A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects

Luciana Cadore Stefani; Suzana Muller; Iraci L S Torres; Bruna Razzolini; Joanna R Rozisky; Felipe Fregni; Regina Markus; Wolnei Caumo

doi:10.1371/journal.pone.0074107

A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects

PLoS One. 2013 Oct 2;8(10):e74107. doi: 10.1371/journal.pone.0074107. eCollection 2013.

Authors

Luciana Cadore Stefani¹, Suzana Muller², Iraci L S Torres³, Bruna Razzolini⁴, Joanna R Rozisky¹, Felipe Fregni⁵, Regina Markus⁶, Wolnei Caumo³

Affiliations

¹ Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
² Associate Professor, Pharmacology Department, Instituto de CiênciasBásicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
³ 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.
⁴ 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.
⁵ 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.
⁶ Laboratory of Chronopharmacology, Department of Physiology, Institute of Bioscience, University of São Paulo, São Paulo, Brazil.

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.

Publication types

Clinical Trial, Phase II
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Sublingual
Adult
Analgesics / administration & dosage*
Anxiety / metabolism
Brazil
Depression / metabolism
Dose-Response Relationship, Drug
Female
Hot Temperature
Humans
Male
Melatonin / administration & dosage*
Melatonin / blood
Middle Aged
Pain / drug therapy*
Pain Threshold / drug effects*
Pressure
Young Adult

Substances

Analgesics
Melatonin

Associated data

ReBec/U1111-1123-5109

Grants and funding

The present research was supported by the following Brazilian agencies: Research grant: National Council for Scientific and Technological Development - CNPq (Dr. I.L.S. Torres and Dr. W. Caumo; Dr. Regina Markus). Post-doctoral grant: Committee for the Development of Higher Education Personnel - CAPES - PNPD/CAPES. Doctoral grant: Postgraduate Program in Medical Sciences at the School of Medicine of the Federal University of Rio Grande do Sul (Joanna R. Rozisky). Assistance, medicines, equipment, and administrative support: Postgraduate Research Group at the Hospital de Clínicas de Porto Alegre. The institution (HCPA, UFRGS) received support from following governmental Brazilian agencies: The Foundation of Support of Research at Rio Grande do Sul (FAPERGS), National Council for Scientific and Technological Development – CNPq and Committee for the Development of Higher Education Personnel. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.