Adverse effects of modified release oxycodone/naloxone in patients with moderate to severe liver impairment

To the Editor:

Due to the adverse effects of modified release (MR)-oxycodone/naloxone in patients with moderate to severe liver impairment as a result of advanced cirrhosis or with spontaneous or artificially created portosystemic shunts (Box), its use in this patient population is contraindicated.1

In our clinician roles, we have observed both poor analgesic efficacy and opioid withdrawal in such patients, and similar observations are reported in the literature.2,3 There are clear pharmacological and physiological bases for these outcomes.

MR-oxycodone/naloxone is an oral combination opioid analgesic. The naloxone component is subject to a significant first-pass metabolism, and bioavailability is less than 2%.4 The benefit of low level oral bioavailability of naloxone is reduced opioid-induced constipation due to antagonism of opioid receptors in the gut while permitting the desired analgesic opioid effects. The recommended dose of MR-oxycodone/naloxone ranges from 2.5/1.25 mg to 80/40 mg twice daily — the upper limit guiding prescribers to avoid further opioid dose escalation.1

In patients with compensated cirrhosis (mild hepatic impairment) (Box), MR-oxycodone/naloxone may cautiously be prescribed.1 Satisfactory analgesia without significant adverse effects has been observed in selected patients with compensated cirrhosis and pain from hepatocellular cancer.5

In moderate to severe liver impairment, the first-pass (hepatic) metabolism of both medications are markedly but disproportionately reduced, thereby increasing the systemic relative exposure to naloxone (C_max > 5000% of control) compared with oxycodone (C_max > 200%).1 The mechanisms are hepatocellular dysfunction and spontaneous portosystemic shunting.3 Artificially created surgical or transjugular intrahepatic portosystemic shunts also reduce hepatic extraction. Hepatic infiltration due to malignancy similarly reduces the liver’s ability to metabolise MR-oxycodone/naloxone effectively.2

The relative increase in exposure to naloxone reduces analgesic efficacy through increased antagonism of opioid pain receptors. Escalating doses of MR-oxycodone/naloxone (or other opioid) may not achieve improved analgesia.2 The relatively high systemic naloxone exposure may also induce opioid withdrawal symptoms.3 Switching from MR-oxycodone/naloxone to oxycodone immediate-release in a patient with hepatic impairment contributed to opioid toxicity due to the sudden loss of the high level systemic naloxone exposure.2

In patients with moderate to severe liver impairment due to advanced cirrhosis or with portosystemic shunts, clinicians should be aware of the contraindication of MR-oxycodone/naloxone.