257: High-Frequency Stimulation in Inducing Central Sensitization and Modulation by Oxycodone and Nefopam

Topic: Clinical Science
Subtopic: Non-specific to any diagnosis, Pharmacological treatments, Drug development, Quantitative Sensory testing (static and dynamic, e.g., HPT, PPT, CPM, TSP, offset analgesia)

Background and Aims: High-frequency electrocutaneous stimulation (HFS) of peripheral nerve fibers is a method used to induce secondary hyperalgesia and allodynia in the human skin, which has been proposed as a surrogate model for studying central sensitization. We aimed to evaluate an HFS-model and evaluate the analgesic effects of oxycodone and nefopam on HFS-induced allodynic changes. Additionally, we explored whether HFS could induce an increase in pain facilitation (∆NRS>2) characteristic of chronic pain states through multimodal temporal summation (TS) testing.

Methods: In this randomized, double-blind/-dummy, placebo-controlled, crossover study, 24 healthy volunteers received 20mg oxycodone (p.o.), 20mg nefopam (i.v.), or placebo. Central sensitization was induced by HFS on the forearm and leg. Endpoints included primary allodynia, secondary allodynic area, and pain detection thresholds (PDTs) and TS across four modalities: mechanical (pinprick), thermal (heat), electrocutaneous, and pressure (cuff). Endpoints were measured pre- and post-HFS and pre- and post-dose, and analyzed with a mixed-effects model with treatment, time, period, and treatment-by-time as fixed factors. Participant effects (by treatment and time) were included as random factors with baseline measurements as covariate.

Results: Central sensitization was successfully induced, with a significant increase in primary allodynia and secondary allodynic area (mean∆ 46cm2 post-dose) on the arm and leg, but did not increase temporal summation responses compared to unchallenged skin. Oxycodone and nefopam significantly increased pain detection thresholds and reduced both primary allodynia and secondary allodynic area post-HFS compared to placebo.

Conclusions: HFS induced significant primary and secondary allodynia in healthy volunteers without affecting temporal summation. Oxycodone and nefopam significantly reduced both primary and secondary allodynia, indicating that HFS is a useful experimental challenge model for inducing symptoms similar to central sensitization in healthy volunteers and for evaluating analgesic drug effects.

References: -

Presenting Author: Koen Rietdijk
Submitting Author: Koen Rietdijk

Senior Author: Marieke Niesters

IASP 2026 Global Year theme of Neuropathic Pain: No

• Koen Rietdijk: MD, MPH, MChem - Centre for Human Drug Research, Leiden University Medical Centre
• Ingrid Koopmans: MSc, PhD - Centre for Human Drug Research, Leiden University Medical Centre
• Marieke Niesters: MD, PhD - Centre for Human Drug Research, Leiden University Medical Centre
• Mihir Kapadia: MSc - Centre for Human Drug Research
• Robert-Jan Doll: PhD - Centre for Human Drug Research, Leiden University Medical Centre
• Geert Jan Groeneveld: MD, PhD - Centre for Human Drug Research, Leiden University Medical Centre
• Frodo Muijzer: MSc - EEMCS BSS University of Twente
• Jan Buitenweg: PhD - EECMS BSS University of Twente