Inspired by Daneffel et al 2025.[1]
ARF – axon reflex flare
MSK – musculoskeletal
EA – electroacupuncture
R – rectangular square wave
HS – half-sine wave
CSI – closed-state inactivation– ket to acronyms
I am not sure how this paper ended up in my search results, but it captured my attention for a few reasons. Axon reflex flare (ARF) is a common observation in acupuncture treatment, and we have long debated its relevance or lack thereof. Silent C-nociceptors are particularly relevant to those of us treating chronic MSK pain, since they help to explain why subjective pain rarely seems to correlate with imaging findings. Finally, this paper describes a method of electrical stimulation that favours stimulation of C-fibres as opposed to A-fibres. This was entirely new to me, and I wonder if it might have implications on the design of waveforms for EA devices.
This is an experimental study on healthy human volunteers. Intradermal electrical stimulation was applied to the volar forearm in two distinct forms. The more familiar form was a rectangular square wave (R) of 0.5ms duration and alternating polarity at 2Hz. The more novel form was a half-sine wave (HS) of 25ms duration and alternating polarity at 2Hz. The stimulation was applied using microdialysis catheters of 0.2mm external diameter and an internal stainless-steel wire. This method has clearly developed from a single intradermal needle and a surface electrode over the top.[2]
Stimulation was increased to the threshold of perception, the pain threshold, and then to a level of pain equivalent to 3 on a 0–10 NRS or 6 on the same scale depending on the experiment.
Flare around the stimulation site was measured with laser doppler. A pixel was considered to be positive for flare if it exceeded 2 standard deviations above baseline.
Pinprick hyperalgesia was measured using a 256mN von Frey filament – see Strong EA & CPM in OAK for a mention of Max von Frey. Allodynia was measured with a dry cotton swab and subjects were asked to indicate when stimulation became unpleasant or ‘rougher’. These assessments were made in 4 separated directions (proximal, distal, medial, and lateral to the stimulation area), starting at a distance (12cm proximal / distal or 6cm medial / lateral) and working towards the stimulation area.
The slow rising waveform (HS) of 25ms preferentially stimulates C-fibres and the classic rectangular waveform (R) of 0.5ms preferentially stimulates A-fibres, including Aδ fibres of course. Why is that I hear you ask? Well, now it gets a little complicated… It seems to be due to the different voltage gated sodium channels (NaV) expressed on myelinated and unmyelinated nerves. There are currently 9 different NaVs described, and the ones of most relevance here are NaV 1.6, which sits in nodes of Ranvier on myelinated fibres, NaV 1.7, which is found in both myelinated and unmyelinated sensory nerves, and NaV 1.8, which is primarily expressed in unmyelinated C-fibres.
NaV 1.6 is moderately sensitive to closed-state inactivation (CSI). This is when the channel enters an inactivated state without first opening. It seems that a slow rising waveform such as HS allows more time for channels to enter CSI. NaV 1.7 is particularly sensitive to this phenomenon and thus acts as a threshold amplifier. By contrast, NaV 1.8 on unmyelinated C-fibres is rather insensitive to CSI. Thus, HS waveforms preferentially stimulate C-fibres by virtue of their NaV 1.8 channels.
So, what did they find in this experiment?
The HS waveform stimulation was associated with a significantly larger flare (roughly double the area than R waveform stimulation) and the size of the flare correlated with the size of the area of punctate hyperalgesia. There was no such correlation with H waveform stimulation.
The size and areas of hyperalgesia and allodynia did not really differ between the two stimulation modalities, which was disappointing to the authors, since this is what they expected to find. They thought that silent C-nociceptors might be more involved in generating central sensitisation than myelinated nociceptors.
It has got me thinking that we might experiment with the HS waveform stimulation inside muscle tissue to see whether focussing stimulation of C-fibres might augment the effect of EA in chronic pain… You heard it here first!
References
1 Daneffel L, Rukwied R, Schmelz M, et al. Preferential C-nociceptor stimulation facilitates peripheral axon reflex flare, but not secondary mechanical hyperalgesia. Front Pain Res. 2025;6:1556429. doi: 10.3389/fpain.2025.1556429
2 Koppert W, Dern SK, Sittl R, et al. A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology. 2001;95:395–402. doi: 10.1097/00000542-200108000-00022
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