Morphine-6-Glucuronide might Mediate the Prolonged Opioid Effect of Morphine in Acute Renal Failure

Abstract

<jats:p> 1 A 43-year-old male developed acute kidney failure due to ethylene glycol poisoning. He was treated with bicarbonate to combat metabolic acidosis, ethanol as an antimetabolite and haemodialysis to remove the glycol and its toxic metabolites. He was kept on a respirator and sedated with morphine. Peritoneal dialysis was given for 36 d. Following sedation with morphine for 11 d, the patient was given naloxone and then extubated. The antidote had to be continued for 14 d to prevent respiratory depression, until kidney function improved. </jats:p><jats:p> 2 Only morphine-6-glucuronide (M-6-G) was found in the plasma and CSF at concentrations which might explain the opioid effects observed in the patient during the days after the cessation of morphine treatment. The ratio of the area under the concentration-time curve (AUC) of morphine-3-glucuronide (M-3-G) to M-6-G was 2:1. The elimination half-lives of M-3-G and M-6-G were 55 and 82 h, respectively. The clearance data indicate that most of the glucuronides were eliminated by peritoneal dialysis during renal failure. </jats:p><jats:p> 3 The data suggest that M-6-G exerts opioid effects and is retained in acute kidney failure. Morphine should therefore not be used preferentially as a sedative/analgesic in pronounced kidney failure. </jats:p>

Respiratory Arrest Precipitated by Codeine in a Child with Chronic Renal Failure

“…In particular, M-6-G is more potent than morphine, has a longer halflife, and has delayed clearance in renal failure. 3 In the child presented here, the peak codeine concentration of 468 nmol/L (140 ng/mL) is comparable to the "therapeutic" range reported in normal adults,7 and the peak serum morphine concentration (derived from codeine), 64.6 nmol/L (18.4 ng/mL), has been associated with analgesia but not respiratory depression in children after cardiac surgery.8 M-6-G was elevated to a peak concentration of 481 nmol/L (230 ng/mL), which alone is within the range associated with respiratory and CNS depression in patients reported in Respiratory Arrest by Codeine in a Child with Chronic Renal Failure the literature9 and supports the hypothesis that an etiology for our patient's respiratory arrest was accumulation of the potent codeine metabolite M-6-G. The calculated apparent half-lives of the morphine and M-6-G in our patient are markedly prolonged compared with values derived from healthy adults.6 However, the true half-life of each compound may have been shorter because the production of morphine and M-6-G was simultaneously occurring from ongoing codeine metabolism.…”

“…However, a hazardous side effect may include accumulation of active codeine metabolites in patients with renal dysfunction.2, 3 We present a child with chronic renal failure who received acetaminophen-codeine elixir after outpatient surgery, resulting in accumulation of codeine metabolites that precipitated respiratory arrest.…”

Morphine-6-O-?-D-glucuronide but not morphine-3-O-?-D-glucuronide binds to ?-, ?- and ?- specific opioid binding sites in cerebral membranes

“…Bodd et al 1990 andCalleja 1990), chronic nausea (Hagen et al 1991) and myoclonic spasms (Sj6gren 1993) following administration of morphine to Fig. 2A patients with renal impairment raised the possibility of an accumulating active metabolite of morphine (e.g.…”

The analgesic activity of morphine‐6‐glucuronide.

“…Thus, although extensive metabolism of morphine-6-glucuronide to the diglucuronide may be an explanation for its low recovery in the urine, the case is by no means proven. The very long morphine-6-glucuronide elimination half-life observed in severe renal failure (Bodd et al, 1990;Osborne et al, 1986) would suggest that metabolism of the drug is not a major fate (unless reversible, or influenced by renal impairment), and raises the possibility that formation of the diglucuronide can only proceed through the initial formation of the 3-mono-glucuronide. Biliary excretion of morphine-6-glucuronide also requires investigation.…”