Effects of Transcranial Direct Current Stimulation Block Remifentanil-Induced Hyperalgesia: A Randomized, Double-Blind Clinical Trial

Abstract

Background: Remifentanil-induced hyperalgesia (r-IH) involves an imbalance in the inhibitory and excitatory systems. As the transcranial Direct Current Stimulation (tDCS) modulates the thalamocortical synapses in a top-down manner, we hypothesized that the active (a)-t-DCS would be more effective than sham(s)-tDCS to prevent r-IH. We used an experimental paradigm to induce temporal summation of pain utilizing a repetitive cold test (rCOLDT) assessed by the Numerical Pain Score (NPS 0-10) and we evaluated the function of the descending pain modulatory system (DPMS) by the change on the NPS (0–10) during the conditioned pain modulation (CPM)-task (primary outcomes). We tested whether a-tDCS would be more effective than s-tDCS to improve pain perception assessed by the heat pain threshold (HPT) and the reaction time during the ice-water pain test (IPT) (secondary outcomes).Methods: This double-blinded, factorial randomized trial included 48 healthy males, ages ranging 19–40 years. They were randomized into four equal groups: a-tDCS/saline, s-tDCS/saline, a-tDCS/remifentanil and s-tDCS/remifentanil. tDCS was applied over the primary motor cortex, during 20 min at 2 mA, which was introduced 10 min after starting remifentanil infusion at 0.06 μg⋅kg-1⋅min-1 or saline.Results: An ANCOVA mixed model revealed that during the rCOLDT, there was a significant main effect on the NPS scores (F = 3.81; P = 0.01). The s-tDCS/remifentanil group presented larger pain scores during rCOLDT, [mean (SD) 5.49 (1.04)] and a-tDCS/remifentanil group had relative lower pain scores [4.15 (1.62)]; showing its blocking effect on r-IH. a-tDCS/saline and s-tDCS/saline groups showed lowest pain scores during rCOLDT, [3.11 (1.2)] and [3.15 (1.62)], respectively. The effect of sedation induced by remifentanil during the rCOLDT was not significant (F = 0.76; P = 0.38). Remifentanil groups showed positive scores in the NPS (0–10) during the CPM-task, that is, it produced a disengagement of the DPMS. Also, s-tDCS/Remifentanil compared to a-tDCS showed lower HPT and larger reaction-time during the IPT.Conclusion: These findings suggest that effects of a-tDCS prevent the summation response induced by r-IH during rCOLDT and the a-tDCS blocked the disengagement of DPMS. Thereby, tDCS could be considered as a new approach to contra-regulate paradoxical mechanisms involved in the r-IH. Clinical trials identification: NCT02432677. URL:https://clinicaltrials.gov/.

Transcranial Direct Current Stimulation to Improve the Dysfunction of Descending Pain Modulatory System Related to Opioids in Chronic Non-cancer Pain: An Integrative Review of Neurobiology and Meta-Analysis

“…Few studies investigated the application of tDCS to counter-regulate the dysfunction in the DPIS induced by opioids. In healthy subjects in an experimental model, we showed that the tDCS applied over M1 blocked the dysfunction caused by remifentanil on the inhibitory pathways or up-regulation of the pain-facilitating pathways (Braulio et al, 2018). This effect of tDCS was demonstrated to prevent both the disengagement of the DPIS and the summation effect on pain scores during the cold pressor test (Braulio et al, 2018).…”

“…In healthy subjects in an experimental model, we showed that the tDCS applied over M1 blocked the dysfunction caused by remifentanil on the inhibitory pathways or up-regulation of the pain-facilitating pathways (Braulio et al, 2018). This effect of tDCS was demonstrated to prevent both the disengagement of the DPIS and the summation effect on pain scores during the cold pressor test (Braulio et al, 2018). When focusing on opioid dependence, a recent review (Gallucci et al, 2019) found only one study that used tDCS.…”

Developing an optimized strategy with transcranial direct current stimulation to enhance the endogenous pain control system in fibromyalgia

“…This positive scenario will allow us to determine specific biomarkers (e.g., TSPS, CPM, TMS TSPS results may indicate that both interventions and EEG) that could help to predict treatment response in future clinical trials. Preliminary data suggested a positive effect of tDCS and exercise alone in TSPS [15, 86, 87] and CPM [88], however, so far, these specific markers have not been used to guide specific interventions. Furthermore, with these results regarding TMS and EEG, it is possible to indirectly assess how changes in the endogenous pain regulatory control are related to alterations in abnormal cortical excitability [81] as indexed by TMS and thalamic dysrhythmia [83, 89, 90] as indexed by EEG.…”

“…Strategy I: effects of tDCS on CPM in patients with chronic pain - effect size (ES) of 0.79[98]. Strategy II: effects of tDCS on CPM in healthy volunteers - pooled ES of 1.02 [87, 91, 99, 100] and Strategy III: effect of exercise on CPM in chronic pain - ES of 0.78[86]. Based on this analysis, a conservative approach with the lowest ES was chosen using an ES of 0.78.…”

<p>TRPV1 channel contributes to remifentanil-induced postoperative hyperalgesia via regulation of NMDA receptor trafficking in dorsal root ganglion</p>

“…Nonetheless, many studies have demonstrated that remifentanil could enhance postoperative analgesic consumption and cause pain hypersensitivity. However, its mechanism and effective therapy are still unclear 7,8. This study focused on the mechanism of remifentanil-induced postoperative hyperalgesia; we are hoping to provide new ideas for the treatment and prevention of remifentanil-induced postoperative hyperalgesia to relieve patients’ pain.…”