title: 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.
authors: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre, Brazil.
authors: Nádia Regina Jardim
authors: NR
authors: da Silva
authors: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre, Brazil.
authors: Gabriela
authors: G
authors: Laste
authors: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre, Brazil.
authors: Alícia
authors: A
authors: Deitos
authors: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre, Brazil ; Pain and Anesthesia in Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil.
authors: Luciana Cadore
authors: LC
authors: Stefani
authors: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre, Brazil.
authors: Gustavo
authors: G
authors: Cambraia-Canto
authors: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre, Brazil ; Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil.
authors: Iraci L S
authors: IL
authors: Torres
authors: Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, USA.
authors: Andre R
authors: AR
authors: Brunoni
authors: Service of Interdisciplinary Neuromodulation, Department and Institute of Psychiatry, University of São Paulo São Paulo, Brazil.
authors: Felipe
authors: F
authors: Fregni
authors: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre, Brazil ; Pain and Anesthesia in Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil ; Pain and Palliative Care Service at Hospital de Clínicas de Porto Alegre (HCPA), Laboratory of Pain and Neuromodulation at UFRGS Porto Alegre, Brazil.
authors: Wolnei
authors: W
authors: Caumo
keywords: CPM; TMS; clinical trial; melatonin; pain threshold; tDCS