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Rep"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Magnesium ions (Mg<jats:sup>2+<\/jats:sup>) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg<jats:sup>2+<\/jats:sup> alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Tramadol was administered to healthy Caucasian subjects with and without Mg<jats:sup>2+<\/jats:sup> as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg<jats:sup>2+<\/jats:sup> was administered orally at doses of 150\u00a0mg and 75\u00a0mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for C<jats:sub>max<\/jats:sub> and AUC<jats:sub>0-t<\/jats:sub> geometric mean ratios for tramadol were 91.95\u2013102.40% and 93.22\u2013102.76%. The 90% confidence intervals for C<jats:sub>max,ss<\/jats:sub> and AUC<jats:sub>0-\u03c4<\/jats:sub> geometric mean ratios for tramadol were 93.85\u2013103.31% and 99.04\u2013105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p\u2009&gt;\u20090.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg<jats:sup>2+<\/jats:sup>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The absence of Mg<jats:sup>2+<\/jats:sup> interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphic abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s43440-021-00239-x","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T17:02:52Z","timestamp":1615222972000},"page":"604-614","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies"],"prefix":"10.1007","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-4849","authenticated-orcid":false,"given":"Piotr J.","family":"Rudzki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarzyna","family":"Jarus-Dziedzic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Filist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edyta","family":"Gilant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4484-7142","authenticated-orcid":false,"given":"Katarzyna","family":"Bu\u015b-Kwa\u015bnik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrzej","family":"Le\u015b","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0142gorzata","family":"Sasinowska-Motyl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u0141ukasz","family":"Nagraba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4270-6373","authenticated-orcid":false,"given":"Magdalena","family":"Bujalska-Zadro\u017cny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"239_CR1","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s40122-017-0091-4","volume":"6","author":"D Fornasari","year":"2017","unstructured":"Fornasari D. 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