PK-PD and clinical application of morphine metabolites

 

Jörn Lötsch

 pharmazentrum frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany,

 

Morphine is mainly cleared from the body by glucuronidation. While most of a morphine dose will be metabolized into morphine-3-glucuronide, approximately 10% account for formation of morphine-6-glucuronide (M6G), which exerts agonist actions at opioid receptors. Therefore, the latter has received considerable interest related to its role in the clinical effects of morphine.

M6G crosses the blood brain barrier very slowly. Studies employing pupil diameter and experimental pain showed that the transfer half-life of M6G between plasma and effect site is approximately 6 hours, as compared to 2.5 – 3 hours for morphine, or 5 minutes for fast equilibrating opioids such as alfentanil. Therefore, M6G is unlikely to play a role in the short-term effects of morphine with central nervous site of action. Indeed, plasma concentrations of M6G of 500 ng/ml, which is approximately 10 times more than the plasma M6G after intravenously administered analgesic doses of morphine, failed to exert any miotic effect throughout 4 hours, which strongly suggests an absence of central nervous opioid effects. In contrast, when M6G, which is almost exclusively eliminated via the kidney, accumulates in the body of patients with impaired renal function, it may cause severe opioid side effects. Because of the slow equilibration between plasma and effect site, the M6G-mediated side effects appear with insidious onset but persist for a long period of time, which may even exceed the presence of morphine and M6G in the plasma compartment of those patients. In addition to its role during morphine therapy in patients with renal failure, M6G may contribute to the opioid effects during long-term morphine treatment, especially with oral morphine intake, due to M6G-accumulation at effect site. However, this has not yet been conclusively demonstrated. In contrast, M6G has been shown to produce peripheral opioid analgesia in pain with an inflammatory component, thereby contributing to morphine analgesia to various degrees depending on the involvement of the peripheral opioid system in the targeted pain.

Thus, depending on the particular clinical setting, the active metabolite M6G appears to contribute to the clinical effects of morphine to various degrees, however, without surpassing the importance of morphine itself, which remains the main active compound of morphine therapy.