Morphine-3-glucuronide

Abstract: Pharmacological properties of morphine-3-glucuronide and morphine-6-glucuronide were studied in mice and compared with those of morphine. 1) The analgesic effect of morphine-6-glucuronide was 3 to 4 times as potent and approximately 2 times as long in duration as that of morphine when injected subcutaneously. Morphine-3-glucuronide, however, showed no analgesic effect even in a dose of 27.6mg/kg. 2) The analgesic effect of morphine-6-glucuronide was about 45 times as potent as that of morphine, when injected intracerebrally in mice, but morphine-3-glucuronide had no effect. 3) After intraperitoneal injection of morphine-6-glucuronide in rats, only conjugated morphine was detected in the brain by chromatographic examination but not free morphine. 4) Morphine-6-glucuronide was also antagonized by nalorphine though to slightly lesser degree than morphine. 5) Development of tolerance to morphine-6-glucuronide in analgesic effect was almost the same in degree as that to morphine. Cross tolerance between morphine-6-glucuronide and morphine was observed as well.

Abstract: 1. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain. 2. Education of health professionals in the past decade has resulted in a large increase in the prescribing of opioids, such as morphine, and in the magnitude of the doses administered, resulting in an improvement in the quality of pain relief available for many cancer patients. 3. However, the reported incidence of neuroexcitatory side effects (allodynia, myoclonus, seizures) in patients administered large doses of systemic morphine or its structural analogue, hydromorphone (HMOR), has also increased. 4. Clinically, increasing the magnitude of the morphine or HMOR dose administered to patients already exhibiting neuroexcitatory opioid related side effects, results in an exacerbation rather than an attenuation of the excitatory behaviours. 5. In contrast, cessation of the opioid or rotation to a structurally dissimilar opioid (e.g. from morphine/HMOR to methadone or fentanyl), usually results in a restoration of analgesia and resolution of the neuroexcitatory opioid side effects over a period of hours to days. 6. To explain the clinical success of 'opioid rotation', it is essential to understand the in vivo metabolic fate of morphine and HMOR. 7. Following systemic administration, morphine and HMOR are metabolized primarily to the corresponding 3-glucuronide metabolites, morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G), which are not only devoid of analgesic activity but evoke a range of dose-dependent excitatory behaviours, including allodynia, myoclonus and seizures, following intracerebroventricular (i.c.v.) administration to rats. 8. Several studies have shown that, following chronic oral or subcutaneous morphine administration to patients with cancer pain, the cerebrospinal fluid (CSF) concentrations of M3G exceed those of morphine and morphine-6-glucuronide (analgesically active morphine metabolite) by approximately two- and five-fold, respectively. 9. These findings suggest that when the M3G concentration (or H3G by analogy) in the CSF exceeds the neuroexcitatory threshold, excitatory behaviours will be evoked in patients. 10. Thus, rotation of the opioid from morphine/HMOR to a structurally dissimilar opioid, such as methadone or fentanyl, will allow clearance of M3G/H3G from the patient central nervous system over hours to days, thereby producing a time-dependent resolution of the neuroexcitatory behaviours while maintaining analgesia with methadone or fentanyl.