In their response to my editorial, 1Romberg et al.  question my conclusion that the jury is still out regarding the relative effects of morphine-6-glucuronide (M6G) and morphine sulfate on analgesia vis-à-vis  respiratory depression. Clearly, the clinical question is, Does M6G cause less respiratory depression than an equianalgesic dose of morphine sulfate? Unfortunately, the study 2addressed in the editorial did not directly answer this question. Although the authors determined the relative effects of M6G and morphine sulfate on ventilatory drive, no data were presented to establish whether the doses (or brain concentrations) of the two compounds provided equivalent analgesia. For M6G, the brain concentration required to decrease the ventilatory response to hypercapnia by 25% was 528 nm (with n = 9, their reported SE of 88 nm translates to 95% confidence limits of 329–727 nm).

The data that Romberg et al.  cite in their letter to establish the analgesic potency of M6G come from an abstract that was presented at the October 2003 Annual Meeting of the American Society of Anesthesiologists (San Francisco, California) 3after my editorial had appeared in print. Furthermore, based on the data presented in the abstract, the confidence limits for the analgesic potency of M6G were even wider than those for respiratory depression. The mean brain concentration estimated to increase pain tolerance by 25% was 275 nm, with 95% confidence limits ranging from −7 to 557 nm; these values clearly overlap the 95% confidence range for respiratory depression. Thus, the combined data from the two studies of Romberg et al.  do not demonstrate a statistically or clinically significant respiratory-sparing effect of M6G. Therefore, I stand by my conclusion that even with their new data, the authors have yet to demonstrate an increased margin of safety for M6G as compared with morphine.

Romberg et al.  raised concerns regarding the placement of the “most important statement” of my Editorial View in a footnote. This was not done to minimize the importance of model selection, but rather to avoid interfering with the flow of the associated text.

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
Romberg R, Olofsen E, Sarton E, Taschner P, Dahan A: Variability of morphine-6-glucuronide analgesic potency is related to μ-opioid receptor polymorphism (abstract). Anesthesiology 2003; 99:A-517