page":"e023715","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":47,"title":["Tramadol\/dexketoprofen (TRAM\/DKP) compared with tramadol\/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study)"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct02777970","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02777970","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Cosme","family":"Gay-Escoda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdi","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Montero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Milleri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Giergiel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T\u00f3th Bagi","family":"Zolt\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giustino","family":"Varrassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2019,2,6]]},"reference":[{"key":"2024051714022157000_9.2.e023715.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2015.12.008"},{"key":"2024051714022157000_9.2.e023715.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atc.2004.11.013"},{"key":"2024051714022157000_9.2.e023715.3","doi-asserted-by":"publisher","DOI":"10.3111\/13696998.2010.516709"},{"key":"2024051714022157000_9.2.e023715.4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jopan.2010.11.010","article-title":"Persistent postsurgical and posttrauma pain","volume":"26","author":"Pasero","year":"2011","journal-title":"Journal of PeriAnesthesia Nursing"},{"key":"2024051714022157000_9.2.e023715.5","first-page":"76","article-title":"Multimodal analgesia: its role in preventing postoperative pain","volume":"9","author":"White","year":"2008","journal-title":"Curr Opin Investig Drugs"},{"key":"2024051714022157000_9.2.e023715.6","doi-asserted-by":"crossref","first-page":"46S","DOI":"10.1002\/jcph.1998.38.s1.46","article-title":"Clinical comparison of dexketoprofen trometamol, ketoprofen, and placebo in postoperative dental pain","volume":"38","author":"McGurk","year":"1998","journal-title":"J Clin Pharmacol"},{"key":"2024051714022157000_9.2.e023715.7","first-page":"CD007355","article-title":"Single dose oral ketoprofen and dexketoprofen for acute post-operative pain in adults","volume":"7","author":"Barden","year":"2009","journal-title":"Cochrane Database Syst Rev"},{"key":"2024051714022157000_9.2.e023715.8","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1080\/03007995.2017.1310092","article-title":"Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol","volume":"33","author":"Varrassi","year":"2017","journal-title":"Curr Med Res Opin"},{"key":"2024051714022157000_9.2.e023715.9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2165\/00003495-199400471-00005","article-title":"Tramadol for the management of acute pain","volume":"47 Suppl 1","author":"Lehmann","year":"1994","journal-title":"Drugs"},{"key":"2024051714022157000_9.2.e023715.10","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200443130-00004"},{"key":"2024051714022157000_9.2.e023715.11","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1186\/s10194-015-0541-5","article-title":"Dexketoprofen\/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain","volume":"16","author":"Moore","year":"2015","journal-title":"J Headache Pain"},{"key":"2024051714022157000_9.2.e023715.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.09.002"},{"key":"2024051714022157000_9.2.e023715.13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12871-016-0174-5","article-title":"Dexketoprofen\/tramadol 25 mg\/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy","volume":"16","author":"Moore","year":"2016","journal-title":"BMC Anesthesiol"},{"key":"2024051714022157000_9.2.e023715.14","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aev457"},{"key":"2024051714022157000_9.2.e023715.15","first-page":"CD012232","article-title":"Single fixed-dose oral dexketoprofen plus tramadol for acute postoperative pain in adults","volume":"9","author":"Derry","year":"2016","journal-title":"Cochrane Database Syst Rev"},{"key":"2024051714022157000_9.2.e023715.16","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1358\/dot.2017.53.6.2636487","article-title":"Tramadol hydrochloride 75 mg\/dexketoprofen 25 mg oral fixed-dose combination in moderate-to-severe acute pain: sustained analgesic effect over a 56-h period in the postoperative setting","volume":"53","author":"Montero Matamala","year":"2017","journal-title":"Drugs Today"},{"key":"2024051714022157000_9.2.e023715.17","unstructured":"Skudexa SmPC. http:\/\/www.mhra.gov.uk\/home\/groups\/spcpil\/documents\/spcpil\/con1489125195346.pdf (Accessed May 2017)."},{"key":"2024051714022157000_9.2.e023715.18","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.semarthrit.2016.07.006","article-title":"Review of head-to-head study designs in rheumatoid arthritis","volume":"46","author":"R","year":"2016","journal-title":"Semin Arthritis Rheum"},{"key":"2024051714022157000_9.2.e023715.19","doi-asserted-by":"crossref","DOI":"10.1016\/S0140-6736(06)69615-3","article-title":"Indirect comparisons: the mesh and mess of clinical trials","volume":"368","author":"Ioannidis","year":"2006","journal-title":"Lancet"},{"key":"2024051714022157000_9.2.e023715.20","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-002-0491-0"},{"key":"2024051714022157000_9.2.e023715.21","doi-asserted-by":"crossref","first-page":"611","DOI":"10.14219\/jada.archive.2002.0237","article-title":"The analgesic efficacy of valdecoxib vs. oxycodone\/acetaminophen after oral surgery","volume":"133","author":"Daniels","year":"2002","journal-title":"J Am Dent Assoc"},{"key":"2024051714022157000_9.2.e023715.22","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aen103"},{"key":"2024051714022157000_9.2.e023715.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2009.03.017"},{"key":"2024051714022157000_9.2.e023715.24","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1097\/j.pain.0000000000000375","article-title":"Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations","volume":"157","author":"Cooper","year":"2016","journal-title":"Pain"},{"key":"2024051714022157000_9.2.e023715.25","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.pain.2004.01.004","article-title":"A double-blind placebo-controlled comparison of tramadol\/acetaminophen and tramadol in patients with postoperative dental pain","volume":"109","author":"Fricke","year":"2004","journal-title":"Pain"},{"key":"2024051714022157000_9.2.e023715.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2003.09.021"},{"key":"2024051714022157000_9.2.e023715.27","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.clinthera.2013.07.422","article-title":"Efficacy and speed of onset of pain relief of fast-dissolving paracetamol on postsurgical dental pain: two randomized, single-dose, double-blind, placebo-controlled clinical studies","volume":"35","author":"Yue","year":"2013","journal-title":"Clin Ther"},{"key":"2024051714022157000_9.2.e023715.28","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s10787-012-0121-0","article-title":"Evaluation of onset of pain relief from micronized aspirin in a dental pain model","volume":"20","author":"Cooper","year":"2012","journal-title":"Inflammopharmacology"},{"key":"2024051714022157000_9.2.e023715.29","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1586\/14737175.8.11.1625","article-title":"Dexketoprofen trometamol: clinical evidence supporting its role as a painkiller","volume":"8","author":"Rodr\u00edguez","year":"2008","journal-title":"Expert Rev Neurother"},{"key":"2024051714022157000_9.2.e023715.30","doi-asserted-by":"crossref","first-page":"e124","DOI":"10.1016\/j.clinthera.2015.05.353","article-title":"Pharmacokinetics of Dexketoprofen and tramadol given in combination: an open-label, randomized, 3-period crossover study in Healthy subjects","volume":"37","author":"Mazzei","year":"2015","journal-title":"Clin Ther"},{"key":"2024051714022157000_9.2.e023715.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2005.09.009"},{"key":"2024051714022157000_9.2.e023715.32","doi-asserted-by":"publisher","DOI":"10.1097\/00045391-200501000-00008"}],"updated-by":[{"DOI":"10.1136\/bmjopen-2018-023715corr1","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T00:00:00Z","timestamp":1560470400000}}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2018-023715","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T00:17:03Z","timestamp":1715991423000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2018-023715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2]]},"references-count":32,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1136\/bmjopen-2018-023715"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2018-023715","relation":{"correction":[{"id-type":"doi","id":"10.1136\/bmjopen-2018-023715corr1","asserted-by":"object"}]},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2]]}}}