Correspondence  |   June 2004
Increased Margin of Safety of Morphine-6-glucuronide Relative to Morphine
Author Affiliations & Notes
  • Albert Dahan, M.D., Ph.D.
  • * Leiden University Medical Center, Leiden, The Netherlands.
Article Information
Correspondence   |   June 2004
Increased Margin of Safety of Morphine-6-glucuronide Relative to Morphine
Anesthesiology 6 2004, Vol.100, 1622. doi:
Anesthesiology 6 2004, Vol.100, 1622. doi:
To the Editor:—  With interest we read the Editorial View by Dr. Jeffrey Gross in the October 2003 issue of Anesthesiology 1 commenting on our article in that same issue. 2 In this article, we estimated an effect site (i.e.  , brain) concentration of morphine-6-glucuronide (M6G) to cause 25% reduction in breathing during hypercapnic and hypoxic stimulation (C25) of 530 and 870 nm, respectively. Dr. Gross compares these values to plasma concentrations of 400 nm from a study by Lötsch et al.  3 at which no analgesia was perceived. We believe that these numbers are incomparable. Our C25values are the estimated brain concentrations, whereas the value of Lötsch et al.  is a plasma concentration. Taking into account a blood effect site equilibration half-life of approximately 6 h for M6G, 4,5 we calculated that the brain M6G concentration in the study of Lötsch et al.  was maximally 144 nm, which is a factor of 4–6 less than our values. For morphine, the corresponding C25values estimated by us were 30 and 20 nm for hypercapnic and hypoxic breathing, respectively. 2 
In fact, in a subsequent study in which we tested the analgesic properties of M6G, we observed that a steady state or brain M6G concentration (C25) of 275 nM is needed for a 25% increase in electrical current (pain tolerance). 5 The corresponding C25value for morphine is 20–30 nm. 6 This indicates that much greater M6G concentrations are needed to suppress respiration relative to the values needed to induce analgesia greater than placebo. 5 In sharp contrast, for morphine, these values are of the same order of magnitude. Evidently, how our C25and C25values derived from an electrical pain model reflect concentrations needed for postoperative pain relief necessitates further study.
Finally, we were surprised to find the most important statement in the Editorial View in a footnote. In that footnote, Dr. Gross indicates the need for a respiratory model that adequately describes apnea at relatively high opioid concentrations. In contrast to the other model described in the review, the model used by us (the power or Leiden model) is able to predict apnea at realistic opioid concentrations. For example, the Leiden model indicates that hypercapnic breathing is abolished at a morphine brain concentration of approximately 100 nm in a volunteer without pain or stress. This is a very realistic value.
Gross JB: When you breathe IN you inspire, when you DON’T breathe, you. . .expire. Anesthesiology 2003; 99:767–70
Romberg R, Olofsen E, Sarton E, Teppema L, Dahan A: Pharmacodynamic effect of morphine-6-glucuronide versus  morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology 2003; 99:788–98
Lötsch J, Kobal G, Stockmann A, Brune K, Geisslinger G: Lack of analgesic activity of morphine-6-glucuronide after short-term intravenous administration in healthy volunteers. Anesthesiology 1997; 87:1348–58
Lötsch J, Schmidt H, Grösch S, Geisslinger G: The transfer half-life of morphine-6-glucuronide from plasma to effect-site assessed by pupil size measurement in healthy volunteers. Anesthesiology 2001; 95:1329–38
Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PEM, Dahan A: Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers. Anesthesiology 2004; 100:120–33
Sarton E, Sarton E, Olofsen E, Romberg R, den Hartigh J, Kest B, Nieuwenhuijs D, Burm A, Teppema L, Dahan A: Sex differences in morphine analgesia. Anesthesiology 2000; 93:1245–54