Abstract
Whether the analgesic effects of opioids change as a neonate matures is not well understood. To address this issue, we determined the pharmacokinetics and pharmacodynamics of analgesic effects of morphine and fentanyl in 35 dogs aged 1 to 34 days. Opioids were infused to produce analgesia, response times to a noxious thermal stimulus were measured and plasma opioid concentrations were determined. An effect compartment pharmacodynamic model was fit to the values for time to response to determine the rate constant for equilibration (keo) between plasma and effect-site (Ce) concentrations and analgesic effect (increase in time to response to a noxious stimulus) above baseline per μg/ml of Ce (Δ). A time-to-event data analysis (modeled with a Weibull function) was used to account for censored time to response values. For both opioids, values for keo did not vary with age. Values for Δ decreased with age (i.e., decreasing sensitivity with increasing age), and the magnitude of the change during the first month of life was similar for the two opioids. In the context of our previous study concerning ventilatory depressant effects of these opioids (that sensitivity to morphine, but not to fentanyl, decreased markedly during the first month of life), these results in dogs suggest that fentanyl has greater utility than morphine in neonates during spontaneous ventilation.
Footnotes
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Send reprint requests to: Dennis M. Fisher, M.D., Department of Anesthesia, University of California, San Francisco, CA 94143-0648.
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↵1 This work was supported in part by National Institutes of Health Grant GM37795 (D.M.F.).
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↵3 These data could have been obtained had we performed additional studies in which we administered these metabolites and measured analgesic effects.
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↵2 The code for the NONMEM analysis is available from Dr. Fisher at e-mail: fisher{at}zachary.ucsf.edu
- Abbreviations:
- Ce
- opioid concentration at effect site
- keo
- rate constant for equilibration between plasma and effect-site opioid concentrations
- Cl
- total plasma clearance
- Clrapid
- rapid distributional clearance
- Clslow
- slow distributional clearance
- Δ
- analgesic effect (increase in time to response to a noxious stimulus) per μg/ml of Ce
- V1
- volume of the central compartment
- V2
- volume of the shallow peripheral compartment
- V3
- volume of the deep peripheral compartment
- Vss
- volume of distribution at steady state
- Received February 28, 1997.
- Accepted September 3, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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