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Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Aim

To compare the time course of morphine and metabolite concentrations in serum and cerebrospinal fluid (CSF) after intravenous and intramuscular administration after surgery.

Methods

This was a randomized double-blind, double-dummy study in patients who had undergone hip replacement surgery. Morphine (M, 10 mg) was administered intravenously (IV) or intramuscularly (IM). Arterial blood and CSF samples (from a spinal catheter) were drawn simultaneously at 10, 30, 60, and 120 min after administration. Morphine and metabolites [morphine-3-glucuronide (M-3-G), morphine-6-glucuronide (M-6-G), and normorphine (NM)] were determined by a validated liquid chromatography–tandem mass spectrometry method.

Results

Thirty-eight patients were included: 13 men and 25 women, 20 in the IV, 18 in the IM group. Serum concentrations of M after 10 min were consistently higher after IM than IV, concentrations of M-3-G and M-6-G after IM surpassed those of IV after 45 min. NM was not found. None of the metabolites was found in CSF. CSF morphine concentrations and CSF/serum concentration ratios were consistently higher after IV compared to IM. The mean AUCCSF/AUCserum (0–120 min) concentration ratios were 0.18 and 0.09 after IV and IM, respectively.

Conclusions

The uptake of morphine to the CSF was consistently higher after IV administration than after IM already after 10 min. The higher CSF concentration may be caused by an initially higher morphine blood/CSF gradient following IV morphine injection. The pharmacokinetic findings are compatible with a more rapid and extensive initial effect of IV morphine compared with IM.

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Abbreviations

AUC:

area under the time-concentration curve

CSF:

cerebrospinal fluid

IV:

intravenous

IM:

intramuscular

LCMSMS:

liquid chromatography–tandem mass spectrometry

LOQ:

limit of quantification

M:

morphine

M-3-G:

morphine-3-glucuronide

M-6-G:

morphine-6-glucuronide

NM:

normorphine

t max :

time to maximum concentration

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Acknowledgements

The authors are grateful to Trine N Andreassen, M.Sc., for analysing the biological samples. We are also grateful to Dr. Ingolf Meineke, Ph.D., University of Göttingen, Germany, for placing his data to our disposal for analysis of his 90- and 120-min samples. This study complied with Norwegian legislation.

Conflict of interest

None

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Authors and Affiliations

  1. Pain and Palliation Research Group, Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    O. Dale, T. Nilsen, P. C. Borchgrevink & P. Klepstad

  2. Department of Anaesthesiology and Emergency Medicine, St. Olav University Hospital, Trondheim, Norway

    O. Dale, P. C. Borchgrevink & P. Klepstad

  3. Department of Anaesthesiology and Intensive Care, University Hospital of North Norway, Tromsø, Norway

    J. Thoner & T. Tveita

Authors
  1. O. Dale
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  2. J. Thoner
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  3. T. Nilsen
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  4. T. Tveita
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  5. P. C. Borchgrevink
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  6. P. Klepstad
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Corresponding author

Correspondence to O. Dale.

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Dale, O., Thoner, J., Nilsen, T. et al. Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery. Eur J Clin Pharmacol 63, 837–842 (2007). https://doi.org/10.1007/s00228-007-0329-x

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  • DOI: https://doi.org/10.1007/s00228-007-0329-x

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