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Non-invasive combined surrogates of remifentanil blood concentrations with relevance to analgesia

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Abstract

Surrogates may provide easy and quick access to information about pharmacological parameters of interest that can be directly measured only with difficulty. Surrogates have been proposed for opioid blood concentrations to replace invasive sampling, serving as a basis for target-controlled infusion systems to optimize analgesia. We aimed at identifying surrogates of remifentanil steady-state blood concentrations with relevance for its clinical, in particular, analgesic, effects. A “single ascending dose” study design assessed concentration-dependent effects of remifentanil in a double-blind randomized fashion in 16 healthy volunteers. Remifentanil was administered by means of computerized infusion aimed at steady-state effect–site concentrations of 0, 1.2, 1.8, 2.4, 3, 3.6, 4.8, and 6 ng/ml (one concentration per subject, two subjects per concentration). Arterial remifentanil blood concentrations were measured during apparent steady state. Pharmacodynamic parameters were measured at baseline and during steady-state conditions. Potential surrogate parameters included the pupil diameter, the amplitude of pupil light reflex, and the performance in a visual tracking task. Clinical parameters were analgesia to experimental pain, nausea, tiredness, and visual acuity. Remifentanil blood concentrations were well predicted by its effects on the pupil light reflex amplitude, better than by its miotic effects. However, the best prediction for both remifentanil blood concentrations and analgesic effects was obtained using a combination of three surrogate parameters (pupil diameter, light reflex amplitude, and tracking performance). This combination of pharmacodynamic parameters provided even better predictions of analgesia than could be obtained using the measured opioid blood concentrations. Develo** surrogates only for opioid blood concentrations is insufficient when opioid effects are the final goal. Combining pharmacodynamic surrogate parameters seems to provide a promising approach to obtain acceptable predictions of relevant clinical effects, with better results than obtained with measuring or estimating blood concentrations.

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Notes

  1. These parameters had been obtained by a standard fit of pooled data using a classical sigmoid pharmacodynamic model. Details about goodness-of-fit are: the standard error of estimate of EC50 = 0.1, E max did not significantly differ from a value of −100 % and had therefore been fixed, and goodness-of-fit, R 2 = 0.984.

  2. Again, these values had been obtained using a standard sigmoidal model: The standard error of the estimate of EC50 was 4; E max did not significantly differ from a value of −100 % and had therefore been fixed, and R 2 was 0.274.

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Acknowledgments

All the authors declare that there are no personal financial holdings that could be perceived as constituting a potential conflict of interests. All authors, except JL, further declare that no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service. One author, JL, declares that he received research support from Cortex Pharmaceuticals, Irvine, California, USA, and received counselling compensation from BioMed Valley Discoveries, Inc., Kansas City, USA, and a presentation honorarium from Janssen-Cilag, all without any relation to the present analysis, which was an effort in the context of the “Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz”: “LOEWE-Schwerpunkt: Anwendungsorientierte Arzneimittelforschung”. The study medication had been provided by Glaxo Wellcome GmbH & Co., Hamburg, Germany, who had no further involvement in the project, including planning, performance, data analysis, and writing of this report. There was no further assistance with the study. There was no further financial support or sponsorship. Data from the reported study, non-redundant with the present analysis, have been published in another context in Life Sciences 2001;69(19):2279–85 and Clin Pharmacokinet 2012;51(10):629–38.

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Author notes

  1. Carsten Skarke

    Present address: Institute for Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, 8036 Maloney Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA

  2. Jutta Darimont

    Present address: Department of Nephrology and Rheumatology, Krankenhaus der Barmherzigen Brüder, Teaching Hospital of the University of Mainz, Trier, Germany

Authors and Affiliations

  1. Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany

    Jörn Lötsch, Carsten Skarke, Jutta Darimont, Lutz Bräutigam, Gerd Geisslinger & Bruno G. Oertel

  2. Department of Anesthesia, Intensive Care and Pain Therapy, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt, Germany

    Michael Zimmermann

  3. Department of Computer Science and Mathematics, Data Bionics Research Group, University of Marburg, Hans-Meerwein-Straße 22, 35032, Marburg, Germany

    Alfred Ultsch

  4. Fraunhofer Project Group Translational Medicine and Pharmacology (IME-TMP), Theodor Stern Kai 7, 60590, Frankfurt, Germany

    Jörn Lötsch, Gerd Geisslinger & Bruno G. Oertel

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Correspondence to Jörn Lötsch.

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Lötsch, J., Skarke, C., Darimont, J. et al. Non-invasive combined surrogates of remifentanil blood concentrations with relevance to analgesia. Naunyn-Schmiedeberg's Arch Pharmacol 386, 865–873 (2013). https://doi.org/10.1007/s00210-013-0889-5

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