651: Low-Temperature Offset Analgesia Supports C-Fibre Sufficiency

Topic: Experimental (Non-clinical) Human Studies
Subtopic: Non -specific to any diagnosis, Psychology, Pain mechanisms (e.g. descending inhibitory control, placebo, inflammation), Quantitative Sensory testing (static and dynamic, e.g., HPT, PPT, CPM, TSP, offset analgesia)

Background and Aims: Offset analgesia (OA) is a rapid and disproportionately large reduction in pain following a small decrease in noxious stimulation [1]. The mechanisms underlying OA remain uncertain, and recent work has raised the possibility that specific peripheral fibre activation may be required [2]. C-fibres have heat activation thresholds below ~45°C, whereas A-delta mechano-heat (AMH) fibres typically respond at higher temperatures. If C-fibre activation is sufficient to generate OA, then OA should be observable at noxious temperatures below 45°C.

Methods: Previously, 16 healthy volunteers received offset, control, and baseline trials at low, medium, and high temperatures [3]. Each trial included a 5s noxious stimulus (T1), followed by a 5s period (T2) during which temperature either remained constant (control) or increased by 1°C (offset and baseline), and a 5s period (T3) during which temperature either remained constant (control), decreased by 1°C (offset), or returned to a non-noxious 35°C (baseline). Pain ratings were obtained at the end of T1-T3. The low condition (mean T1=40.3°C) allowed assessment of OA temperatures below A-delta heat thresholds without recruiting new participants.

Results: Reanalysis confirmed a significant main effect of condition at T3 (F(2,390)=37.38, p<0.001). Across temperatures, T3 ratings were lower in offset than control trials (t(15)=−2.70, p=0.017, corrected). Critically, OA was also present at low temperatures (t(15)=−2.50, p=0.049, corrected), with a mean T1 of 40.3°C. Although a Condition × Temperature interaction was observed (F(4,390)=5.16, p<0.001), OA was demonstrated at both low and high temperatures. These findings indicate that OA can occur at temperatures below typically reported A-delta activation thresholds.

Conclusions: These findings add to accumulating evidence that OA does not depend on A-delta activation: OA can be observed under conditions consistent with predominantly C-fibre input and persists following A-delta blockade [4]. OA also occurs under higher-temperature conditions engaging both fibre types [1-3]. Whether OA can be generated by predominantly A-delta input alone remains unresolved.

Taken together, the data indicate that C-fibre activation is sufficient to support OA. While the present findings do not resolve whether OA is mediated peripherally, centrally, or through their interaction, they further constrain fibre-specific accounts of this phenomenon.

References: 1. Grill JD, Coghill RC. Transient analgesia evoked by noxious stimulus offset. J Neurophysiol. 2002;87(4):2205-2208.
2. Sun P, Wong APH, Asplund CL, Derbyshire SWG. Peripheral contributions to offset analgesia: effects of stimulus duration, intensity, and location. PAIN. 2025;166(12):e823-e829.
3. Derbyshire SW, Osborn J. Enhancement of offset analgesia during sequential testing. Eur J Pain. 2008;12(8):980-989.
4. Luebke L, Lopes CG, Myka L, Lumma A, Adamczyk WM, Carvalho GF, Scholten-Peeters GGM, Luedtke K, Szikszay TM. Assessing the influence of nonischemic A-fiber conduction blockade on offset analgesia: an experimental study. J Pain. 2024;25(10):104611.

Presenting Author: Stuart WG Derbyshire
Submitting Author: Stuart William George Derbyshire

Senior Author: Stuart WG Derbyshire

IASP 2026 Global Year theme of Neuropathic Pain: No

• Christopher Lee Asplund: PhD - National University of Singapore, Department of Biomedical Engineering