{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T16:32:07Z","timestamp":1759336327091,"version":"3.37.3"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Salix Pharmaceuticals, a division of Bausch Health US, LLC"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Support Care Cancer"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Peripherally acting \u03bc-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor<jats:sup>\u00ae<\/jats:sup>) are indicated for the treatment of opioid-induced constipation (OIC). The structural properties unique to MNTX restrict it from traversing the blood-brain barrier (BBB); however, the BBB may become more permeable in patients with brain metastases. We investigated whether the presence of brain metastases in cancer patients compromises the central effects of opioids among patients receiving MNTX for OIC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This post hoc analysis of pooled data from 3 randomized, placebo-controlled trials included cancer patients with OIC who received MNTX or placebo. Endpoints included changes from baseline in pain scores, rescue-free laxation (RFL) within 4 or 24 h of the first dose, and treatment-emergent adverse events (TEAEs), including those potentially related to opioid withdrawal symptoms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Among 356 cancer patients in the pooled population, 47 (MNTX <jats:italic>n<\/jats:italic> = 27; placebo <jats:italic>n<\/jats:italic> = 20) had brain metastases and 309 (MNTX <jats:italic>n<\/jats:italic> = 172; placebo <jats:italic>n<\/jats:italic> = 137) did not have brain metastases. No significant differences in current pain, worst pain, or change in pain scores from baseline were observed between patients treated with MNTX or placebo. Among patients with brain metastases, a significantly greater proportion of patients who received MNTX versus placebo achieved an RFL within 4 h after the first dose (70.4% vs 15.0%, respectively, <jats:italic>p<\/jats:italic> = 0.0002). TEAEs were similar between treatment groups and were generally gastrointestinal in nature and not related to opioid withdrawal.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Focal disruptions of the BBB caused by brain metastases did not appear to alter central nervous system penetrance of MNTX.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00520-021-06070-7","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T05:24:57Z","timestamp":1614230697000},"page":"5209-5218","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The influence of brain metastases on the central nervous system effects of methylnaltrexone: a post hoc analysis of 3 randomized, double-blind studies"],"prefix":"10.1007","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8577-7278","authenticated-orcid":false,"given":"Darren M.","family":"Brenner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4389-7343","authenticated-orcid":false,"given":"Neal E.","family":"Slatkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Stambler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4150-2336","authenticated-orcid":false,"given":"Robert J.","family":"Israel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul H.","family":"Coluzzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"issue":"9670","key":"6070_CR1","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1016\/S0140-6736(09)60139-2","volume":"373","author":"G Becker","year":"2009","unstructured":"Becker G, Blum HE (2009) Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus. Lancet 373(9670):1198\u20131206","journal-title":"Lancet"},{"key":"6070_CR2","doi-asserted-by":"publisher","unstructured":"Kumar L, Barker C, Emmanuel A (2014, 2014) Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract. https:\/\/doi.org\/10.1155\/2014\/141737:141737","DOI":"10.1155\/2014\/141737:141737"},{"issue":"1","key":"6070_CR3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1177\/2050640618818305","volume":"7","author":"AD Farmer","year":"2019","unstructured":"Farmer AD, Drewes AM, Chiarioni G, de Giorgio R, O\u2019Brien T, Morlion B, Tack J (2019) Pathophysiology and management of opioid-induced constipation: European expert consensus statement. United European Gastroenterol J 7(1):7\u201320","journal-title":"United European Gastroenterol J"},{"issue":"1","key":"6070_CR4","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/j.1526-4637.2008.00495.x","volume":"10","author":"TJ Bell","year":"2009","unstructured":"Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R (2009) The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med 10(1):35\u201342","journal-title":"Pain Med"},{"issue":"7","key":"6070_CR5","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1111\/j.1742-1241.2007.01415.x","volume":"61","author":"SJ Panchal","year":"2007","unstructured":"Panchal SJ, Muller-Schwefe P, Wurzelmann JI (2007) Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract 61(7):1181\u20131187","journal-title":"Int J Clin Pract"},{"issue":"3","key":"6070_CR6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/S0304-3959(01)00324-4","volume":"93","author":"T Meuser","year":"2001","unstructured":"Meuser T, Pietruck C, Radbruch L, Stute P, Lehmann KA, Grond S (2001) Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93(3):247\u2013257","journal-title":"Pain"},{"issue":"4","key":"6070_CR7","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1111\/j.1526-4637.2006.00184.x","volume":"7","author":"DJ Weschules","year":"2006","unstructured":"Weschules DJ, Bain KT, Reifsnyder J, McMath JA, Kupperman DE, Gallagher RM, Hauck WW, Knowlton CH (2006) Toward evidence-based prescribing at end of life: a comparative analysis of sustained-release morphine, oxycodone, and transdermal fentanyl, with pain, constipation, and caregiver interaction outcomes in hospice patients. Pain Med 7(4):320\u2013329. https:\/\/doi.org\/10.1111\/j.1526-4637.2006.00184.x","journal-title":"Pain Med"},{"issue":"8","key":"6070_CR8","doi-asserted-by":"publisher","first-page":"989","DOI":"10.4155\/tde.15.48","volume":"6","author":"IT Papademetriou","year":"2015","unstructured":"Papademetriou IT, Porter T (2015) Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer. Ther Deliv 6(8):989\u20131016. https:\/\/doi.org\/10.4155\/tde.15.48","journal-title":"Ther Deliv"},{"issue":"suppl 1","key":"6070_CR9","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1186\/1471-2377-9-s1-s3","volume":"9","author":"WA Banks","year":"2009","unstructured":"Banks WA (2009) Characteristics of compounds that cross the blood-brain barrier. BMC Neurol 9(suppl 1):S3. https:\/\/doi.org\/10.1186\/1471-2377-9-s1-s3","journal-title":"BMC Neurol"},{"issue":"6","key":"6070_CR10","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1021\/jm00180a022","volume":"23","author":"VA Levin","year":"1980","unstructured":"Levin VA (1980) Relationship of octanol\/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23(6):682\u2013684","journal-title":"J Med Chem"},{"issue":"11","key":"6070_CR11","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1038\/jcbfm.2012.126","volume":"32","author":"WM Pardridge","year":"2012","unstructured":"Pardridge WM (2012) Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 32(11):1959\u20131972. https:\/\/doi.org\/10.1038\/jcbfm.2012.126","journal-title":"J Cereb Blood Flow Metab"},{"issue":"3","key":"6070_CR12","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s002329900434","volume":"165","author":"H Fischer","year":"1998","unstructured":"Fischer H, Gottschlich R, Seelig A (1998) Blood-brain barrier permeation: molecular parameters governing passive diffusion. J Membr Biol 165(3):201\u2013211","journal-title":"J Membr Biol"},{"issue":"1","key":"6070_CR13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1602\/neurorx.2.1.3","volume":"2","author":"WM Pardridge","year":"2005","unstructured":"Pardridge WM (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2(1):3\u201314. https:\/\/doi.org\/10.1602\/neurorx.2.1.3","journal-title":"NeuroRx"},{"issue":"1-3","key":"6070_CR14","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/0169-409X(95)00003-P","volume":"15","author":"WM Pardridge","year":"1995","unstructured":"Pardridge WM (1995) Transport of small molecules through the blood-brain barrier: biology and methodology. Adv Drug Deliv Rev 15(1-3):5\u201336","journal-title":"Adv Drug Deliv Rev"},{"key":"6070_CR15","unstructured":"Movantik [package insert] (2018) AstraZeneca Pharmaceuticals, Wilmington, DE"},{"key":"6070_CR16","unstructured":"Relistor [package insert] (2018) Salix Pharmaceuticals, Bridgewater, NJ"},{"key":"6070_CR17","unstructured":"Symproic [package insert] (2018) Shionogi Inc., Florham Park"},{"key":"6070_CR18","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3389\/fonc.2018.00239","volume":"8","author":"KE Warren","year":"2018","unstructured":"Warren KE (2018) Beyond the blood brain barrier: the importance of central nervous system (CNS) pharmacokinetics for the treatment of CNS tumors, including diffuse intrinsic pontine glioma. Front Oncol 8:239. https:\/\/doi.org\/10.3389\/fonc.2018.00239","journal-title":"Front Oncol"},{"issue":"2","key":"6070_CR19","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1002\/1098-2299(200006)50:2<133::AID-DDR1>3.0.CO;2-8","volume":"50","author":"CS Yuan","year":"2000","unstructured":"Yuan CS, Foss JF (2000) Methylnaltrexone: investigation of clinical applications. Drug Dev Res 50(2):133\u2013141","journal-title":"Drug Dev Res"},{"issue":"3","key":"6070_CR20","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/0028-3908(85)90072-3","volume":"24","author":"DR Brown","year":"1985","unstructured":"Brown DR, Goldberg LI (1985) The use of quaternary narcotic antagonists in opiate research. Neuropharmacology 24(3):181\u2013191","journal-title":"Neuropharmacology"},{"issue":"3","key":"6070_CR21","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/0014-2999(82)90026-7","volume":"78","author":"J Russell","year":"1982","unstructured":"Russell J, Bass P, Goldberg LI, Schuster CR, Merz H (1982) Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists. Eur J Pharmacol 78(3):255\u2013261","journal-title":"Eur J Pharmacol"},{"issue":"4","key":"6070_CR22","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/S0009-9236(96)90117-4","volume":"59","author":"CS Yuan","year":"1996","unstructured":"Yuan CS, Foss JF, O\u2019Connor M, Toledano A, Roizen MF, Moss J (1996) Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther 59(4):469\u2013475","journal-title":"Clin Pharmacol Ther"},{"issue":"1","key":"6070_CR23","first-page":"39","volume":"7","author":"N Slatkin","year":"2009","unstructured":"Slatkin N, Thomas J, Lipman AG, Wilson G, Boatwright ML, Wellman C, Zhukovsky DS, Stephenson R, Portenoy R, Stambler N, Israel R (2009) Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol 7(1):39\u201346","journal-title":"J Support Oncol"},{"issue":"22","key":"6070_CR24","doi-asserted-by":"publisher","first-page":"2332","DOI":"10.1056\/NEJMoa0707377","volume":"328","author":"J Thomas","year":"2008","unstructured":"Thomas J, Karver S, Cooney GA, Chamberlain BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ (2008) Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 328(22):2332\u20132343","journal-title":"N Engl J Med"},{"issue":"7","key":"6070_CR25","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1089\/jpm.2014.0362","volume":"18","author":"J Bull","year":"2015","unstructured":"Bull J, Wellman CV, Israel RJ, Barrett AC, Paterson C, Forbes WP (2015) Fixed-dose subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation: results of a randomized, placebo-controlled study and open-label extension. J Palliat Med 18(7):593\u2013600. https:\/\/doi.org\/10.1089\/jpm.2014.0362","journal-title":"J Palliat Med"},{"issue":"5","key":"6070_CR26","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.jpain.2010.11.008","volume":"12","author":"E Michna","year":"2011","unstructured":"Michna E, Blonsky ER, Schulman S, Tzanis E, Manley A, Zhang H, Iyer S, Randazzo B (2011) Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain 12(5):554\u2013562","journal-title":"J Pain"},{"issue":"8","key":"6070_CR27","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1093\/pm\/pnx148","volume":"18","author":"LR Webster","year":"2017","unstructured":"Webster LR, Michna E, Khan A, Israel RJ, Harper JR (2017) Long-term safety and efficacy of subcutaneous methylnaltrexone in patients with opioid-induced constipation and chronic noncancer pain: a phase 3, open-label trial. Pain Med 18(8):1496\u20131504. https:\/\/doi.org\/10.1093\/pm\/pnx148","journal-title":"Pain Med"},{"issue":"3","key":"6070_CR28","doi-asserted-by":"publisher","first-page":"293","DOI":"10.3109\/00952998709001515","volume":"13","author":"L Handelsman","year":"1987","unstructured":"Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD (1987) Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 13(3):293\u2013308","journal-title":"Am J Drug Alcohol Abuse"},{"issue":"suppl 1","key":"6070_CR29","first-page":"119","volume":"12","author":"P Holzer","year":"2008","unstructured":"Holzer P (2008) New approaches to the treatment of opioid-induced constipation. Eur Rev Med Pharmacol Sci 12(suppl 1):119\u2013127","journal-title":"Eur Rev Med Pharmacol Sci"},{"issue":"6","key":"6070_CR30","doi-asserted-by":"publisher","first-page":"455","DOI":"10.2217\/pmt-2017-0028","volume":"7","author":"NE Burma","year":"2017","unstructured":"Burma NE, Kwok CH, Trang T (2017) Therapies and mechanisms of opioid withdrawal. Pain Manag 7(6):455\u2013459. https:\/\/doi.org\/10.2217\/pmt-2017-0028","journal-title":"Pain Manag"},{"issue":"3","key":"6070_CR31","doi-asserted-by":"publisher","first-page":"e0229228","DOI":"10.1371\/journal.pone.0229228","volume":"15","author":"H Suzuki","year":"2020","unstructured":"Suzuki H, Aono S, Inoue S, Imajo Y, Nishida N, Funaba M, Harada H, Mori A, Matsumoto M, Higuchi F, Nakagawa S, Tahara S, Ikeda S, Izumi H, Taguchi T, Ushida T, Sakai T (2020) Clinically significant changes in pain along the Pain Intensity Numerical Rating Scale in patients with chronic low back pain. PLoS One 15(3):e0229228. https:\/\/doi.org\/10.1371\/journal.pone.0229228","journal-title":"PLoS One"},{"issue":"2","key":"6070_CR32","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1165\/rcmb.2006-0327OC","volume":"37","author":"PA Singleton","year":"2007","unstructured":"Singleton PA, Moreno-Vinasco L, Sammani S, Wanderling SL, Moss J, Garcia JG (2007) Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 37(2):222\u2013231. https:\/\/doi.org\/10.1165\/rcmb.2006-0327OC","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"1","key":"6070_CR33","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1111\/j.1600-0625.2010.01158.x","volume":"20","author":"S Boehncke","year":"2011","unstructured":"Boehncke S, Hardt K, Schadendorf D, Henschler R, Boehncke WH, Duthey B (2011) Endogenous mu-opioid peptides modulate immune response towards malignant melanoma. Exp Dermatol 20(1):24\u201328. https:\/\/doi.org\/10.1111\/j.1600-0625.2010.01158.x","journal-title":"Exp Dermatol"},{"issue":"4","key":"6070_CR34","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1097\/ALN.0b013e31824babe2","volume":"116","author":"FE Lennon","year":"2012","unstructured":"Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA (2012) Overexpression of the mu-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology 116(4):857\u2013867. https:\/\/doi.org\/10.1097\/ALN.0b013e31824babe2","journal-title":"Anesthesiology"},{"issue":"4","key":"6070_CR35","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1097\/ALN.0b013e31824b96a1","volume":"116","author":"AV Bortsov","year":"2012","unstructured":"Bortsov AV, Millikan RC, Belfer I, Boortz-Marx RL, Arora H, McLean SA (2012) mu-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. Anesthesiology 116(4):896\u2013902. https:\/\/doi.org\/10.1097\/ALN.0b013e31824b96a1","journal-title":"Anesthesiology"},{"issue":"4","key":"6070_CR36","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1007\/s10147-012-0441-5","volume":"18","author":"S Wang","year":"2013","unstructured":"Wang S, Li Y, Liu XD, Zhao CX, Yang KQ (2013) Polymorphism of A118G in mu-opioid receptor gene is associated with risk of esophageal squamous cell carcinoma in a Chinese population. Int J Clin Oncol 18(4):666\u2013669. https:\/\/doi.org\/10.1007\/s10147-012-0441-5","journal-title":"Int J Clin Oncol"},{"issue":"2","key":"6070_CR37","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1111\/cts.12246","volume":"8","author":"YS Yao","year":"2015","unstructured":"Yao YS, Yao RY, Zhuang LK, Qi WW, Lv J, Zhou F, Qiu WS, Yue L (2015) MOR1 expression in gastric cancer: a biomarker associated with poor outcome. Clin Transl Sci 8(2):137\u2013142. https:\/\/doi.org\/10.1111\/cts.12246","journal-title":"Clin Transl Sci"},{"key":"6070_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.canlet.2019.03.038","volume":"453","author":"Y Li","year":"2019","unstructured":"Li Y, Li G, Tao T, Kang X, Liu C, Zhang X, Wang C, Li C, Guo X (2019) The mu-opioid receptor (MOR) promotes tumor initiation in hepatocellular carcinoma. Cancer Lett 453:1\u20139. https:\/\/doi.org\/10.1016\/j.canlet.2019.03.038","journal-title":"Cancer Lett"},{"issue":"6","key":"6070_CR39","doi-asserted-by":"publisher","first-page":"e157","DOI":"10.1016\/j.bja.2018.09.030","volume":"122","author":"DT Chen","year":"2019","unstructured":"Chen DT, Pan JH, Chen YH, Xing W, Yan Y, Yuan YF, Zeng WA (2019) The mu-opioid receptor is a molecular marker for poor prognosis in hepatocellular carcinoma and represents a potential therapeutic target. Br J Anaesth 122(6):e157\u2013e167. https:\/\/doi.org\/10.1016\/j.bja.2018.09.030","journal-title":"Br J Anaesth"},{"issue":"23","key":"6070_CR40","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.1002\/cncr.28345","volume":"119","author":"D Zylla","year":"2013","unstructured":"Zylla D, Gourley BL, Vang D, Jackson S, Boatman S, Lindgren B, Kuskowski MA, Le C, Gupta K, Gupta P (2013) Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer 119(23):4103\u20134110. https:\/\/doi.org\/10.1002\/cncr.28345","journal-title":"Cancer"},{"issue":"11","key":"6070_CR41","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1093\/annonc\/mdw317","volume":"27","author":"F Janku","year":"2016","unstructured":"Janku F, Johnson LK, Karp DD, Atkins JT, Singleton PA, Moss J (2016) Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer. Ann Oncol 27(11):2032\u20132038. https:\/\/doi.org\/10.1093\/annonc\/mdw317","journal-title":"Ann Oncol"},{"issue":"16","key":"6070_CR42","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.1002\/cncr.29460","volume":"121","author":"PA Singleton","year":"2015","unstructured":"Singleton PA, Moss J, Karp DD, Atkins JT, Janku F (2015) The mu opioid receptor: a new target for cancer therapy? Cancer 121(16):2681\u20132688. https:\/\/doi.org\/10.1002\/cncr.29460","journal-title":"Cancer"},{"issue":"6","key":"6070_CR43","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1213\/ANE.0b013e318232b35a","volume":"113","author":"N Fujioka","year":"2011","unstructured":"Fujioka N, Nguyen J, Chen C, Li Y, Pasrija T, Niehans G, Johnson KN, Gupta V, Kratzke RA, Gupta K (2011) Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer. Anesth Analg 113(6):1353\u20131364. https:\/\/doi.org\/10.1213\/ANE.0b013e318232b35a","journal-title":"Anesth Analg"},{"issue":"15","key":"6070_CR44","first-page":"4491","volume":"62","author":"K Gupta","year":"2002","unstructured":"Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP (2002) Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 62(15):4491\u20134498","journal-title":"Cancer Res"}],"container-title":["Supportive Care in Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00520-021-06070-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00520-021-06070-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00520-021-06070-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T10:24:41Z","timestamp":1626863081000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00520-021-06070-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,25]]},"references-count":44,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["6070"],"URL":"https:\/\/doi.org\/10.1007\/s00520-021-06070-7","relation":{},"ISSN":["0941-4355","1433-7339"],"issn-type":[{"type":"print","value":"0941-4355"},{"type":"electronic","value":"1433-7339"}],"subject":[],"published":{"date-parts":[[2021,2,25]]},"assertion":[{"value":"11 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Each study site obtained institutional review board and independent ethics committee approval for the protocols and informed consent forms. Each study was conducted in compliance with the principals of Good Clinical Practice and in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All study participants provided written informed consent.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"NA","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Dr. Brenner is a consultant, advisor, and speaker for Salix Pharmaceuticals. His research is also supported by an unrestricted gift from the Irene D. Pritzker Foundation.Dr. Slatkin is an employee of Salix Pharmaceuticals, a subsidiary of Bausch Health US, LLC.Dr. Stambler is a full-time employee and shareholder of Progenics Pharmaceuticals, Inc., a subsidiary of Lantheus Holdings, Inc.Dr. Israel is an employee of Bausch Health US, LLC.Dr. Coluzzi is a full-time employee of the University of California, Irvine.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}