Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide

Br J Anaesth. 2014 Dec;113(6):935-44. doi: 10.1093/bja/aeu186. Epub 2014 Jul 1.


Background: Morphine-6-glucuronide (M6G) is a strong µ-receptor agonist with higher affinity than morphine itself. It has been suggested that M6G contributes to the analgesic effect after administration of morphine, but the extent of its contribution remains unclear.

Methods: In order to elucidate the relative contribution of both drugs to the overall analgesic effect mediated by the µ-receptor, published data on µ-receptor binding, plasma protein binding, concentrations [preferably area under the concentration-time curve (AUC)] of morphine and M6G in blood or cerebrospinal fluid (CSF), or concentration ratios were used to calculate free CSF concentration corrected for receptor binding for each compound. To compare different routes of administration, free CSF concentrations of M and M6G corrected for potency were added and compared with oral administration.

Results: Based on AUC data, there is a major contribution of M6G to the overall analgesic effect; the mean contributions being estimated as 96.6%, 85.6%, 85.4%, and 91.3% after oral, s.c., i.v., and rectal administration of morphine, respectively. In patients with renal insufficiency, 97.6% of the analgesic effect is caused by M6G when morphine is given orally. Owing to accumulation of M6G over time in these patients, morphine may be regarded as a prodrug.

Conclusions: When administering morphine to patients, the analgesic effect is mainly caused by M6G instead of morphine itself, irrespective of the route of administration. Therefore, the patient's kidney function plays a key role in determining the optimal daily dose of morphine.

Keywords: analgesia; morphine; morphine metabolism; morphine pharmacokinetics.

Publication types

  • Review

MeSH terms

  • Administration, Oral
  • Administration, Rectal
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacokinetics*
  • Humans
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Morphine / administration & dosage
  • Morphine / pharmacokinetics*
  • Morphine Derivatives / administration & dosage
  • Morphine Derivatives / pharmacokinetics*


  • Analgesics, Opioid
  • Morphine Derivatives
  • morphine-6-glucuronide
  • Morphine
  • morphine-3-glucuronide