Analgesic Efficacy and CSF Pharmacokinetics of Intrathecal Morphine-6-Glucuronide: Comparison With Morphine

Hanna, Magdi; Peat, S.J.; Woodham, M.; Knibb, Aston; Fung, C.

doi:10.1093/bja/64.5.547

Cited by 120 publications

(43 citation statements)

References 14 publications

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“…to patients for post-operative analgesia following hip replacement surgery and to patients for post-operative analgesia following major joint replacements. [40][41][42] Recently, in post-operative pain studies following orthopedic surgery, analgesic effects of M6G equivalent to those of morphine after administration of M6G bolus doses (10-30 mg/ 70 kg) or in patient-controlled analgesia (PCA) have been reported. 43,44 Since the relevance of pain models in human volunteers to clinical analgesia in patients with acute or chronic pain is unknown, studies in patients are of greater value to assess the clinical analgesic value of M6G.…”

Section: C L I N I C a L P A I N S T U D I E Smentioning

confidence: 99%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

131

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Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.

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Section: C L I N I C a L P A I N S T U D I E Smentioning

confidence: 99%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

131

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“…pdf) have both proposed that metabolites that are present at .25% of the parent area under time-concentration curve (AUC) (EMA and FDA) and .10% of the total drug-related exposure (EMA) should trigger further in vitro characterization of the metabolite as a possible contributor to drug-drug interactions (DDIs), as a consequence of inhibition or induction. There is already an appreciation that metabolites can contribute to the main component of the pharmacology of a parent molecule [e.g., morphine 6-glucuronide (Hanna et al, 1990)] or be partial contributors [e.g., N-desmethylsertraline (Rudorfer and Potter, 1997)]. Metabolites have also been implicated in adverse effects [e.g., the quinone-imine metabolite of acetaminophen (Manyike et al, 2000) and trifluoroacetyl chloride of halothane (Satoh et al, 1989)].…”

Section: Introductionmentioning

confidence: 99%

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Tweedie

2012

Drug Metab Dispos

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The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at >25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and >10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential. This commentary attempts to rationalize the clinically relevant levels of metabolite(s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite. A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment. When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite(s).When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro. The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC. It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e.g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e.g., mechanism-based inhibition). A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety.

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“…M6G appears to be active and more potent than morphine in several systems. Thus, it has been shown to produce analgesia in man (Osborne et al, 1988;Hanna et al, 1990) and in rodent (Shimomura et al, 1971;Yoshimura et al, 1973;Pasternak et al, 1987;Abbott & Palmour et al, 1988;Paul et al, 1989;Sullivan et al, 1989;Gong et al, 1991;1992;Frances et al, 1992). It also possesses a respiratory depressant action in guinea-pigs (Murphey & Olsen, 1994).…”

Section: Introductionmentioning

confidence: 99%

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Barjavel

Scherrmann

Bhargava

1995

British J Pharmacology

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1 The effect of morphine (10 mg kg-', s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF).2 The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3 The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4 The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cma, and AUCO4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5 At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.

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Analgesic Efficacy and CSF Pharmacokinetics of Intrathecal Morphine-6-Glucuronide: Comparison With Morphine

Cited by 120 publications

References 14 publications

Morphine‐6‐glucuronide: Actions and mechanisms

Morphine‐6‐glucuronide: Actions and mechanisms

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

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