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In consequence, physicians and pharmacists are currently confronted with numerous patients willing to use<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone against their malignancies. Well\u2010performed<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>models have in fact shown pro\u2010apoptotic effects of<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone or other opioids, but also proliferation\u2010stimulating properties. Moreover, the mechanisms of proposed opioid\u2010stimulated apoptosis are incompletely described or contradicting. Finally, the receptors mostly responsible for induction of apoptosis by<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone remain unclear as contributions of both \u00b5\u2010opioid receptors, Fas cell death receptors, toll\u2010like receptors,<jats:italic>N<\/jats:italic>\u2010Methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate receptors and opioid growth factor receptors were suggested. Such ambiguity prevents rational application of<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone or patient stratification to enhance beneficial antineoplastic effects. From a clinical point of view,<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone and other opioids might in fact prolong survival, but such effects likely originate from their analgesic and neuro\u2010psychotropic properties and, thus, improvements of quality of life. Crucial obstacles to the administration of<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone are incomplete knowledge about its systemic disposition, highly variable pharmacokinetics, profound drug\u2013drug\u2010 or drug\u2013disease interaction and QT\u2010prolongation potential. This article summarizes and rates the pharmacological basis of<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone as an antineoplastic agent and puts its administration in clinical oncology into perspective. Despite enthralling experimental findings about<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone\u2010mediated apoptosis in cancerous cells or tissues, clinicians should realize the current lack of evidence for the use of<jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010methadone as an antineoplastic agent. 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