title: A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain.
abstract: Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.
authors: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Eva
authors: E
authors: Sverrisdóttir
authors: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Trine Meldgaard
authors: TM
authors: Lund
authors: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark.
authors: Anne Estrup
authors: AE
authors: Olesen
authors: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 11, DK-9000 Aalborg, Denmark.
authors: Asbjørn Mohr
authors: AM
authors: Drewes
authors: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Lona Louring
authors: LL
authors: Christrup
authors: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: mads.kreilgaard@sund.ku.dk.
authors: Mads
authors: M
authors: Kreilgaard
mesh_terms: D059787:Acute Pain / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D006207:Half-Life; D006801:Humans; D008954:Models, Biological; D009020:Morphine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D009022:Morphine Derivatives / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D057285:Precision Medicine; D051437:Renal Insufficiency / Q000150:complications; D014018:Tissue Distribution
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine
keywords: Analgesia; Modelling; Morphine; Morphine-6-glucuronide; Pharmacokinetics/pharmacodynamics; Simulations