Advertisement

Pharmacy World & Science

, Volume 32, Issue 6, pp 737–743 | Cite as

Relationship between plasma concentrations of morphine and its metabolites and pain in cancer patients

  • Tomoya SakuradaEmail author
  • Shinya Takada
  • Hisae Eguchi
  • Keishiro Izumi
  • Nobunori Satoh
  • Shiro Ueda
Research Article

Abstract

Objective This study was undertaken to investigate the relationship between the plasma concentration of morphine, morphine-3-glucuronide and morphine-6-glucuronide and pain in cancer patients receiving oral morphine. Methods The trough value of plasma concentrations of morphine and its metabolites were measured by high performance liquid chromatography using an ultraviolet detector. Using this assay system, the plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide in 26 cancer pain patients were measured and compared with pain intensity. The pain intensity was assessed at the time of blood sampling using the visual analog scale. Results The trough value of morphine and morphine-6-glucuronide did not show a significant correlation with pain intensity by visual analog scale assessment, but morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine showed a significantly positive correlation (r = 0.528, P = 0.006 and r = 0.671, P < 0.001, respectively). By dividing the group according to low (≤ median value) or high (> median value) VAS scores a significant difference was found between the two groups in morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine (P = 0.045 and P = 0.007, respectively). Conclusion These results indicated that the level of morphine-3-glucuronide is related to the patient’s perception of morphine effect, and the plasma concentration of morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine indicated potency to assess clinical effect.

Keywords

Cancer pain Morphine Morphine-3-glucuronide Morphine-6-glucuronide Pain assessment Plasma concentration 

Notes

Funding

None.

Conflict of interest

The authors declare no conflict of interest directly relevant to the content of this manuscript.

References

  1. 1.
    Potter JM, Reid DB, Shaw RJ, Hackett P, Hickmann PE. Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs. Br Med J. 1989;299:150–3.CrossRefGoogle Scholar
  2. 2.
    Eisele JH, Grisby EJ, Den G. Clonazepam treatment of myoclonic contractions associated with high-dose opioids: case report. Pain. 1992;49:213–32.CrossRefGoogle Scholar
  3. 3.
    Sjogren P, Jonsson T, Jensen NH, Drenck NE, Jensen TS. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain. 1993;55:93–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Sjogren P, Jensen NH, Jensen TS. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain. 1994;59:313–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Mercadante S. Dantrolene treatment of opioid-induced myoclonus. Anesth Analg. 1995;81:1307–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Iwamoto K, Klaassen CD. First-pass effect of morphine in rats. J Pharmacol Exp Ther. 1977;200:236–44.PubMedGoogle Scholar
  7. 7.
    Bock KW, Brunner G, Hoensch M, Huber E, Josting D. Determination of microsomal UDP-glucuronyl transferase in needle-biopsy specimens of human liver. Eur J Clin Pharmacol. 1978;14:367–73.CrossRefPubMedGoogle Scholar
  8. 8.
    Paul D, Standifer KM, Inturrisi CE, Pasternak GW. Pharmacological characterization of morphine-6-beta-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther. 1989;251:477–83.PubMedGoogle Scholar
  9. 9.
    Frances B, Gout R, Monsarrat B, Cros J, Zajac J-M. Further evidence that morphine-6-glucuronide is a more potent opioid agonist than morphine. J Pharmacol Exp Ther. 1992;262:25–31.PubMedGoogle Scholar
  10. 10.
    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;28:345–472.CrossRefPubMedGoogle Scholar
  11. 11.
    Labella FS, Pinsky C, Havlicek V. Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity. Brain Res. 1979;174:263–71.CrossRefPubMedGoogle Scholar
  12. 12.
    Wright AWE, Nocente M-L, Smith MT. Hydromorphone-3-glucuronide: biochemical synthesis and preliminary pharmacological evaluation. Life Sci. 1998;63:401–11.CrossRefPubMedGoogle Scholar
  13. 13.
    Yaksh TL, Harty GJ, Onofrio BM. High doses of spinal morphine produce a non-opiate receptor-mediated hyperesthesia: clinical and theoretic implications. Anesthesiology. 1986;64:590–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Bartlett SE, Cramond T, Smith MT. The excitatory effects of M3G are attenuated by LY274614, a competitive NMDA receptor antagonist and by midazolam, an agonist at the benzodiazepine site on the GABAA receptor complex. Life Sci. 1994;54:68–94.CrossRefGoogle Scholar
  15. 15.
    Urca G, Frenk H, Liebeskind J, Taylor A. Morphine and enkephalin: analgesic and epileptic properties. Science. 1977;197:83–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Woolf C. Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Res. 1981;209:491–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide—a potent antagonist of morphine analgesia. Life Sci. 1990;47:579–85.CrossRefPubMedGoogle Scholar
  18. 18.
    Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Lond. 1969;62(10):989–93.Google Scholar
  19. 19.
    Meng QC, Cepeda MS, Kramer T, Zou H, Matoka DJ, Farrar J. High-performance liquid chromatographic determination of morphine and its 3- and 6-glucuronide metabolites by two-step solid-phase extraction. J Chromatogr B Biomed Sci Appl. 2000;742:115–23.CrossRefPubMedGoogle Scholar
  20. 20.
    Arty K, Róna K. LC determination of morphine and morphine glucuronides in human plasma by coulometric and UV detection. J Pharm Biomed Anal. 2001;26:179–87.CrossRefGoogle Scholar
  21. 21.
    Freiermuth M, Plasse JC. Determination of morphine and codeine in plasma by HPLC following solid phase extraction. J Pharm Biomed Anal. 1997;15:759–64.CrossRefPubMedGoogle Scholar
  22. 22.
    Fernández P, Morales L, Vázquez C, Bermejo AM, Tabernero MJ. HPLC-DAD determination of opioids, cocaine and their metabolites in plasma. Forensic Sci Int. 2006;161:31–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Groenendaal D, Blom-Roosemalen MC, Danhof M, Lange EC. High-performance liquid chromatography of nalbuphine, butorphanol and morphine in blood and brain microdialysate samples: application to pharmacokinetic/pharmacodynamic studies in rats. J Chromatogr B Anal Technol Biomed Life Sci. 2005;822:230–7.CrossRefGoogle Scholar
  24. 24.
    Bogusz MJ, Maier RD, Erkens M, Driessen S. Determination of morphine and its 3- and 6-glucuronides, codeine, codeine-glucuronide and 6-monoacetylmorphine in body fluids by liquid chromatography atmospheric pressure chemical ionization mass spectrometry. J Chromatogr B Biomed Sci Appl. 1997;5(703):115–27.CrossRefGoogle Scholar
  25. 25.
    Cheremina O, Bachmakov I, Neubert A, Brune K, Fromm MF, Hinz B. Simultaneous determination of oxycodone and its major metabolite, noroxycodone, in human plasma by high-performance liquid chromatography. Biomed Chromatogr. 2005;19:777–82.CrossRefPubMedGoogle Scholar
  26. 26.
    Musshoff F, Trafkowski J, Kuepper U, Madea B. An automated and fully validated LC-MS/MS procedure for the simultaneous determination of 11 opioids used in palliative care, with 5 of their metabolites. J Mass Spectrom. 2006;41:633–40.CrossRefPubMedGoogle Scholar
  27. 27.
    Fredheim OM, Borchgrevink PC, Klepstad P, Kaasa S, Dale O. Long term methadone for chronic pain: a pilot study of pharmacokinetic aspects. Eur J Pain. 2007;11:599–604.CrossRefPubMedGoogle Scholar
  28. 28.
    Moran TD, Smith PA. Morphine-3 beta-d-glucuronide suppresses inhibitory synaptic transmission in rat substantia gelatinosa. J Pharmacol Exp Ther. 2002;302:568–76.CrossRefPubMedGoogle Scholar
  29. 29.
    Hemstapat K, Monteith GR, Smith D, Smith MT. Morphine-3-glucuronide’s neuro-excitatory effects are mediated via indirect activation of N-methyl-d-aspartic acid receptors: mechanistic studies in embryonic cultured hippocampal neurones. Anesth Analg. 2003;97(2):494–505.CrossRefPubMedGoogle Scholar
  30. 30.
    Smith GD, Smith MT. Morphine-3-glucuronide: evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat. Pain. 1995;62(1):51–60.CrossRefPubMedGoogle Scholar
  31. 31.
    Vigano A, Fan D, Bruera E. Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators. Pain. 1996;67:115–9.CrossRefPubMedGoogle Scholar
  32. 32.
    De Armendi AJ, Fahey M, Ryan JF. Morphine-induced myoclonic movements in a pediatric pain patient. Anesth Analg. 1993;77:191–2.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Tomoya Sakurada
    • 1
    Email author
  • Shinya Takada
    • 2
  • Hisae Eguchi
    • 3
  • Keishiro Izumi
    • 4
  • Nobunori Satoh
    • 5
  • Shiro Ueda
    • 1
  1. 1.Department of Drug Information and CommunicationGraduate School of Pharmaceutical Sciences, Chiba UniversityChuo-kuJapan
  2. 2.Department of PharmacyNational Hospital Organization Hokkaido Cancer CenterSapporoJapan
  3. 3.Department of PharmacyNational Hospital Organization Shikoku Cancer CenterMatsuyamaJapan
  4. 4.Department of PharmacyNational Cancer Center Hospital EastKashiwaJapan
  5. 5.Department of Clinical Education and ResearchGraduate School of Pharmaceutical Sciences, Chiba UniversityChuo-kuJapan

Personalised recommendations