Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2016

Open Access 01-06-2016 | Original Research Article

Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Terminally Ill Adult Patients

Authors: Linda G. Franken, Anniek D. Masman, Brenda C. M. de Winter, Birgit C. P. Koch, Frans P. M. Baar, Dick Tibboel, Teun van Gelder, Ron A. A. Mathot

Published in: Clinical Pharmacokinetics | Issue 6/2016

Login to get access

Abstract

Background and Objective

Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis.

Methods

Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis.

Results

The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates.

Conclusions

Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients.
Literature
1.
World Health Organization. Essential medicines in palliative care: executive summary. Geneva: World Health Organization; 2013.
2.
Masman AD, van Dijk M, Tibboel D, Baar FP, Mathot RA. Medication use during end-of-life care in a palliative care centre. Int J Clin Pharm. 2015;37(5):767–75.CrossRefPubMedPubMedCentral
3.
Portenoy RK, Thaler HT, Inturrisi CE, Friedlander-Klar H, Foley KM. The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clin Pharmacol Ther. 1992;51(4):422–31.CrossRefPubMed
4.
Milne RW, Nation RL, Somogyi AA. The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. Drug Metab Rev. 1996;28(3):345–472.CrossRefPubMed
5.
Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth. 2014;113(6):935–44.CrossRefPubMed
6.
Lewis SS, Hutchinson MR, Rezvani N, Loram LC, Zhang Y, Maier SF, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience. 2010;165(2):569–83.CrossRefPubMedPubMedCentral
7.
8.
Morita T, Tei Y, Inoue S. Impaired communication capacity and agitated delirium in the final week of terminally ill cancer patients: prevalence and identification of research focus. J Pain Symptom Manage. 2003;26(3):827–34.CrossRefPubMed
9.
van Herk R, van Dijk M, Baar FP, Tibboel D, de Wit R. Observation scales for pain assessment in older adults with cognitive impairments or communication difficulties. Nurs Res. 2007;56(1):34–43.CrossRefPubMed
10.
11.
Rietjens J, van Delden J, Onwuteaka-Philipsen B, Buiting H, van der Maas P, van der Heide A. Continuous deep sedation for patients nearing death in the Netherlands: descriptive study. BMJ. 2008;336(7648):810–3.CrossRefPubMedPubMedCentral
12.
13.
Trobec K, Kerec Kos M, von Haehling S, Springer J, Anker SD, Lainscak M. Pharmacokinetics of drugs in cachectic patients: a systematic review. PLoS One. 2013;8(11):e79603.
14.
Kemik O, Sumer A, Kemik AS, Hasirci I, Purisa S, Dulger AC, et al. The relationship among acute-phase response proteins, cytokines and hormones in cachectic patients with colon cancer. World J Surg Oncol. 2010;8:85.CrossRefPubMedPubMedCentral
15.
Launay-Vacher V, Oudard S, Janus N, Gligorov J, Pourrat X, Rixe O, et al. Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study. Cancer. 2007;110(6):1376–84.CrossRefPubMed
16.
17.
18.
19.
Campbell CF, Mason JB, Weiler JM. Continuous subcutaneous infusion of morphine for the pain of terminal malignancy. Ann Intern Med. 1983;98(1):51–2.CrossRefPubMed
20.
Starlander J, Melin-Johansson C, Jonsson H, Axelsson B. Oral-parenteral conversion factor for morphine in palliative cancer care: a prospective randomized crossover pilot study. Pain Res Treat. 2011;2011:504034.PubMedPubMedCentral
21.
Meineke I, Freudenthaler S, Hofmann U, Schaeffeler E, Mikus G, Schwab M, et al. Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br J Clin Pharmacol. 2002;54(6):592–603.PubMed
22.
Hasselstrom J, Sawe J. Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet. 1993;24(4):344–54.CrossRefPubMed
23.
Lötsch J, Skarke C, Schmidt H, Liefhold J, Geisslinger G. Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther. 2002;72(2):151–62.CrossRefPubMed
24.
Comets E, Brendel K, Mentre F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed. 2008;90(2):154–66.CrossRefPubMed
25.
Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008;35(4):401–21.CrossRefPubMed
26.
27.
Hunt A, Joel S, Dick G, Goldman A. Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain. J Pediatr. 1999;135(1):47–55.CrossRefPubMed
28.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247–54.CrossRefPubMed
29.
Säwe J, Dahlstrom B, Paalzow L, Rane A. Morphine kinetics in cancer patients. Clin Pharmacol Ther. 1981;30(5):629–35.CrossRefPubMed
30.
Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61.CrossRefPubMed
31.
Patwardhan RV, Johnson RF, Hoyumpa A Jr, Sheehan JJ, Desmond PV, Wilkinson GR, et al. Normal metabolism of morphine in cirrhosis. Gastroenterology. 1981;81(6):1006–11.PubMed
32.
Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet. 1998;34(5):359–73.CrossRefPubMed
33.
Ahlers SJGM, Peeters MYM, van Gulik L, van Dongen EPA, Dahan A, Tibboel D, et al. Glucuronidatie en eliminatie van morfine bij intensivecarepatiënten: een vergelijking met gezonde vrijwilligers. Pharm Weekbl. 2014;8–9:166–71.
34.
Poulain P, Hoskin PJ, Hanks GW, A-Omar O, Walker VA, Johnston A, et al. Relative bioavailability of controlled release morphine tablets (MST continus) in cancer patients. Br J Anaesth. 1988;61(5):569–74.CrossRefPubMed
35.
Ohde S, Hayashi A, Takahasi O, Yamakawa S, Nakamura M, Osawa A, et al. A 2-week prognostic prediction model for terminal cancer patients in a palliative care unit at a Japanese general hospital. Palliat Med. 2011;25(2):170–6.CrossRefPubMed
36.
Maltoni M, Caraceni A, Brunelli C, Broeckaert B, Christakis N, Eychmueller S, et al. Prognostic factors in advanced cancer patients: evidence-based clinical recommendations. A study by the Steering Committee of the European Association for Palliative Care. J Clin Oncol. 2005;23(25):6240–8.CrossRefPubMed
37.
38.
Osborne R, Joel S, Grebenik K, Trew D, Slevin M. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther. 1993;54(2):158–67.CrossRefPubMed
39.
Faura CC, Collins SL, Moore RA, McQuay HJ. Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain. 1998;74(1):43–53.CrossRefPubMed
40.
McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013;39(5):534–40.CrossRefPubMed
41.
Woo J, Chan HS, Or KH, Arumanayagam M. Effect of age and disease on two drug binding proteins: albumin and alpha-1-acid glycoprotein. Clin Biochem. 1994;27(4):289–92.CrossRefPubMed
42.
Bergman P, Sperneder S, Hoijer J, Bergqvist J, Bjorkhem-Bergman L. Low vitamin D levels are associated with higher opioid dose in palliative cancer patients: results from an observational study in Sweden. PLoS One. 2015;10(5):e0128223.CrossRefPubMedPubMedCentral
Metadata
Title
Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Terminally Ill Adult Patients
Authors
Linda G. Franken
Anniek D. Masman
Brenda C. M. de Winter
Birgit C. P. Koch
Frans P. M. Baar
Dick Tibboel
Teun van Gelder
Ron A. A. Mathot
Publication date
01-06-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0345-4

Other articles of this Issue 6/2016

Clinical Pharmacokinetics 6/2016 Go to the issue

Original Research Article

Development of a Physiologically Based Pharmacokinetic Model for Itraconazole Pharmacokinetics and Drug–Drug Interaction Prediction

Review Article

Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa

Review Article

Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and Pharmacodynamics

Original Research Article

Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure

Original Research Article

The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin

Review Article

Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models