Sjoerd de Hoogd (1), Pyry Välitalo (2), Albert Dahan (3), Simone van Kralingen (4,5), Eric P.A. van Dongen (4), Bert van Ramshorst (6), Catherijne A.J. Knibbe (1,2)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands, (2) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (3) Department of Anaesthesiology, Leiden University Medical Center, Leiden, The Netherlands, (4) Department of Anaesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands, (5) Department of Anaesthesiology, Sint Lucas Andreas Hospital, Amsterdam, The Netherlands (6) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Morbidly obese patients are at increased risk of side effects of opioids, especially after surgery[1]. While in clinical practice postoperative pain management in adults with morphine is generally fixed dosed[2], the pharmacokinetics of morphine and metabolites in morbidly obese patients are poorly studied[3]. The aim of this study is therefore to investigate the pharmacokinetics of morphine and morphine metabolites (morphine-3-glucuronidate (M3G) and morphine-6-glucuronidate (M6G)) in morbidly obese patients and non-obese healthy volunteers.
Methods: In a prospective study, 20 morbidly obese patients, with a mean BMI of 49.9 kg/m2 (range 37.6 – 78.6 kg/m2 ) and a mean weight of 151.3 kg (range 112 – 251.9 kg) and 20 healthy volunteers[4] with a mean weight of 70.6 kg (range 58 – 85 kg) were included in the study. Morbidly obese patients received 10 mg intravenous (I.V.) morphine for postoperative pain management after gastric bypass surgery, with additional morphine I.V. doses as needed. Morphine, M3G and M6G blood concentrations were measured at T=0, 5, 15, 30, 45, 60, 90, 120, 150, 240, 420. Healthy volunteers[4] received an I.V. bolus morphine 0.1 mg/kg followed by an infusion of 0.030 mg/kg/hr for 1 hour. Morphine, M3G and M6G was measured at T=0, 5, 10, 20, 40, 60, 65, 80, 100, 130, 180, 300, 420. Population pharmacokinetic modeling and covariate analysis characterizing the influence of body weight was performed using NONMEM 7.3.
Results: A three compartment pharmacokinetic model best described the data for morphine in morbidly obese and non-obese individuals. For both glucuronides, one compartment models were used with multiple transit compartments for the formation of these metabolites with a mean transit time (MTT) for M3G and M6G of 2.98 and 12.6 min, respectively. The covariate analysis identified body weight as covariate for peripheral volume of distribution of morphine (P<.001). With increasing body weight a delay in the formation of M3G was found (P<.001), as well as a decrease in formation clearance of M6G (P<.001) and decrease elimination clearance of M3G and M6G (both P<.001).
Conclusions: No weight-based dosing adjustments are necessary in adult morbidly obese patients in terms of morphine exposure. However, increased concentrations of both M3G and M6G in obese patients could impact the efficacy of morphine and the occurrence of side effects.
References:
[1]Lloret Linares C, Decleves X, Oppert JM, Basdevant A, Clement K, Bardin C, et al. Pharmacology of morphine in obese patients: clinical implications. Clin Pharmacokinet 2009;48(10):635-651.
[2]Centrafarm B.V. Summary of product characteristics, Morphine HCl CF 10 mg/ml. 2010.
[3]Lloret-Linares C, Lopes A, Decleves X, Serrie A, Mouly S, Bergmann JF, et al. Challenges in the optimisation of post-operative pain management with opioids in obese patients: a literature review. Obes Surg 2013 Sep;23(9):1458-1475.
[4]Sarton E, Olofsen E, Romberg R, den Hartigh J, Kest B, Nieuwenhuijs D, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000 Nov;93(5):1245-54; discussion 6A.
Reference: PAGE 24 (2015) Abstr 3566 [www.page-meeting.org/?abstract=3566]
Poster: Drug/Disease modeling - CNS