{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:36:57Z","timestamp":1777941417515,"version":"3.51.4"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2004,10,4]],"date-time":"2004-10-04T00:00:00Z","timestamp":1096848000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Clin Pharmacol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Background<\/jats:title>\n                        <jats:p>The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean\/SD) \u00d7100).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>The patients' median morphine doses were 90 (range; 20\u20131460) mg\/24 h and 135 (range; 30\u2013440) mg\/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/1472-6904-4-7","type":"journal-article","created":{"date-parts":[[2004,10,8]],"date-time":"2004-10-08T06:24:20Z","timestamp":1097216660000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study"],"prefix":"10.1186","volume":"4","author":[{"given":"P\u00e5l","family":"Klepstad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priscilla","family":"Hilton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorunn","family":"Moen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stein","family":"Kaasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petter C","family":"Borchgrevink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kolbj\u00f8rn","family":"Zahlsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ola","family":"Dale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2004,10,4]]},"reference":[{"key":"23_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/00007691-199101000-00001","volume":"13","author":"PA Glare","year":"1991","unstructured":"Glare PA, Walsh TD: Clinical pharmacokinetics of morphine. Ther Drug Monit. 1991, 13: 1-23.","journal-title":"Ther Drug Monit"},{"key":"23_CR2","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/clpt.1992.42","volume":"51","author":"RK Portenoy","year":"1992","unstructured":"Portenoy RK, Thaler HT, Inturrisi CE, Friedlander-Klar H, Foley KM: The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clin Pharmacol Ther. 1992, 51: 422-31.","journal-title":"Clin Pharmacol Ther"},{"key":"23_CR3","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1007\/s002280050003","volume":"55","author":"P Klepstad","year":"2000","unstructured":"Klepstad P, Kaasa S, Borchgrevink PC: Start of oral morphine to cancer patients: effective serum morphine concentrations and contribution from morphine-6-glucuronide to the analgesia produced by morphine. Eur J Clin Pharmacol. 2000, 55: 713-9. 10.1007\/s002280050003.","journal-title":"Eur J Clin Pharmacol"},{"key":"23_CR4","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1177\/096032719000900509","volume":"9","author":"E Bodd","year":"1990","unstructured":"Bodd E, Jacobsen D, Lund E, Ripel \u00c5, M\u00f8rland J, Wiik-Larsen E: Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure. Hum Exp Toxicol. 1990, 9: 317-21.","journal-title":"Hum Exp Toxicol"},{"key":"23_CR5","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/0885-3924(91)90961-3","volume":"6","author":"NA Hagen","year":"1991","unstructured":"Hagen NA, Foley KM, Cerbone DJ, Portenoy RK, Inturrisi CE: Chronic nausea and morphine-6-glucuronide. J Pain Symptom Manage. 1991, 6: 125-8. 10.1016\/0885-3924(91)90961-3.","journal-title":"J Pain Symptom Manage"},{"key":"23_CR6","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1067\/mcp.2003.5","volume":"73","author":"C Skalke","year":"2003","unstructured":"Skalke C, Scmidt H, Geisslinger G, L\u00f6tsch J: Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharm Ther. 2003, 73: 107-21. 10.1067\/mcp.2003.5.","journal-title":"Clin Pharm Ther"},{"key":"23_CR7","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1111\/j.1399-6576.1998.tb05378.x","volume":"42","author":"P Sj\u00f8gren","year":"1998","unstructured":"Sj\u00f8gren P, Thunedborg LP, Christrup L, Hansen LH, Franks J: Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration ? Six case stories. Acta Anaesthesiol Scand. 1998, 42: 1070-5.","journal-title":"Acta Anaesthesiol Scand"},{"key":"23_CR8","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/0304-3959(92)90065-J","volume":"48","author":"Q-L Gong","year":"1992","unstructured":"Gong Q-L, Hedner J, Bjorkman R, Hedner T: Morphine-3-glucuronide may functionally aantagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain. 1992, 48: 249-55. 10.1016\/0304-3959(92)90065-J.","journal-title":"Pain"},{"key":"23_CR9","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/0024-3205(90)90619-3","volume":"47","author":"MT Smith","year":"1990","unstructured":"Smith MT, Watt JA, Cramond T: Morphine-3-glucuronide \u2013 a potent antagonist of morphine analgesia. Life Sci. 1990, 47: 579-85. 10.1016\/0024-3205(90)90619-3.","journal-title":"Life Sci"},{"key":"23_CR10","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1067\/mcp.2000.111934","volume":"68","author":"RT Penson","year":"2000","unstructured":"Penson RT, Joel SP, Bakhshi K, Clark SJ, Langford RM, Slevin ML: Randomized placebo-controlled trial of the activity of the morphine glucuronides. Clin Phar Ther. 2000, 68: 667-676. 10.1067\/mcp.2000.111934.","journal-title":"Clin Phar Ther"},{"key":"23_CR11","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1038\/clpt.1990.145","volume":"48","author":"HJ McQuay","year":"1990","unstructured":"McQuay HJ, Carroll D, Faura CC, Gavaghan DJ, Hand CW, Moore RA: Oral morphine in cancer pain: influences on morphine and metabolite concentration. Clin Pharmacol Ther. 1990, 48: 236-44.","journal-title":"Clin Pharmacol Ther"},{"key":"23_CR12","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0885-3924(97)00020-1","volume":"14","author":"MA Ashby","year":"1997","unstructured":"Ashby MA, Fleming BG, Wood MJ, Somogyi A: Plasma morphine and glucoronide (M3G and M6G) concentrations in hospice inpatients. J Pain Symptom Manage. 1997, 14: 157-67. 10.1016\/S0885-3924(97)00020-1.","journal-title":"J Pain Symptom Manage"},{"key":"23_CR13","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1034\/j.1399-6576.2003.00138.x","volume":"47","author":"P Klepstad","year":"2003","unstructured":"Klepstad P, Dale O, Kaasa S, Zahlsen K, Aamo T, Fayers P, Borchgrevink PC: Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring:: A prospective survey in 300 cancer patients. Acta Anaesthesiol Scand. 2003, 47: 725-731.","journal-title":"Acta Anaesthesiol Scand"},{"key":"23_CR14","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1007\/s002280050387","volume":"53","author":"A Vermeire","year":"1998","unstructured":"Vermeire A, Remon JP, Rosseel MT, Belpaire F, Devoulder J, Bogaert MG: Variability of morphine disposition during long-term subcutaneous infusion in terminally ill cancer patients. Eur J Clin Pharmacol. 1998, 53: 325-30. 10.1007\/s002280050387.","journal-title":"Eur J Clin Pharmacol"},{"key":"23_CR15","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1002\/1097-0142(194811)1:4<634::AID-CNCR2820010410>3.0.CO;2-L","volume":"1","author":"DA Karnofsky","year":"1948","unstructured":"Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH: The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer. 1948, 1: 634-656.","journal-title":"Cancer"},{"key":"23_CR16","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1093\/jat\/21.5.346","volume":"21","author":"MJ Bogusz","year":"1997","unstructured":"Bogusz MJ, Maier R-D, Driessen S: Morphine, morphine-3-glucuronide, morphine-6-glucuronide, and 6-monoacetylmorphien determined by means of atmospheric pressure chemical ionization-mass-spectrometry-liquid cromatography in body fluids of heroin victims. J Anal Toxicol. 1997, 21: 346-55.","journal-title":"J Anal Toxicol"},{"key":"23_CR17","doi-asserted-by":"publisher","first-page":"409","DOI":"10.3109\/10408368909106595","volume":"27","author":"CG Fraser","year":"1989","unstructured":"Fraser CG, Harris EK: Generation and application of data on biological variation in clinical chemistry. Crit Rev Clin Lab Sci. 1989, 27: 409-37.","journal-title":"Crit Rev Clin Lab Sci"},{"key":"23_CR18","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1515\/CCLM.1998.081","volume":"36","author":"O Ahokoski","year":"1998","unstructured":"Ahokoski O, Virtanen A, Huupponen R, Scheinn H, Salminen E, Kairisto V, Irjala K: Biological day-to-day variation and daytime changes of testosterone, follitropin, lutropin and oestradiol-17- in healthy men. Clin Chem Lab Med. 1998, 36: 485-91. 10.1515\/CCLM.1998.081.","journal-title":"Clin Chem Lab Med"},{"key":"23_CR19","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1191\/0269216303pm835oa","volume":"17","author":"P Klepstad","year":"2003","unstructured":"Klepstad P, Borchgrevink PC, Dale O, Zahlsen K, Aamo T, Fayers P, Fougner B, Kaasa S: Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients. Palliat Med. 2003, 17: 679-687.","journal-title":"Palliat Med"},{"key":"23_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/bjc.1995.268","volume":"72","author":"P Fayers","year":"1995","unstructured":"Fayers P, Machin D: Sample size: how many patients are necessary?. Br J Cancer. 1995, 72: 1-9.","journal-title":"Br J Cancer"}],"container-title":["BMC Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1472-6904-4-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/1472-6904-4-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1472-6904-4-7","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1472-6904-4-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T13:04:07Z","timestamp":1728306247000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/1472-6904-4-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,10,4]]},"references-count":20,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2004,12]]}},"alternative-id":["23"],"URL":"https:\/\/doi.org\/10.1186\/1472-6904-4-7","relation":{},"ISSN":["1472-6904"],"issn-type":[{"value":"1472-6904","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,10,4]]},"assertion":[{"value":"28 May 2004","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2004","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2004","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"7"}}