Long lasting respiratory depression induced by morphine‐6‐glucuronide?

Hasselström, Jan; Berg, U; Löfgren, A.; Säwe, Juliette

doi:10.1111/j.1365-2125.1989.tb05401.x

Cited by 54 publications

(20 citation statements)

References 23 publications

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“…The glucuronidation of morphine to M3G and M6G is the major metabolic pathway in children and adults Rane et al, 1986;Sawe et al, 1983Sawe et al, , 1985. M6G may be clinically important in relation to analgesia (Osborne et al, 1988;Shimomura etal., 1971) and respiratory depression (Hasselstrom et al, 1989;Pelligrino et al, 1989). (-)-Morphine forms predominantly M3G while the (+)-isomer forms predominantly M6G (Coughtrie et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Morphine sulphation in children.

Choonara

Ekbom

Lindström

et al. 1990

Brit J Clinical Pharma

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The metabolism of morphine was studied in nine children and seven preterm neonates receiving a continuous infusion of morphine. All the neonates and three children had detectable concentrations of morphine-3-sulphate (M3S) in urine. None of the neonates or the children had detectable concentrations of morphine-6-sulphate (M6S) in urine. None of the children had detectable concentrations of M3S in plasma. The M3S/morphine ratios were significantly higher in neonates than children (P < 0.01), suggesting that morphine sulphation decreases after the neonatal period. The amount of M3S formed, even in neonates, is low suggesting that this is a minor metabolic pathway.

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Section: Discussionmentioning

confidence: 99%

Morphine sulphation in children.

Choonara

Ekbom

Lindström

et al. 1990

Brit J Clinical Pharma

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“…The difference in binding affinity also takes on more significance when considering the observation that M6G has approximately three times the systemic analgesic potency of morphine (Shimomura et al, 1971;Pasternak et al, 1987;Abbot & Palmour, 1988, Thompson et al, 1990. Despite this marked reduction in binding affinity for the mu 2 receptor M6G undoubtedly still causes respiratory depression when plasma concentrations are high (Hasselstrom et al, 1989;Osborne et al, 1986). This is particularly observed in patients with renal failure administered morphine as the major excretion route of M6G is renal.…”

mentioning

confidence: 99%

Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

Hucks

Thompson²,

McLoughlin³

et al. 1992

Br J Cancer

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Summary The radiolabelled opioid receptor binding affinities of morphine and its active metabolite morphine 6-glucuronide at the total mu, mu 1, mu 2 and delta receptors were determined. Morphine 6-glucuronide was found to have a 4-fold lower affinity for the mu 2 receptor (IC50 17 nm and 82 nm for morphine and morphine 6-glucuronide respectively, P = 0.01), the receptor postulated to be responsible for mediating the respiratory depression and gastrointestinal effects after morphine. This provides a possible explanation for the reduced respiratory depression and vomiting seen following morphine 6-glucuronide in man. A similar reduction in affinity of morphine 6-glucuronide was seen at the total mu receptor whilst there was no significant difference seen at the mu or delta receptor. Hence the increased analgesic potency of morphine 6-glucuronide over morphine remains unexplained.Morphine is one of the commonest drugs prescribed by cancer physicians and is an effective potent analgesic. However one or more of the side effects of constipation, nausea and vomiting, and sedation are encountered frequently (Jaffe & Martin, 1991). Respiratory depression is a less common problem but is the most potentially dangerous toxicity. An analgesic with equivalent potency but lower toxicity would therefore be of particular use.The major metabolic products of morphine are morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G). Although M3G is devoid of analgesic activity, M6G is now thought to play a major role in mediating the analgesic effect of morphine (Osborne et al., 1986;Hanks et al., 1987;Hoskin & Hanks, 1990 Pasternak, 1981). This model suggests there is a common receptor labelled by either a prototypic delta agonist such as DADLE (D-Ala2, D-Leu5-enkephalin) or with a mu agonist such as morphine which has high affinity for morphine. This they termed the mu 1 receptor. The receptor labelled with a mu agonist which possessed a lower affinity they termed the mu 2 receptor. Similarly the receptor labelled with a delta agonist possessing lower affinity for morphine they termed the true delta receptor.It has been postulated that several of the adverse affects including respiratory depression of morphine are due to activation of the mu 2 or lower affinity mu opioid receptor (Pasternak & Wood, 1986). Using this classification it was therefore hypothesised that M6G has a lower affinity for the mu 2 receptor than morphine at least partially explaining the lower apparent toxicity seen in man. The aim of the current study was

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“…Declining CSF morphine levels did not alter PaCo2-It is possible that the appearance of an active morphine metabolite in CSF such as morphine-6-glucuronide [10] may have caused the plateau in PaCo2 seen. Alter nately, CSF and serum morphine levels may decline more rapidly than brain (i.e.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Morphine in Infant Monkeys

et al. 1991

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We report the pharmacokinetics of morphine administered as intravenous boluses in newborn (<7 days) and 3- to 4-month-old macaque monkeys. Morphine was administered in a series of bolus doses until Pa(CO(2)) was elevated > 50 mm Hg. In newborns < 7 days of age, a mean dose of 1.4 mg/kg was required (range 0.75-2.8 mg/kg), and in the 3-month-olds, a mean dose of 1.88 mg/kg was required (range 1.5-2.5 mg/kg). The respiratory effects measured by Pa(CO(2)) and respiratory rate did not correlate with declining serum or cerebrospinal fluid morphine levels. Both newborn and 3- to 4-month-old macaque monkeys show only mild respiratory depression after intravenous morphine, at serum concentrations as high as 300-400 ng/ml. Infant and young macaque monkeys appear to be less sensitive to the respiratory depressant effect of morphine than humans.

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Long lasting respiratory depression induced by morphine‐6‐glucuronide?

Cited by 54 publications

References 23 publications

Morphine sulphation in children.

Morphine sulphation in children.

Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

Pharmacokinetics and Pharmacodynamics of Morphine in Infant Monkeys

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