Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dummy, controlled trial

Simone Azevedo de Zanette, Rafael Vercelino, Gabriela Laste, Joanna Ripoll Rozisky, André Schwertner, Caroline Buzzatti Machado, Fernando Xavier, Izabel Cristina Custódio de Souza, Alicia Deitos, Iraci L S Torres, Wolnei Caumo, Simone Azevedo de Zanette, Rafael Vercelino, Gabriela Laste, Joanna Ripoll Rozisky, André Schwertner, Caroline Buzzatti Machado, Fernando Xavier, Izabel Cristina Custódio de Souza, Alicia Deitos, Iraci L S Torres, Wolnei Caumo

Abstract

Background: Central disinhibition is a mechanism involved in the physiopathology of fibromyalgia. Melatonin can improve sleep quality, pain and pain threshold. We hypothesized that treatment with melatonin alone or in combination with amitriptyline would be superior to amitriptyline alone in modifying the endogenous pain-modulating system (PMS) as quantified by conditional pain modulation (CPM), and this change in CPM could be associated with serum brain-derived neurotrophic factor (BDNF). We also tested whether melatonin improves the clinical symptoms of pain, pain threshold and sleep quality.

Methods: Sixty-three females, aged 18 to 65, were randomized to receive bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for a period of six weeks. The descending PMS was assessed with the CPM-TASK. It was assessed the pain score on the Visual Analog Scale (VAS 0-100 mm), the score on Fibromyalgia Impact Questionnaire (FIQ), heat pain threshold (HPT), sleep quality and BDNF serum. Delta values (post- minus pre-treatment) were used to compare the treatment effect. The outcomes variables were collected before, one and six weeks after initiating treatment.

Results: Melatonin alone or in combination with amitriptyline reduced significantly pain on the VAS compared with amitriptyline alone (P < 0.01). The delta values on the VAS scores were-12.85 (19.93),-17.37 (18.69) and-20.93 (12.23) in the amitriptyline, melatonin and melatonin+amitriptyline groups, respectively. Melatonin alone and in combination increased the inhibitory PMS as assessed by the Numerical Pain Scale [NPS(0-10)] reduction during the CPM-TASK:-2.4 (2.04) melatonin + amitriptyline,-2.65 (1.68) melatonin, and-1.04 (2.06) amitriptyline, (P < 0.05). Melatonin + amitriptyline treated displayed better results than melatonin and amitriptyline alone in terms of FIQ and PPT improvement (P < 0.05, fort both).

Conclusion: Melatonin increased the inhibitory endogenous pain-modulating system as assessed by the reduction on NPS(0-10) during the CPM-TASK. Melatonin alone or associated with amitriptyline was better than amitriptyline alone in improving pain on the VAS, whereas its association with amitriptyline produced only marginal additional clinical effects on FIQ and PPT.

Trial registration: Current controlled trail is registered at clinical trials.gov upon under number NCT02041455. Registered January 16, 2014.

Figures

Figure 1
Figure 1
Flow chart showing recruitment and progress through the study. FMS: fibromyalgia syndrome; FIQ: fibromyalgia impact questionnaire; PPT: pain pressure threshold; QST: quantitative sensory testing; SCID: Structured Clinical Interview for DSM-IV; pain VAS: visual analog scale of pain; major side effects (MJSE) (severe dizziness, vivid nightmares, crippling drowsiness, severe headache, behavioral changes, and pain worsening).
Figure 2
Figure 2
Mean pain levels as Delta value (scores on VAS (0-100 mm) in last week of treatment minus scores one week pretreatment) in the three experimental groups. The error bars indicate the standard error of the mean. A letter b indicates a significant difference between the melatonin group and melatonin + amitriptyline groups compared with the amitriptyline group (P < 0.05). All comparisons were performed using a mixed analysis of variance (ANOVA) model, followed by the Bonferroni correction for post hoc multiple comparisons.
Figure 3
Figure 3
Delta value on the pain NPS(0-10) during the CPM-TASK. The error bars indicate the standard error of the mean. A letter b indicates a significant difference between the melatonin + and melatonin + amitriptyline compared with the amitriptyline group. All comparisons were performed using a mixed analysis of variance (ANOVA) model, followed by the Bonferroni correction for post hoc multiple comparisons.
Figure 4
Figure 4
Mean serum BDNF (ng/mL) at baseline and the after treatment presented as the mean ± SEM. The asterisk indicates a significant within group difference according to Mixed ANOVA model with Bonferroni test. Delta values (serum BDNF before treatment minus serum BDNF after pretreatment) were performed using a Mixed ANOVA. The error bars indicate the standard error of the mean. aIndicates that the treatment did not induce an effect that was significantly different between treatment groups (P > 0.05).

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