Can metabolites of hydromorphone accumulate and give rise to symptoms in renal failure?/nA patient

Fråga: Can metabolites of hydromorphone accumulate and give rise to symptoms in renal failure? A patient with renal insufficiency is treated with morphine. Due to the well known risk of accumulation of metabolites, hydromorphone is contemplated as an alternative.

Sammanfattning: A scanty line of indirect evidence indicate that accumulation of hydromorphone metabolites in renal failure may be a cause of concern. Direct evidence for this is lacking.

Svar: It is well known that the morphine metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) are accumulated in renal insufficiency. Whereas M6G is a more potent agonist on the mu receptor than the parent compound, M3G may cause toxicity such as myoclonus and seizures (1).

Hydromorphone is a semisynthetic derivative of morphine (1). It differs from morphine in that it has a carbonyl instead of a hydroxyl group at the 6-position. It is biotransformed to hydromorphone-3-glucuronide (H3G), which is excreted in the urine. Since it does not have a hydroxyl group at the 6 position, no 6-glucuronide is formed.

Clinical observation suggest that high dose hydromorphone therapy in renal insufficiency may cause neuroexcitation and cognitive impairment (1, 2). Pharmacokinetic studies in cancer patients with normal renal function indicate a steady state concentration ratio of H3G to hydromorphone of 27:1. A single case study in renal failure showed the same ratio to be 100:1. This patient did not display toxicity symtoms (2). In a rodent model, administration of H3G caused myoclonus and convulsive seizures in a similar manner to those reported when administering M3G (3).