Lack of Analgesic Activity of Morphine-6-glucuronide after Short-term Intravenous Administration in Healthy Volunteers

Lötsch, Jörn; Kobal, Gerd; Stockmann, Anne; Brune, Kay; Geißlinger, Gerd

doi:10.1097/00000542-199712000-00014

Cited by 73 publications

(39 citation statements)

References 54 publications

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“…Morphine-3-glucuronide has no clinical effect and does not influence morphine effects. 31,32 Morphine-6-glucuronide is an active metabolite, but crosses the blood–brain barrier slowly and is considered noncontributory to the short-term effects of morphine, 33-35 and, the observed morphine-6-glucuronide concentrations were never more than 10% of the median EC 50 for miosis reported previously. 30 Therefore, morphine-6-glucuronide was not included in the model, as described previously.…”

Section: Methodsmentioning

confidence: 84%

Cyclosporine-inhibitable Blood–Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

et al. 2013

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Background The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans. Methods Fourteen healthy volunteers received morphine (0.1 mg/kg, 1 h intravenous infusion) in a crossover study after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2 h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia. Results Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml•hr (p < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm-hr), plasma-effect site transfer rate constant (ke0, median 0.27 vs. 0.17 hr−1), and maximum calculated effect site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml) (all p < 0.05). Analgesia testing was confounded by cyclosporine-related pain. Conclusions Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects.

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Section: Methodsmentioning

confidence: 84%

Cyclosporine-inhibitable Blood–Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

et al. 2013

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“…These studies have demonstrated both an analgesic efficacy, 18,[33][34][35][36] a lack of analgesic effect of M6G, 37,38 or a peripherally-mediated analgesic effect 39 over a wide range of M6G bolus or infusion regimes. The analgesic activity of single doses of M6G has also been demonstrated when administered i.v.…”

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

128

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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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“…Thus, when M6G was injected in humans by Lötsch et al to yield plasma concentrations equivalent to those following an analgesic morphine dosage, no analgesic activity was observed. [51] Motamed et al also found injection of M6G was ineffective for postoperative pain relief in humans. [52]…”

Section: Heroin and Its Metabolismmentioning

confidence: 99%

Developing a Vaccine Against Multiple Psychoactive Targets: A Case Study of Heroin

Stowe

Schlosburg²,

Vendruscolo³

et al. 2011

CNSNDDT

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Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin’s effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.

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Lack of Analgesic Activity of Morphine-6-glucuronide after Short-term Intravenous Administration in Healthy Volunteers

Cited by 73 publications

References 54 publications

Cyclosporine-inhibitable Blood–Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

Cyclosporine-inhibitable Blood–Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

Morphine‐6‐glucuronide: Actions and mechanisms

Developing a Vaccine Against Multiple Psychoactive Targets: A Case Study of Heroin

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