title: A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects.
abstract: BACKGROUND
  Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation.
  
  
  OBJECTIVE
  The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects.
  
  
  METHODS
  Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis.
  
  
  RESULTS
  Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R(2)  = 0.492 for HPT, R(2)  = 0.538 for PPT, R(2)  = 0.558 for HPTo and R(2)  = 0.584 for PPTo).
  
  
  CONCLUSIONS
  The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre.
authors.affiliation: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Luciana Cadore
authors.initials: LC
authors.lastname: Stefani
authors.affiliation: Associate Professor, Pharmacology Department, Instituto de CiênciasBásicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Suzana
authors.initials: S
authors.lastname: Muller
authors.affiliation: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil ; Anesthetist, Pain and Palliative Care Service at Hospital de Clínicas de Porto Alegre, Laboratory of Pain and Neuromodulation, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil ; Associate Professor, Pharmacology Department, Instituto de CiênciasBásicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Iraci L S
authors.initials: IL
authors.lastname: Torres
authors.affiliation: Anesthetist, Pain and Palliative Care Service at Hospital de Clínicas de Porto Alegre, Laboratory of Pain and Neuromodulation, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Bruna
authors.initials: B
authors.lastname: Razzolini
authors.affiliation: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Rozisky
authors.affiliation: Associate Professor of Physical Medicine and Rehabilitation, Associate Professor of Neurology Harvard Medical School. Berenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Felipe
authors.initials: F
authors.lastname: Fregni
authors.affiliation: Laboratory of Chronopharmacology, Department of Physiology, Institute of Bioscience, University of São Paulo, São Paulo, Brazil.
authors.forename: Regina
authors.initials: R
authors.lastname: Markus
authors.affiliation: Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil ; Anesthetist, Pain and Palliative Care Service at Hospital de Clínicas de Porto Alegre, Laboratory of Pain and Neuromodulation, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil ; Associate Professor, Pharmacology Department, Instituto de CiênciasBásicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Wolnei
authors.initials: W
authors.lastname: Caumo
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage*; D001007:Anxiety / Q000378:metabolism; D001938:Brazil; D003863:Depression / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000097:blood; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy*; D017288:Pain Threshold / Q000187:drug effects*; D011312:Pressure; D055815:Young Adult
chemical_list: D000700:Analgesics; D008550:Melatonin