TY - JOUR

T1 - Quantification of the Pharmacodynamic Interaction of Morphine and Gabapentin Using a Response Surface Approach

AU - Papathanasiou, Theodoros

AU - Juul, Rasmus Vestergaard

AU - Gabel-Jensen, Charlotte

AU - Kreilgaard, Mads

AU - Heegaard, Anne Marie

AU - Lund, Trine Meldgaard

PY - 2017/11/1

Y1 - 2017/11/1

N2 - The combination of morphine and gabapentin has shown to be promising for managing postoperative pain but finding the right dose for the combination has proven to be a challenge. The purpose of this study was to quantitatively characterize the pharmacodynamic interaction between the two drugs and to identify the optimal concentration–effect relationship of the combination. Information regarding plasma concentrations and von Frey withdrawal thresholds following incisional surgery on Sprague Dawley rats, after administration of morphine, gabapentin, or their combination was available from published studies. The combined pharmacodynamic effect of morphine and gabapentin was analyzed and linked to drug plasma concentrations via a response surface approach using non-linear mixed-effect modeling. Full reversal of withdrawal thresholds for the pain stimulation to presurgery values was estimated at morphine plasma concentration of 435.1 ng/mL. Co-administration of up to 40 μg/mL of gabapentin led to a reduction of the needed morphine concentration down to 307.5 ng/mL (~ 29% reduction). Combination of concentration ranges of gabapentin between 20 and 40 μg/mL with any morphine concentrations between 100 and 600 ng/mL were found to lead up to 50% increased effect relatively to the effect attained by morphine alone. This study highlights the importance of finding the right combination in multimodal analgesia and demonstrates the usefulness of the response surface approach for the study of pharmacodynamic interactions. The proposed pharmacokinetic–pharmacodynamic model may provide the basis for a rational clinical trial design with the aim to identify the optimal dose combination ratios in humans.

AB - The combination of morphine and gabapentin has shown to be promising for managing postoperative pain but finding the right dose for the combination has proven to be a challenge. The purpose of this study was to quantitatively characterize the pharmacodynamic interaction between the two drugs and to identify the optimal concentration–effect relationship of the combination. Information regarding plasma concentrations and von Frey withdrawal thresholds following incisional surgery on Sprague Dawley rats, after administration of morphine, gabapentin, or their combination was available from published studies. The combined pharmacodynamic effect of morphine and gabapentin was analyzed and linked to drug plasma concentrations via a response surface approach using non-linear mixed-effect modeling. Full reversal of withdrawal thresholds for the pain stimulation to presurgery values was estimated at morphine plasma concentration of 435.1 ng/mL. Co-administration of up to 40 μg/mL of gabapentin led to a reduction of the needed morphine concentration down to 307.5 ng/mL (~ 29% reduction). Combination of concentration ranges of gabapentin between 20 and 40 μg/mL with any morphine concentrations between 100 and 600 ng/mL were found to lead up to 50% increased effect relatively to the effect attained by morphine alone. This study highlights the importance of finding the right combination in multimodal analgesia and demonstrates the usefulness of the response surface approach for the study of pharmacodynamic interactions. The proposed pharmacokinetic–pharmacodynamic model may provide the basis for a rational clinical trial design with the aim to identify the optimal dose combination ratios in humans.

U2 - 10.1208/s12248-017-0140-2

DO - 10.1208/s12248-017-0140-2

M3 - Journal article

C2 - 28853055

AN - SCOPUS:85028773083

VL - 19

SP - 1804

EP - 1813

JO - A A P S Journal

JF - A A P S Journal

SN - 1550-7416

IS - 6

ER -