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Morphine-6-glucuronide

JPH Fee Anaesthetics & Intensive Care Medicine, Queen’s University, Belfast

Morphine-6-glucuronide (M6G) is the principal active metabolite of morphine. It is produced by the glucuronidation of the parent drug in the liver and accounts for some 10% of its breakdown. A large number of studies, laboratory and clinical, have examined its analgesic and other properties over the past 50 years. Much of the impetus driving this research has been based on the suggestion that M6G might have a more favourable side-effect profile than morphine, and in particular that its respiratory depressant effects might be less marked.

The actions of M6G at receptor sites have been extensively studied. It binds to μ, δ, and κ opioid receptors but the affinity for these is different from that of morphine: four times less for μ₂; similar for μ_1; similar for δ; and twenty times less for κ.  Despite suggestions that there might be a specific μ-receptor for M6G the evidence for this is weak. The subclassification of μ-receptors into μ₁ and μ₂ types is increasingly unsatisfactory and it has been proposed that there might be series of μ-receptor splice variants in various parts of the body in different ratios or concentrations. Until this is further elucidated, the precise modes of action of M6G and other opioids will remain unclear.

The volume of distribution (Vd) and clearance of M6G are about one-tenth that of morphine but it has a similar half-life (Romberg, 2004). The smaller Vd is probably related to its lower lipophilicity. The mechanisms by which M6G is transported across the blood brain barrier (BBB) are unclear but comparison of the blood-effect site equilibration half-lives shows that transfer of M6G is delayed by a factor of two compared to morphine. This does not appear to greatly affect the time to onset of analgesia as reported in most studies. In the brain, M6G is found mainly in extracellular fluid whereas morphine accumulates intracellularly. This, along with other factors, may contribute to small differences in the time to onset and duration of action of M6G compared to morphine. Excretion is by the kidneys (>95%) with a small amount passing into the bile and the enterohepatic circulation.

M6G has a powerful and prolonged analgesic effect in both animals and humans. There is evidence from clinical studies that its onset of action is slightly delayed compared to morphine. Its potency compared to morphine varies according to the species tested and the route of administration. Administered intrathecally, it is effective in relieving postoperative orthopaedic and cancer pain and it is as effective as morphine for intravenous PCA use after joint replacement. It would appear that in terms of intravenous bolus doses the M6G:morphine potency ratio is between 1:2 and 1:3, meaning that M6G must be given in at least twice the dosage to achieve the same analgesic effect as morphine. The effective intravenous dose is in the range 0.2-0.4 mg/kg for most people. The potency ratio appears to be reversed when it is administered intrathecally with a M6G:morphine ratio of at least 4:1.

Animal studies indicate that M6G and morphine have similar respiratory depressant effects at equianalgesia. In a placebo-controlled trial in human volunteers, Romberg and her colleagues (2003) showed that when end-tidal CO2 was controlled at equal analgesia levels, the ventilatory response to acute hypoxia was attenuated much less by M6G than by morphine. There was a similar pattern with hypercarbia but the differences were less marked.

If M6G is to find a place in the management of acute pain, its efficacy will have to be at least as good as that of morphine and its side-effect profile will have to be substantially better. There is plenty of evidence to support the former, but the situation regarding side-effects is less convincing. More well controlled studies are justified, and would be particularly informative in major gynaecological surgery.

Suggested reading

Grace D, Fee JPH. A comparison of intrathecal morphine-6-glucuronide and intrathecal morphine sulfate as analgesics for total hip replacement. Anesthesia Analgesia 1996;83:1055-9.

Hanna MH, Elliott KM, Fung M. Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery. Anesthesiology 2005;102:815-21.

Hucks D, Thompson PL, McLoughlin L. Explanation at the opioid receptor level of differing toxicity of morphine and morphine-6-glucuronide. Br J Cancer 1992;65:122-6.

Romberg  R, Olofsen E, Sarton E, Tepperna L, Dahan A. Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology 2003;99:788-98.

Romberg  R, Olofsen E, Sarton E, Dahan A. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide – induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology 2004;100:120-33. 

Van Dorp ELA, Romberg R, Sarton E, Bovill JG, Dahan A. Morphine-6-Glucuronide: Morphine’s successor for postoperative pain relief? Anesthesia Analgesia 2006;102:1789-97.