Plasma Morphine and Metabolite Concentrations Are Associated With Clinical Effects of Morphine in Cancer Patients

Abstract Context Morphine is the opioid of choice for cancer-related pain, but for many patients the benefits of morphine are outweighed by its side effect profile. Morphine is metabolized to morphine-3-glucuronide and morphine-6-glucuronide; however, little is known about the contribution of these metabolites to analgesia and morphine-related side effects. Objectives We investigated the association between plasma morphine and metabolite concentrations and the clinical effects of morphine in cancer patients. Methods A prospective study was performed in cancer patients taking oral morphine for moderate-to-severe cancer pain. Subjects who responded well to morphine (responders) and subjects who failed to respond to morphine because of lack of analgesia and/or the presence of intolerable side effects (nonresponders/switchers) were recruited. Pain and toxicity scores were recorded and blood samples were analyzed for plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide concentrations. Results Results showed that 1) morphine responders have higher plasma morphine and metabolite concentrations compared with nonresponders, 2) lower pain scores are associated with higher plasma morphine and metabolite concentrations, 3) central side effects are associated with a higher metabolite:plasma morphine ratio, and 4) myoclonus is associated with extremely high concentrations of plasma morphine and metabolites. Conclusion This study has shown that plasma morphine and metabolite concentrations are associated with the clinical effects of morphine therapy. These results are important because they demonstrate the relevance of measuring plasma metabolite concentrations in clinical trials and the potential for metabolite data to deepen our understanding of factors that influence an individual's response to morphine.