Background & Aims

The BioPain subtopic of the IMI-PainCare project (https://imi-paincare.eu) was designed to address the critical gap in effective chronic pain management strategies, focusing on the discrepancy between animal model research and human clinical outcomes. Its core aim was to evaluate the effectiveness of selected biomarkers at various neurological levels — peripheral, spinal, and central — for assessing drug impact and target interaction in the development of new analgesics.
As part of the IMI-PainCare project, IMI2-PainCare-BioPain-RCT2 specifically tested, in healthy participants, the efficacy against placebo of three analgesics (lacosamide, pregabalin and tapentadol) on biomarkers derived from non-invasive neurophysiological spinal measurements,namely the RIII flexion reflex and the cervical N13 component of somatosensory evoked potentials (SEP), in both normal and hyperalgesic conditions, induced by high-frequency electrical stimulation (HFS) of the skin.

Methods

A multi-center, exploratory, single-dose, double-blind, randomized, placebo controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal activity (RIII flexion reflex and N13-SSEP component), were recorded before and at three distinct time points after administering three medications (lacosamide 2×100 mg, pregabalin 2x75mg, tapentadol 2x50mg), and a placebo. The impact of these drugs on neurophysiological responses was evaluated under conditions of induced hyperalgesia (HFS) and normal, non-sensitized states. Participant feedback on pain and psychological assessments were gathered, along with blood samples for pharmacokinetic analysis. The study used a detailed statistical approach, balancing the primary analysis’s alpha error across the primary endpoints: changes in the amplitude of RIII and N13 under tapentadol. Secondary analyses focused on the effects of other treatments on these biomarkers.

Results

Three different centres enrolled a total of 24 subjects. We obtained observations for 23 participants in the placebo arm, 24 for lacosamide, 22 for pregabalin, and 23 for tapentadol. The blinded analysis showed an effect of tapentadol at PD2 on the area under the curve of the R3 (0.047) and a trend towards the significance of pregabalin (0.072) only at the sensitized side, even if the predetermined level of significance (0.025) was not reached. There was no significant effect of drugs on the N13. The exploratory analysis showed an overall effect of drugs on the RIII threshold, as compared to placebo (PD3 and PD4) and an effect of tapentadol and pregabalin on pain ratings during the first measurement after drug intake (PD2). The Mixed Model Repeated Measure (MMRM) for tiredness disclosed a significant higher rating in the pregabalin arm as compared to placebo (PGB: 45 ± 22.17; PL: 31.3 ± 22.01; p=0.025) while the level of anxiety was not different across the four study periods.

Conclusions

Tapentadol prevent the spinal excitability changes induced by secondary hyperalgesia models as assessed with the nociceptive flexion reflex. This experimental design failed to identify a significant effect of tapentadol on the N13. Pregabalin seems to have the same efficacy as tapentadol in preventing changes in spinal excitability, proving to have an antihyperalgesic effect, detectable with the use of the nociceptive flexion reflex. Both the area and the threshold of RIII are useful biomarkers in identifying the effect of drugs on changes in spinal excitability, although the threshold of the reflex seems to be the more robust parameter. The very low incidence of adverse events confirmed the safety of the drugs tested.

References

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Leone, C et al. «IMI2-PainCare-BioPain-RCT2 Protocol: A Randomized, Double-Blind, Placebo-Controlled, Crossover, Multicenter Trial in Healthy Subjects to Investigate the Effects of Lacosamide, Pregabalin, and Tapentadol on Biomarkers of Pain Processing Observed by Non-Invasive Neurophysiological Measurements of Human Spinal Cord and Brainstem Activity». Trials 23, fasc. 1 (5 settembre 2022): 739. https://doi.org/10.1186/s13063-022-06431-5.

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Presenting Author

Andrea Truini

Poster Authors

Caterina Leone, MD PhD

MD, PhD

Department of Human Neuroscience, Sapienza University of Rome

Lead Author

E-mail

Giuseppe di Pietro

Lead Author

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Kenneth Steel

University of Bristol

Lead Author

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Ombretta Caspani

Mannheim Center for Translational Neuroscience, Heidelberg University

Lead Author

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Rolf-Detlef Treede

Heidelberg University

Lead Author

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Andrè Mouraux

Lead Author

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Luis Garcia-Larrea

INSERM U1028 / CRNL

Lead Author

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Andrea Truini

University Sapienza

Lead Author

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Topics

  • Models: Chronic Pain - Neuropathic