Neurophysiologic assessment of small fibre damage in chemotherapy-induced peripheral neuropathy.

OBJECTIVE: In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects. METHODS: Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli. RESULTS: For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively. CONCLUSIONS: In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together. SIGNIFICANCE: LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.

Need for Thorough Standardization of CO2 Laser Evoked Potential Procedure.

PURPOSE: The objective of this study was to determine normative values of laser evoked potentials and anthropometric correlations in a healthy middle-aged working population. METHODS: In 51 subjects, CO2 laser stimulation was applied bilaterally onto dorsal surface of the feet, hands, and neck using constant duration of stimulus and beam diameter, changing just the intensity of stimulation. Amplitudes and latencies of the laser evoked potential negative-positive complex were recorded, and relationship with height, age and gender was statistically analyzed. RESULTS: There was a significant correlation between the latencies obtained for feet, hands, and height. P2 amplitudes for feet, hands, and neck, and negative-positive pk-pk amplitudes for hands and neck correlated negatively with age. The values obtained did not differ significantly between male and female gender, except for N2 latencies for hands. CONCLUSIONS: Clinically useful reference values for laser evoked potentials in a healthy middle-aged population were provided, which are interesting from the physiological point of view.

A Phase I, Randomized, Double-Blind, Laser-Evoked Potential Study to Evaluate the Analgesic/Antihyperalgesic Effect of ASP9226, a State-Dependent N-Type Voltage-Gated Calcium Channel Inhibitor, in Healthy Male Subjects.

Objective: Evaluate the analgesic/antihyperalgesic effects of ASP9226, a state-dependent N-type voltage-gated calcium channel inhibitor, in healthy male subjects. Design: Randomized, double-blind, double-dummy, placebo- and active comparator-controlled crossover study. Setting: HPR Dr. Schaffler GmbH, Munich, Germany. Subject: Healthy male subjects aged 18-55 years. Methods: Twenty-four eligible subjects were randomly assigned to one of four treatment sequences and received single doses of ASP9226 (30 mg or 50 mg), pregabalin (150 mg), or placebo during four treatment periods. Laser-evoked potentials (LEP) and postlaser pain visual analog scales (VAS) on capsaicin-treated skin were assessed during main assessment days (the first day of each study period). Primary and secondary end points were the differences in LEP N2-P2 peak-to-peak (PtP) amplitudes and VAS score, respectively, in all subjects. Results: Overall, treatment with pregabalin resulted in a significantly lower LEP N2-P2 PtP amplitude vs placebo (-3.30 µV, P < 0.0001). There were no clinically relevant differences in N2-P2 PtP amplitudes between placebo and either ASP9226 dose (-0.31 µV and -0.27 µV). Furthermore, subjects reported significantly lower VAS pain scores with pregabalin vs placebo (-9.90%, P < 0.0001) in contrast to ASP9226 30 mg (-2.1%) and ASP9226 50 mg (1.2%) vs placebo. Subgroup analysis of LEP and VAS pain in participants with positive prestudy capsaicin response (n = 13) were in keeping with results in all subjects. Conclusions: ASP9226 was well tolerated; however, there was no improvement in LEP and VAS pain scores with ASP9226 at either dose vs placebo.

Skin denervation does not alter cortical potentials to surface concentric electrode stimulation: A comparison with laser evoked potentials and contact heat evoked potentials.

BACKGROUND: In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated. METHODS: In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis. RESULTS: We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs. CONCLUSION: The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function. SIGNIFICANCE: Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system.

Effects of OnabotulintoxinA on Habituation of Laser Evoked Responses in Chronic Migraine.

Onabotulintoxin A (BontA) is an efficacious preventive treatment for chronic migraine, though the specific mechanism of action is still under discussion. The study aims: (1) To evaluate pain processing modifications in chronic migraine patients (CM) under single BontA administration in pericranial muscles, by means of CO² Laser Evoked Potentials (LEPs) obtained by the stimulation of the skin over the right frontal and trapezius injection sites and hand dorsum, in a double blind placebo controlled crossover design. (2) To correlate main LEPs findings with clinical outcome after one year of BontA treatment. Twenty refractory CM patients were included in the analysis. The LEPs were recorded in basal conditions and seven days after BontA (PREEMPT protocol) and saline solution injection. The N1, N2 and P2 amplitude and latencies and N2P2 habituation index were evaluated and correlated with the percent change of headache frequency after one year of toxin treatment. After seven days of BontA treatment, a normalization of the trigeminal habituation index was observed, which was correlated with the clinical outcome after one year of BontA therapy. Patients displaying trigeminal LEPs facilitation at T0 time showed a more efficient therapeutic outcome. Neurotoxin may exert a modulating effect on trigeminal nociception, normalizing central neurotransmission.

Short lasting transient effects of a capsaicin 8% patch on nociceptor activation in humans.

BACKGROUND: At high concentration, the TRPV-1 agonist capsaicin de-sensitizes nociceptors and reduces the intra-epidermal nerve density. METHODS: We investigated the effects of a 5 × 10 cm capsaicin 8% patch on C- and A-delta-nociceptor activation in ten healthy subjects before and at days 1-3-7-21 after patch application. Thermal thresholds, infrared thulium-YAG laser-evoked potentials (LEP) and heat pain (numeric rating scale, NRS, 0-10), electrically induced pain (10 pulses, 1.5-fold pain threshold intensity, five randomized series of 5-10-20-50-100 Hz), and axon-reflex flare (laser Doppler imaging) were recorded. RESULTS: Thermal hypoesthesia developed upon capsaicin 8% treatment. Warmth detection thresholds increased at day 1-3, heat pain thresholds were increased by about 2.6 °C after day 3, and laser-evoked heat pain remained significantly reduced for 7 days. Axon-reflex flare responses (days 1-3), but not supra-threshold electrically induced pain were significantly reduced by the capsaicin patch. CONCLUSIONS: Axonal nociceptor function assessed by electrical excitability tests supplements threshold tests of nociceptive endings. The differential analgesic effects of 8% capsaicin patches may be attributed to the kinetics of capsaicin and the different depth of nociceptive nerve fibres, yet, the time course does not match the long-lasting analgesia observed in neuropathic pain patients treated with the same patch. WHAT DOES THIS STUDY ADD?: Axonal nociceptor function assessed by supra-threshold electrical excitability tests did not coincide with capsaicin-induced transduction changes supplementing threshold measures of terminal nociceptor endings. Threshold measurements do not reflect the sustained effect of pain relief seen in neuropathic pain patients. Capsaicin-sensitive nociceptors responsible for spontaneous pain are either not specifically tested with currently available sensory stimulation protocols or have higher capsaicin sensitivity or slower recovery under neuropathic conditions.

The Analgesic Effect of Oxytocin in Humans: A Double-Blind, Placebo-Controlled Cross-Over Study Using Laser-Evoked Potentials.

Oxytocin is a neuropeptide regulating social-affiliative and reproductive behaviour in mammals. Despite robust preclinical evidence for the antinociceptive effects and mechanisms of action of exogenous oxytocin, human studies have produced mixed results regarding the analgesic role of oxytocin and are yet to show a specific modulation of neural processes involved in pain perception. In the present study, we investigated the analgesic effects of 40 IU of intranasal oxytocin in 13 healthy male volunteers using a double-blind, placebo-controlled, cross-over design and brief radiant heat pulses generated by an infrared laser that selectively activate Aδ- and C-fibre nerve endings in the epidermis, at the same time as recording the ensuing laser-evoked potentials (LEPs). We predicted that oxytocin would reduce subjective pain ratings and attenuate the amplitude of the N1, N2 and P2 components. We observed that oxytocin attenuated perceived pain intensity and the local peak amplitude of the N1 and N2 (but not of P2) LEPs, and increased the latency of the N2 component. Importantly, for the first time, the present study reports an association between the analgesic effect of oxytocin (reduction in subjective pain ratings) and the oxytocin-induced modulation of cortical activity after noxious stimulation (attenuation of the N2 LEP). These effects indicate that oxytocin modulates neural processes contributing to pain perception. The present study reports preliminary evidence that is consistent with electrophysiological studies in rodents showing that oxytocin specifically modulates Aδ/C-fibre nociceptive afferent signalling at the spinal level and provides further specificity to evidence obtained in humans indicating that oxytocin may be modulating pain experience by modulating activity in the cortical areas involved in pain processing.

Role of explicit verbal information in conditioned analgesia.

BACKGROUND: The exact role of expectation in conditioned analgesia is still elusive as it is not clear whether conditioning is an automatic process or rather it is cognitively mediated. This study is aimed at understanding the role of explicit verbal information in conditioned analgesia. METHODS: Two groups of healthy subjects received a conditioning procedure whereby two visual cues were paired with increase and decrease in stimulus intensity. In the 'conditioning/verbal information' group (VER), subjects were informed about the meaning of the cues, whereas no information was given to the second group (noVER). After two conditioning blocks, an evocation session was run in which the stimulus intensity was the same, irrespective of the cues. Pain perception was assessed according to a numerical rating scale from 0 (no pain) to 10 (maximal pain). The N2-P2 component of laser-evoked potentials (LEP) was used as an index of index of brain responses to nociceptive stimuli. RESULTS: In the evocation session, only the VER group reported a decrease in pain rating and LEP amplitude when the cues were presented, suggesting that the visual-analgesic association does not occur without explicit verbal information. CONCLUSIONS: In line with the cognitive theory of conditioning, our results indicate that just pairing a cue with different pain stimulus intensities is not sufficient, per se, to produce a learning process. What matters is the informational cognitive content of the cue, i.e. the meaning assigned to the cue itself. These findings may help understand the mechanisms of conditioned analgesia and more in general of learning.