Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? - Six case histories

Background: Recently, clinical reports have suggested a relationship between the occurrence of hyperalgesia, allodynia and/or myoclonus and treatment with high doses of morphine in humans. Although few clinical descriptions of these phenomena are available, experimental work supports the notion that high doses of morphine may play a pathogenetic role in the observed behavioural syndrome. Methods: Six patients, four with malignant and two with chronic, non-malignant pain conditions, treated with moderate to high doses of oral, continuous intravenous infusion or intrathecal morphine developed hyperalgesia, allodynia and/or myoclonus. When the side-effects occurred, blood or CSF samples were taken and analyzed for contents of morphine, morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G). Results: When comparing the plasma and CSF concentrations from these patients with data from available literature obtained from patients not suffering from those side-effects, it was demonstrated that the values deviated in five patients. In all six patients, the side-effects disappeared after substituting morphine with-other opioid agonists or after lowering the daily dose of morphine. Conclusion: These results may indicate that elevated concentrations of M-3-G in plasma as well as the plasma and CSF M-3-G/M-6-G ratios may play a pathogenetic role in the development of hyperalgesia, allodynia and myoclonus.