Assessing signs of central sensitization: A critical review of physiological measures in experimentally induced secondary hyperalgesia

Abstract

Background and objectives: Central sensitization (CS) is believed to play a role in many chronic pain conditions. Direct non-invasive recording from single nociceptive neurons is not feasible in humans, complicating CS establishment. This review discusses how secondary hyperalgesia (SHA), considered a manifestation of CS, affects physiological measures in healthy individuals and if these measures could indicate CS. It addresses controversies about heat sensitivity changes, the role of tactile afferents in mechanical hypersensitivity and detecting SHA through electrical stimuli. Additionally, it reviews the potential of neurophysiological measures to indicate CS presence.

Databases and data treatment: Four databases, PubMed, ScienceDirect, Scopus and Cochrane Library, were searched using terms linked to 'hyperalgesia'. The search was limited to research articles in English conducted in humans until 2023.

Results: Evidence for heat hyperalgesia in the SHA area is sparse and seems to depend on the experimental method used. Minimal or no involvement of tactile afferents in SHA was found. At the spinal level, the threshold of the nociceptive withdrawal reflex (RIII) is consistently reduced during experimentally induced SHA. The RIII area and the spinal somatosensory potential (N13-SEP) amplitude are modulated only with long-lasting nociceptive input. At the brain level, pinprick-evoked potentials within the SHA area are increased.

Conclusions: Mechanical pinprick hyperalgesia is the most reliable behavioural readout for SHA, while the RIII threshold is the most sensitive neurophysiological readout. Due to scarce data on reliability, sensitivity and specificity, none of the revised neurophysiological methods is currently suitable for CS identification at the individual level.

Significance: Gathering evidence for CS in humans is a crucial research focus, especially with the increasing interest in concepts such as 'central sensitization-like pain' or 'nociplastic pain'. This review clarifies which readouts, among the different behavioural and neurophysiological proxies tested in experimental settings, can be used to infer the presence of CS in humans.

FIGURE 1

Flow diagram of the systematic searches of databases according to PRISMA guidelines (Page et al., 2021). Reason 1 refers to the type of article included (original research papers conducted in healthy volunteers) and reason 2 refers to the fact that the outcomes were obtained from stimuli delivered in the area of secondary hyperalgesia, which was identified using pinprick stimuli.

FIGURE 2

(a) Pain intensity to laser (Nd‐YAP) pulses delivered in the area of secondary hyperalgesia before (T0), 20 and 45 min after high‐frequency stimulation (HFS, 20× detection threshold) of the skin was delivered. Participants used a numerical rating scale (NRS) ranging from 0 (no perception) to 100 (the maximal imaginable pain) with 50 representing the border between non‐painful and painful sensations. In red: on the volar forearm onto which HFS was applied and in blue: on the contralateral arm. Sixteen participants (10 women; aged 20–32 years; 24.5 ± 3.8 years [mean ± SD]) were asked to rate 20 stimuli whose intensity (4.0 ± 0.5 J, [mean ± SD]) was individually adjusted to be qualified as clearly painful (NRS > 50/100). (b) Predefined sites for laser stimulation according to the location where the HFS electrode was positioned. The same template was drawn on both volar forearms. Laser pulses were in a random order on the 20 possible circles with a random inter‐stimulus‐interval (3–5 s). The laser pulses delivered at the location indicated by the two red circles were withdrawn from analysis. Mean and 95% confidence intervals are displayed. The asterisk indicates a significant difference in the perceived intensity between the control and HFS arm at T2. (Unpublished data Lenoir et al., 2019).

FIGURE 3

Increased perceived intensity for different pinprick mechanical stimuli and not for tactile stimuli delivered in the area of secondary hyperalgesia induced by HFS. The change in perceived intensity was computed by subtracting the ratings obtained before HFS (baseline T0) from the ratings obtained 20 min after HFS (T1). Participants used a numerical rating scale (NRS) ranging from 0 (no perception) to 100 (the maximal imaginable sensation) and additionally provided descriptors for the quality of the sensation and if the sensation was painful or not. Pinprick stimuli with a blunt tip (P; in red; diameter 0.35 mm) and tactile stimuli with a round tip (T; in blue; diameter 2 mm) of four intensities (32, 64, 128 and 256 mN) were delivered in a counterbalanced manner onto the skin surrounding the site where the HFS electrode was positioned. In addition, a tactile stimulator with a round tip of 2072 mN which matched the pressure elicited by the pinprick 64 mN was also used. Mean and 95% confidence intervals are displayed. Across all intensities, the perception of pinprick stimuli (in red) was enhanced after HFS which was not the case with the tactile stimuli (in blue) of the same intensities or stimuli exerting the same pressure when applied onto the skin. (21 participants; 11 women; aged 18–29 years; 21.1 ± 2.7 years [mean ± SD]). (Unpublished data Lenoir et al., 2021).

FIGURE 4

(a) Proportion of each descriptor used to describe the quality of perception of the pinprick and tactile stimuli delivered in the area of secondary hyperalgesia before (T0) and after (T1) HFS. (a, c) Pinprick stimuli (P; stimulator with blunt tip; diameter 0.35 mm) and (b, d) tactile stimuli (T; stimulator with round tip; diameter 2 mm) of four intensities (32, 64, 128 and 256 mN) were delivered in a counter‐balanced manner onto the skin surrounding the site where the HFS electrode was positioned. In addition, a tactile stimulator of 2072 mN which matched the pressure elicited by the pinprick 64 mN was also used. Descriptors considered to qualify are displayed in light blue for ‘touch’, dark blue for ‘tingling’, in orange for ‘pricking’ and red for ‘burning’. When applied to sensitized skin the quality of pinprick stimuli and to a lesser extent of tactile stimuli was changed with pinprick stimuli more often perceived as ‘pricking’ and tactile ones more often perceived as ‘pricking’ and ‘burning’. (21 participants; 11 women; aged 18–29 years; 21.1 ± 2.7 years [mean ± SD]). (Unpublished data Lenoir, van den Broeke et al., 2021). (b) Proportion of stimuli perceived as ‘painful’ and ‘non‐painful’ before (T0) and after (T1) HFS. (a, c) Pinprick stimuli (P; stimulator with blunt tip; diameter 0.35 mm) and (b, d) tactile stimuli (T; stimulator with round tip; diameter 2 mm) of four intensities (32, 64, 128 and 256 mN) were delivered in a counter‐balanced manner onto the skin surrounding the site where the HFS electrode was positioned. In addition, a tactile stimulator of 2072 mN which matched the pressure elicited by the pinprick 64 mN was also used. Proportions of stimuli perceived as ‘painful’ and ‘non‐painful’ are displayed respectively in blue and red. When applied to sensitized skin pinprick stimuli of different intensities are in 30%–70% of the cases perceived as ‘painful’ which is the case for only 6% maximum of the cases for tactile stimuli. The increase of pinprick stimuli perceived as painful after HFS is clearly visible which is not the case for tactile stimuli (21 participants; 11 women; aged 18–29 years; 21.1 ± 2.7 years [mean ± SD]). (Unpublished data Lenoir et al., 2021).

FIGURE 5

Time course of the force recorded from a force sensor during manually or robotically delivered 64 mN pinprick stimuli on a force sensor ([mean ± SD]). (a) The normal force (along the perpendicular axis of the stimulation) and (b) the tangential force (perpendicular to the axis of stimulation) were recorded during manual or robotic delivery of 30 pinprick stimuli (64 mN) on a 6‐axis strain‐gauge force‐torque transducer. In the manual condition, the experimenter delivered the pinprick stimuli before and after a training period. The training aimed at improving the perpendicular orientation of the pinprick stimulator with respect to the skin with minimal lateral movements (tangential force), and at as constant as possible speed, with a contact held for approximately 1 s. Note after training the reduced overshoot of normal force at the onset of the stimulation. By comparing the inserts in (a), note after training the more constant normal force of 64 mN applied during stimulation and its reduced variability. In (b), note after training that the tangential force is reduced by a factor of 10. After training both lateral and tangential force values induced by manual stimulation are closer to the forces induced by robotic stimulation. Robot‐controlled pinprick stimulation leads to even less variable normal and tangential force and offers the advantage of constant stimulation over time in contrast to the performance of a human experimenter that could suffer from its fatigue throughout an experiment. (Unpublished data Lambert et al., 2017)