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Randomized Controlled Trial
. 2025 Nov 1;143(5):1279-1295.
doi: 10.1097/ALN.0000000000005694. Epub 2025 Aug 4.

Effects of Lacosamide, Pregabalin, and Tapentadol on Peripheral Nerve Excitability: A Randomized, Double-blind, Placebo-controlled, Crossover, Multicenter Trial in Healthy Subjects

Zahra Nochi  1 , Hossein Pia  2 , Petra Bloms-Funke  3 , Irmgard Boesl  4 , Ombretta Caspani  5 , Sonya C Chapman  6 , Giuseppe Di Pietro  7 , Francesca Fardo  8 , Bernd Genser  9 , Marcus Goetz  10 , Bo Jiang  11 , Anna V Kostenko  5 , Louisien Lebrun  12 , Caterina M Leone  7 , Thomas Li  13 , Niko Möller-Grell  14 , André Mouraux  12 , Bernhard Pelz  10 , Esther Pogatzki-Zahn  15 , Clarence Rong  13 , Andreas Schilder  16 , Erik Schnetter  17 , Karin Schubart  18 , Irene Tracey  19 , Andrea Truini  7 , Katy Vincent  20 , Jan Vollert  21 , Vishvarani Wanigasekera  22 , Matthias Wittayer  5 , Rolf-Detlef Treede  5 , Hatice Tankisi  23 , Nanna B Finnerup  1
Affiliations
Randomized Controlled Trial

Effects of Lacosamide, Pregabalin, and Tapentadol on Peripheral Nerve Excitability: A Randomized, Double-blind, Placebo-controlled, Crossover, Multicenter Trial in Healthy Subjects

Zahra Nochi et al. Anesthesiology. .

Abstract

Background: Chronic pain is a leading cause of disability globally, with limited treatment options and frequent adverse effects. The IMI-PainCare-BioPain project aimed to enhance analgesic drug development by standardizing biomarkers. This study, IMI2-PainCare-BioPain-RCT1, evaluated the effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability in healthy subjects through a randomized, double-blind, placebo-controlled crossover trial.

Methods: The study included 43 healthy participants aged 18 to 45 yr. Participants underwent four treatment periods during which they received single doses of lacosamide (200 mg), pregabalin (150 mg), tapentadol (100 mg), or placebo. High-frequency stimulation was applied to induce hyperalgesia. The two primary endpoints were changes in strength-duration time constant (SDTC) in large sensory and motor fibers between lacosamide and placebo periods at the first postdose timepoint compared to baseline (60 min). Other predefined endpoints included recovery cycle, threshold electrotonus (TEd), and S2 accommodation, as well as effects of pregabalin and tapentadol.

Results: Lacosamide statistically significantly reduced SDTC in large sensory fibers (mean reduction, 0.04; 95% CI, 0.01 to 0.08; P = 0.012) and in motor fibers (mean reduction, 0.04; 95% CI, 0.00 to 0.07; P = 0.039) but had no effect on small sensory fibers at the first timepoint compared to placebo. There were no effects of pregabalin and tapentadol on SDTC. Of other predefined endpoints, lacosamide produced statistically significant changes in subexcitability, S2 accommodation TEd(peak), and TEd40(Accom) in large sensory fibers. No statistically significant changes were observed in refractoriness, relative refractory period, or accommodation half-time at the first timepoint compared to placebo.

Conclusions: This study demonstrates that nerve excitability testing can detect pharmacodynamic effects on large myelinated fibers in healthy subjects. Lacosamide statistically significantly reduced peripheral nerve excitability, particularly in large sensory fibers.

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Conflict of interest statement

Dr. Bloms-Funke was an employee of Grünenthal GmbH (Aachen, Germany) when she contributed to the study protocol and reports consultancy fees from Consultech GmbH (Berlin, Germany) during the conduct of the study. Dr. Boesl is an employee of Grünenthal GmbH. Dr. Chapman is an employee of Eli Lilly and Company. Dr. Goetz and Dr. Pelz are employees and shareholders of MRC Systems GmbH (Heidelberg, Germany), a company that manufactures and markets the HFS electrodes used in this study, as well as other instruments for quantitative testing of pain. Dr. Kostenko was an employee of Heidelberg University and received salary as a research assistant when she contributed to the study. Dr. Möller-Grell was an employee of the Heidelberg University Institute for Medical Informatics and the University Hospital Heidelberg Department of Anesthesia. Dr. Pogatzki-Zahn has received payments from Grünenthal, Merck, MSD Sharp and Dohme GmbH, and Medtronic for advisory board activities and lecture fees and has received funding for research from the Gemeinsamer Bundesausschuss, the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777500 (this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations), Grünenthal, the (DFG, German Research Foundation, Bonn, Germany), and the Bundesministerium für Bildung und Forschung (BMBF, German Federal Ministry of Education and Research, Berlin, Germany) (all payments were made to the institution Dr. Pogatzki-Zahn works for). Dr. Schubart is an employee of ConsulTech GmbH. Dr. Vincent has received payments to her institution for lectures, consultancy, and associated travel costs from Reckitts, Gesynta, and Gedeon Richter. Dr. Truini has received consultancy fees and research funding from Abbvie, Amgen, Epitech, Grünenthal, and Viatris. Dr. Vollert has conducted contract research for Viatris and AstraZeneca. Dr. Wanigasekera is funded by Oxford Health BioMedical Research Center. Dr. Treede reports grants from the IMI2-PainCare project of the European Union and grants from TEVA and Esteve during the conduct of the study, as well as personal fees from Bayer, Grünenthal, GSK, Merz, Saluda, Sanofi, and Vertex outside the submitted work; in addition, Dr. Treede holds patent No. DE 103 31 250.1-35 with royalties paid by MRC Systems. Dr. Finnerup has received consultancy fees from PharmNovo, Vertex, NeuroPN, Saniona, Nanobiotix, and Neurvati and has undertaken consultancy work for Aarhus University with remunerated work for AKIGAI, Biogen, Merz, and Confo Therapeutics outside the submitted work. The other authors declare no competing interests.

The article processing charge was funded by Lundbeck Foundation through grant No. R359-2020-2620 (to Dr. Finnerup).

Figures

Fig. 1.
Fig. 1.
Trial design of each study period. Motor and sensory nerve excitability tests, perception threshold tracking, and pain assessments were conducted after HFS at four timepoints (PD1 to PD4), with drug administration after PD1. Five blood samples (PK1 to PK5) were collected to model drug kinetics. HFS, high-frequency stimulation; PD, pharmacodynamic; PK, pharmacokinetics; PROM, patient-reported outcome measure. *, anxiety and expectation of pain; **, expectation of pain relief; ***, tiredness and state of anxiety.
Fig. 2.
Fig. 2.
Overview of participant flow. ECG, electrocardiogram; PD, pharmacodynamic measurements.
Fig. 3.
Fig. 3.
Strength–duration time constant (SDTC; ms) and plasma concentration levels (ng/ml) for lacosamide (red), pregabalin (blue), tapentadol (green), and placebo (black) across PD1 to PD4. (A, B) Mean (± SD) SDTC in large sensory (A) and motor (B) fibers measured at four PD sessions; PD1 (−1 h), PD2 (1 h), PD3 (3 h), and PD4 (6 h), with time relative to dose. (C) Plasma concentrations (mean ± SD) of lacosamide, pregabalin, and tapentadol at different timepoints (0.75, 2.5, 4, 7, and 24 h) postadministration. The timepoints for pharmacokinetic (PK) measurements do not align perfectly with the PD blocks (see fig. 1). (D, E) The change in SDTC from baseline (PD1) in large sensory (D) and motor (E) fibers is shown for each drug and placebo condition across PD blocks 2 to 4, with statistically significant reductions observed for lacosamide (*, P < 0.025) compared to placebo in large sensory fibers. PD, pharmacodynamic.
Fig. 4.
Fig. 4.
Strength duration relationship for lacosamide (red), pregabalin (blue), and tapentadol (green) compared to placebo (black) in large sensory (A to C) and motor (D to F) nerve excitability testing recording. Statistically significant reduction in strength–duration time constant induced by lacosamide is highlighted in the graph.
Fig. 5.
Fig. 5.
Strength–duration time constant (SDTC; ms) for lacosamide (red), pregabalin (blue), tapentadol (green), and placebo (black) in small sensory perception threshold tracking (PTT) of nonsensitized arm (A) and sensitized arm (B) across PD1 to PD4. PD, pharmacodynamic.
Fig. 6.
Fig. 6.
Sensory nerve excitability threshold tracking recordings. (A to C) Threshold electrotonus (A, B) and recovery cycle (C) of lacosamide (red) compared to placebo (black). Statistically significant changes induced by lacosamide are highlighted in the graphs.
See this image and copyright information in PMC

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