Combined neuromodulatory interventions in acute experimental pain: assessment of melatonin and non-invasive brain stimulation

Abstract

Transcranial direct current stimulation (tDCS) and melatonin can effectively treat pain. Given their potentially complementary mechanisms of action, their combination could have a synergistic effect. Thus, we tested the hypothesis that compared to the control condition and melatonin alone, tDCS combined with melatonin would have a greater effect on pain modulatory effect, as assessed by quantitative sensory testing (QST) and by the pain level during the Conditioned Pain Modulation (CPM)-task. Furthermore, the combined treatment would have a greater cortical excitability effect as indicated by the transcranial magnetic stimulation (TMS) and on the serum BDNF level. Healthy males (n = 20), (aged 18–40 years), in a blinded, placebo-controlled, crossover, clinical trial, were randomized into three groups: sublingual melatonin (0.25 mg/kg) + a-tDCS, melatonin (0.25 mg/kg) + sham-(s)-tDCS, or sublingual placebo+sham-(s)-tDCS. Anodal stimulation (2 mA, 20 min) was applied over the primary motor cortex. There was a significant difference in the heat pain threshold (°C) for melatonin+a-tDCS vs. placebo+s-tDCS (mean difference: 4.86, 95% confidence interval [CI]: 0.9 to 8.63) and melatonin+s-tDCS vs. placebo+s-tDCS (mean: 5.16, 95% CI: 0.84 to 8.36). There was no difference between melatonin+s-tDCS and melatonin+a-tDCS (mean difference: 0.29, 95% CI: −3.72 to 4.23). The mean change from the baseline on amplitude of motor evocate potential (MEP) was significantly higher in the melatonin+a-tDCS (−19.96% ± 5.2) compared with melatonin+s-tDCS group (−1.36% ± 5.35) and with placebo+s-tDCS group (3.61% ± 10.48), respectively (p < 0.05 for both comparisons). While melatonin alone or combined with a-tDCS did not significantly affect CPM task result, and serum BDNF level. The melatonin effectively reduced pain; however, its association with a-tDCS did not present an additional modulatory effect on acute induced pain.

Oral Supplementation of Melatonin Protects against Fibromyalgia-Related Skeletal Muscle Alterations in Reserpine-Induced Myalgia Rats

“…Probably, melatonin treatment causes an improvement in rat’s spontaneous running activity because of its antioxidants and ant-inflammatory mechanisms of action, well known melatonin properties [ 47 , 48 , 49 , 50 , 51 ]. Although these beneficial effects are potentially related also to analgesic [ 30 , 52 , 53 , 54 , 55 ] melatonin properties, experimental studies as well as clinical trials in humans have demonstrated that melatonin has an analgesic properties in chronic, acute, inflammatory and neuropathic pain conditions, including fibromyalgia [ 44 , 56 , 57 , 58 ]. Importantly, these effects seem MT2 receptor-mediated, as shown by the group of Granados-Soto describing that selective MT2 receptor partial agonists have analgesic properties through modulation of brainstem descending anti-nociceptive pathways [ 28 , 59 , 60 ].…”

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

“…The number of subjects in each study group was determined by the parameters of a previous survey ( da Silva et al, 2015 ). To achieve 80% power at 1% significance, with a 0.5 variation coefficient, we need a total of 48 subjects divided into four equal groups ( n = 12) in 1:1:1:1 ratio to test 1 point [ Standard deviation ( SD = 2)] mean a difference between groups for the NPS (0–10).…”

Transcranial Direct Current Stimulation as a Therapeutic Tool for Chronic Pain

“…A total of 592 subjects were randomized in thirteen clinical trials involving different chronic pain conditions; 4 in low back pain 26,27,63,64 ; 2 in fibromyalgia 65,66 , 2 in Myofascial Pain Syndrome 67,68 , 1 in chronic visceral pain 69 , 1 in chronic regional pain (CRPS) 70 , 1 in spinal cord injury (SCI) 71 , 1 in general neuropathic pain subjects 72 and 4 ongoing studies. 73–77 Most of the studies combined tDCS with a behavioral therapy such as cognitive behavioral training, exercise, visual illusion or with other types of stimulation such as peripheral electrical stimulation (PES) or transcranial pulsed current stimulation (tPCS).…”