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Abstract

High-frequency stimulation (HFS) is a human surrogate model of secondary hyperalgesia and a key experimental tool for understanding the mechanisms and modulation of central nociceptive pathways. An emerging area of research focuses on the role of top-down endogenous analgesic systems during secondary hyperalgesia development. However, the test-retest reliability of the early temporal changes in sensitivity are poorly understood. In the present study, we investigated the between-session reliability of the early temporal dynamics and late-phase expression of HFS-induced changes in mechanical pinprick sensitivity in a heterotopic area on the forearm in 28 healthy participants across five time points relative to HFS conditioning: −15, 5, 20, 35, and 50 min. Homotopic changes in single-pulse electrically evoked responses were also assessed although no primary hyperalgesia was evident. Baseline conditioned pain modulation (CPM), temporal summation of pain (TSP), and state-trait anxiety (STAI) were also assessed to investigate potential influences on heterotopic and homotopic responses. The present findings demonstrate the consistent induction of mechanical pinprick secondary hyperalgesia by the end of the HFS window (50 min) across repeated test session. However, a distinct reduction in the development of sensitivity was present during session 2. Furthermore, pain during HFS conditioning, anxiety, CPM, and TSP demonstrated no influence on secondary hyperalgesia development and were inadequate to explain between-session variance. These results suggest that careful planning around experimental designs, and the counterbalancing of experimental conditions should be considered when investigating modulating factors over the development of secondary hyperalgesia. Further research into factors influencing habituation across sessions is needed. Perspective: High-Frequency Stimulation evokes mechanical secondary hyperalgesia across repeated sessions; however, sensitivity development is diminished, and unexplained by pain intensity during HFS conditioning, anxiety, or cuff algometry CPM and TSP.

Publication Date

2026-05-27

Publication Title

Journal of Pain

Volume

46

ISSN

1526-5900

Acceptance Date

2026-05-24

Deposit Date

2026-06-23

Funding

This work is funded through a PhD studentship from the University of Plymouth (School of Psychology) and an Academy of Medical Sciences Springboard Award (Hughes: SBF007\100108). The authors have no conflicts of interest.

Keywords

Conditioned Pain Modulation (CPM), High Frequency Stimulation (HFS), Pain modulation, Pain sensitivity, Reliability, State and Trait Anxiety (STAI), Temporal Summation of Pain (TSP)

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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