Hydromorphone Metabolism
Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide (H3G) along with minor amounts of 6-hydroxy reduction metabolites. 1
Primary Metabolic Pathway
- The liver is the primary site of hydromorphone metabolism, specifically through Phase II glucuronidation (conjugation) rather than Phase I oxidative metabolism 1
- This metabolic pathway produces H3G as the predominant metabolite, which is analgesically inactive but potentially neurotoxic 2
- Only a small amount of hydromorphone is excreted unchanged in the urine, with most eliminated as H3G along with minor 6-hydroxy reduction metabolites 1
Clinical Significance of Hepatic Metabolism
- Hydromorphone's half-life remains relatively stable even in patients with liver dysfunction because glucuronidation (Phase II metabolism) is generally preserved in hepatic impairment, unlike oxidative (Phase I) metabolism 2
- However, patients with moderate hepatic impairment (Child-Pugh Group B) show a 4-fold increase in hydromorphone exposure (Cmax and AUC), requiring lower starting doses and careful titration 1
- The Korean practice guidelines specifically note that hydromorphone is "metabolized and excreted by conjugation" with a stable half-life in liver dysfunction, making it a preferred option over morphine or oxycodone in cirrhotic patients 2
Renal Considerations for Metabolite Accumulation
- While metabolism occurs in the liver, the kidney is responsible for excreting H3G and other hydromorphone metabolites 3, 4
- Patients with moderate renal impairment show 2-fold increased exposure, while severe renal impairment (CrCl <30 mL/min) shows 3-fold increased exposure with prolonged terminal elimination half-life (40 hours vs 15 hours in normal function) 1
- H3G levels in patients with renal insufficiency are approximately 4 times higher than in those with normal renal function, creating risk for neuroexcitatory phenomena including tremor, myoclonus, agitation, cognitive dysfunction, and seizures 5, 6
Practical Implications
- The ASCO guidelines recommend that hydromorphone should be "carefully titrated and frequently monitored for risk of accumulation" in renal impairment, though it may be preferred over morphine which has more neurotoxic metabolites 2
- The European and Korean guidelines suggest hydromorphone as a safer alternative to morphine in end-stage liver disease specifically because its conjugation pathway is more preserved than oxidative metabolism 2
- When neuroexcitatory symptoms occur from H3G accumulation, opioid rotation to structurally dissimilar agents like methadone or fentanyl (which don't produce glucuronide metabolites) allows H3G clearance over hours to days 6