Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

Klepstad, Pål; Hilton, Priscilla; Moen, Jorunn; Kaasa, Stein; Borchgrevink, Petter C.; Zahlsen, Kolbjørn; Dale, Ola

doi:10.1186/1472-6904-4-7

Cited by 11 publications

(3 citation statements)

References 21 publications

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“…Little is known about the pharmacokinetics of morphine after continuous subcutaneous administration in cancer patients, and solid pharmacokinetic data after oral administration are also lacking. Furthermore, while substantial inter- and intraindividual variability in plasma concentrations of morphine, M3G and M6G has been reported after oral as well as subcutaneous administration [ 16 , 17 ], the causes for this variability and its effects on clinical outcomes of treatment are incompletely understood. Although treatment with morphine is unsuccessful in approximately 30% of patients [ 18 ], it is unknown what causes these treatment failures.…”

Section: Introductionmentioning

confidence: 99%

A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients

et al. 2016

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BackgroundOral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.MethodsBlood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.ResultsA one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration–time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m2 increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m2. The clearance of morphine or its metabolites was not found to be correlated with treatment failure.ConclusionThe influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome.Dutch Trial Register ID: NTR4369.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0471-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients

et al. 2016

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“…The calculated quotas of morphine and its metabolites are within the same range as those reported elsewhere [ 5 , 9 , 13 , 14 ]. Admittedly, this is not an exact science, especially as the day-to-day variations of registered plasma concentrations in constant doses of oral morphine may vary as much as 18% to 46% [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Oral-Parenteral Conversion Factor for Morphine in Palliative Cancer Care: A Prospective Randomized Crossover Pilot Study

Starlander

Melin‐Johansson

Jonsson

et al. 2011

Pain Research and Treatment

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Objective. This pilot study clinically tests whether a conversion factor of 2 to 1 is appropriate when changing from oral to parenteral morphine administration in the treatment of cancer-related nociceptive pain and calculates the size of an adequately powered future study. Methods. Eleven outpatients with incurable cancer and well-controlled nociceptive pain were randomly assigned to either intravenous or subcutaneous morphine using half the previous oral 24-hour dose. Each group crossed over after the first three-day period. Serum concentrations of morphine and its metabolites were monitored as well as intensity of pain. Results. Oral to subcutaneous and oral to intravenous quotas of morphine concentrations were approximately 0.9. Subcutaneous to intravenous morphine quotas were 1. Conclusions. The conversion factor of 2 to 1 seems to be a reasonable average but with an obvious need for individual adjustments. Concurrent medications and substantially higher doses of morphine could potentially affect the appropriate conversion factor. An adequately powered study to validate these findings would need at least 121 patients.

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“…153 Thus, the interaction of variation in the alleles of multiple genes, together with the effect of environmental factors (eg, nutritional status, food intake, comorbid disease, administration of other drugs), may potentially influence a patient's response to a given opioid. 159,[171][172][173][174][175][176] Polymorphisms in the mu-opioid receptor gene are potential primary sources of clinical variability in opioid effects. 177,178 These mutations may affect ligand binding, G protein-effector activation, constitutive activity (in the absence of agonists), receptor dimerization, and receptor desensitization, endocytosis, and downregulation.…”

Section: Genetic Polymorphismsmentioning

confidence: 99%

Pain Management with Opioid Analgesics

Stanos

Fishbain

Fishman

2009

American Journal of Physical Medicine &Amp; Rehabilitation

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Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

Cited by 11 publications

References 21 publications

A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients

A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients

Oral-Parenteral Conversion Factor for Morphine in Palliative Cancer Care: A Prospective Randomized Crossover Pilot Study

Pain Management with Opioid Analgesics

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