Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial

Paula, Tânia Maria Hendges de; Castro, Mariane Schäffer; Medeiros, Liciane Fernandes; Paludo, Rodrigo Hernandes; Couto, Fabricia Fritz; Costa, Tainá Ramires da; Fortes, Juliana Pereira; Salbego, Maiara de Oliveira; Behnck, Gabriel Schardosim; Moura, Thielly Amaral Mesquita de; Tarouco, Mariana Lenz; Caumo, Wolnei; Souza, Andressa de

doi:10.1016/j.bjane.2022.08.003

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Brazilian Journal of Anesthesiology

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Original Investigation • para Braz. J. Anesthesiol. 73 (4) • Jul-Aug 2023 • https://doi.org/10.1016/j.bjane.2022.08.003 copy

Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Introduction

Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management.

Objective

The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia.

Methods

This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA). The following categories were assessed: sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Profile of Chronic Pain Scale (PCP:S), Pain Pressure Threshold (PPT), and Conditioned Pain Modulation (CPM). Blood samples were collected to analyze BDNF serum levels.

Results

At baseline, no significant difference was found regarding all measurements. VAS pain was significantly reduced in the LDN + tDCS (p = 0.010), LDN + tDCS Sham (p= 0.001), and placebo+tDCS Sham (p= 0.009) groups. In the PCP:S, the LDN+tDCS group showed reduced pain frequency and intensity (p= 0.001), effect of pain on activities (p= 0.014) and emotions (p= 0.008). Depressive symptoms reduced after all active interventions (p > 0.001).

Conclusion

Combined LDN+tDCS has possible benefits in reducing pain frequency and intensity; however, a placebo effect was observed in pain using VAS, and further studies should be performed to analyze the possible association.

KEYWORDS
Fibromyalgia; Naltrexone; Pain; Transcranial direct current stimulation

	LDN+tDCS	LDN + tDCS Sham	Placebo+tDCS	Placebo + tDCS Sham	p-value
Age (y)	49.74 ± 1.97	48.09 ± 1.56	50.57 ± 2.23	48.95 ± 2.08	0.800^a a One-Way ANOVA - Data expressed as mean ± standard error.
Scholarship (y)	10.00 ± 0.53	11.55 ± 0.99	13.00 ± 0.92	11.95 ± 0.83	0.097^a a One-Way ANOVA - Data expressed as mean ± standard error.
BMI (kg.m⁻²)	27.44 ± 0.88	30.08 ± 1.30	28.37 ± 1.08	27.37 ± 0.87	0.236^a a One-Way ANOVA - Data expressed as mean ± standard error.
Use of Alcohol					0.465^b b Fisher's Exact Test - Data expressed as percentage.
Yes	33.3%	13.6%	18.2%	14.3%
No	66.7%	86.4%	81.8%	85.7%
Smoking					0.744^b b Fisher's Exact Test - Data expressed as percentage.
Yes	19%	18.2%	9.1%	9.5%
No	81%	81.8%	90.9%	90.5%
Use of medicine
Tricyclic AD	23.8%	18.2%	22.7%	23.8%	0.953^b b Fisher's Exact Test - Data expressed as percentage.
Serotonergic AD	33.3%	27.3%	18.2%	14.3%	0.523^b b Fisher's Exact Test - Data expressed as percentage.
MAO Inhibitor	0%	4.5%	0%	0%	1.000^b b Fisher's Exact Test - Data expressed as percentage.
Antipsychotic	0%	0%	4.5%	0%	1.000^b b Fisher's Exact Test - Data expressed as percentage.
Anxiolytic	19%	4.5%	9.1%	23.8%	0.302^b b Fisher's Exact Test - Data expressed as percentage.
Carbamazepine	0%	4.5%	0%	0%	0.948^b b Fisher's Exact Test - Data expressed as percentage.
Valproic Acid	0%	0%	0%	4.8%	0.500^b b Fisher's Exact Test - Data expressed as percentage.

	Day 1	Day 21	Day 26	p-value	Effect size
VAS
LDN + tDCS	7.05 ± 0.34	5.52 ± 0.55	5.10 ± 0.61^a a Different from Day 1.	0.010 ^{^c c Significant difference.} a Different from Day 1.	3.948
LDN + tDCS Sham	6.67 ± 0.32	6.12 ± 0.44	4.67 ± 0.58^a a Different from Day 1. ^b b Different from Day 21.	0.001 ^{^c c Significant difference.} a Different from Day 1.	4.269
Placebo + tDCS	6.14 ± 0.33	5.50 ± 0.49	4.41 ± 0.55	0.090	‒
Placebo + tDCS Sham	6.23 ± 0.35	5.20 ± 0.45^a a Different from Day 1.	5.00 ± 0.59	0.011 ^{^c c Significant difference.} a Different from Day 1.	2.555
PPT - Minimum Pain
LDN + tDCS	0.88 ± 0.15	0.74 ± 0.10	0.98 ± 0.12	0.068	‒
LDN + tDCS Sham	0.78 ± 0.09	0.72 ± 0.91	0.94 ± 0.10	0.170	‒
Placebo + tDCS	0.90 ± 0.11	0.90 ± 0.12	0.95 ± 0.13	0.955	‒
Placebo + tDCS Sham	1.02 ± 0.14	0.74 ± 0.11	0.98 ± 0.15	0.386	‒
PPT - Maximum Pain
LDN + tDCS	2.74 + 0.40	2.62 + 0.48	3.20 + 0.42	0.919	‒
LDN + tDCS Sham	2.99 ± 0.34	2.56 ± 0.24	2.95 ± 0.34	0.244	‒
Placebo + tDCS	3.70 ± 0.51	2.96 ± 0.37	3.16 ± 0.43	0.083	‒
Placebo + tDCS Sham	3.02 ± 0.39	2.78 ± 0.44	2.83 ± 0.49	0.140	‒
CPM
LDN + tDCS	-0.57 ± 0.74	-1.02 ± 0.69	-0.02 ± 0.61	0.589	‒
LDN + tDCS Sham	-1.22 ± 0.56	-0.22 ± 0.50	0.41 ± 0.54	0.129	‒
Placebo + tDCS	-0.68 ± 0.47	-1.18 ± 0.55	-0.22 ± 0.56	0.477	‒
Placebo + tDCS Sham	-1.23 ± 0.69	-0.28 ± 0.59	-0.23 ± 0.70	0.193	‒
PCP:S - Frequency and Intensity
LDN + tDCS	26.80 ± 0.44	26.04 ± 0.50	24.78 ± 0.55^a a Different from Day 1.	0.001 ^{^c c Significant difference.} a Different from Day 1.	4.055
LDN + tDCS Sham	25.40 ± 0.42	24.78 ± 0.65	24.02 ± 0.91	0.559	‒
Placebo + tDCS	25.88 ± 0.56	25.38 ± 0.56	25.77 ± 0.46	0.784	‒
Placebo + tDCS Sham	25.65 ± 0.69	24.92 ± 0.72	24.30 ± 0.95	0.069	‒
PCP:S - Interference in Activities
LDN + tDCS	28.61 ± 1.15	23.52 ± 1.65	22.74 ± 2.14^a a Different from Day 1.	0.014 ^{^c c Significant difference.} a Different from Day 1.	3.417
LDN + tDCS Sham	28.09 ± 1.56	25.28 ± 1.93^a a Different from Day 1.	25.76 ± 1.99^a a Different from Day 1.	0.008 ^{^c c Significant difference.} a Different from Day 1.	1.305
Placebo + tDCS	26.36 ± 1.49	25.65 ± 1.32	25.00 ± 1.49	0.387	‒
Placebo + tDCS Sham	25.40 ± 1.99	23.65 ± 2.11	22.15 ± 2.24	0.432	‒
PCP:S - Interference in Emotions
LDN + tDCS	16.38 ± 0.99	13.61 ± 1.11^a a Different from Day 1.	13.23 ± 1.34^a a Different from Day 1.	0.008 ^{^c c Significant difference.} a Different from Day 1.	2.673
LDN + tDCS Sham	17.31 ± 0.85	15.95 ± 1.21	14.90 ± 1.32	0.080	‒
Placebo + tDCS	15.90 ± 1.22	14.68 ± 1.25	14.09 ± 1.26	0.084	‒
Placebo + tDCS Sham	15.71 ± 1.05	14.61 ± 1.18	14.38 ± 1.32	0.267	‒

	Day 1	Day 21	Day 26	p-value	Effect size
FIQ-Function
LDN + tDCS	15.88 ± 1.53	11.67 ± 0.97^a a Different from Day 1.	12.67 ± 1.06	0.005 ^{^c c Significant difference.} a Different from Day 1.	3.286
LDN + tDCS Sham	13.30 ± 1.38	14.00 ± 1.87	13.89 ± 1.33	0.625	-
Placebo + tDCS	15.02 ± 1.37	13.78 ± 1.30	13.82 ± 1.39	0.403	-
Placebo + tDCS Sham	12.95 ± 1.21	13.79 ± 1.06	13.61 ± 1.07	0.918	-
FIQ-Overall Impact
LDN + tDCS	6.16 ± 0.25	5.85 ± 0.24	5.20 ± 0.23^a a Different from Day 1.	0.004 ^{^c c Significant difference.} a Different from Day 1.	3.996
LDN + tDCS Sham	5.80 ± 0.31	5.23 ± 0.26	5.20 ± 0.27	0.112	‒
Placebo + tDCS	5.23 ± 0.29	5.17 ± 0.22	4.69 ± 0.18	0.304	‒
Placebo + tDCS Sham	6.04 ± 0.23	5.43 ± 0.25	5.28 ± 0.26	0.054	‒
FIQ-Symptoms
LDN + tDCS	8.01 ± 0.33	6.62 ± 0.46	5.94 ± 0.47^a a Different from Day 1.	<0.001 ^{^c c Significant difference.} a Different from Day 1.	5.097
LDN + tDCS Sham	7.96 ± 0.28	6.50 ± 0.42	6.00 ± 0.43^a a Different from Day 1.	0.003 ^{^c c Significant difference.} a Different from Day 1.	5.401
Placebo + tDCS	7.68 ± 0.33	6.20 ± 0.45	5.40 ± 0.47^a a Different from Day 1.	0.003 ^{^c c Significant difference.} a Different from Day 1.	4.630
Placebo + tDCS Sham	7.73 ± 0.36	6.60 ± 0.40	5.97 ± 0.49^a a Different from Day 1.	0.003 ^{^c c Significant difference.} a Different from Day 1.	4.093
BDI-II
LDN + tDCS	24.38 ± 2.18	20.05 ± 1.92	17.33 ± 1.76^a a Different from Day 1.	<0.001 ^{^c c Significant difference.} a Different from Day 1.	3.558
LDN + tDCS Sham	28.86 ± 2.29	23.29 ± 2.52	20.90 ± 2.67^a a Different from Day 1.	0.001 ^{^c c Significant difference.} a Different from Day 1.	3.200
Placebo + tDCS	24.18 ± 1.82	21.36 ± 2.29	17.86 ± 2.45^a a Different from Day 1. ^b b Different from Day 21.	0.001 ^{^c c Significant difference.} a Different from Day 1.	2.928
Placebo + tDCS Sham	22.20 ± 2.35	19.25 ± 2.09	16.40 ± 2.32	0.086	‒
STAI - State
LDN + tDCS	26.33 ± 0.54	27.50 ± 0.72	27.19 ± 0.70	0.590	‒
LDN + tDCS Sham	27.86 ± 0.91	26.43 ± 0.86^a a Different from Day 1.	27.71 ± 1.00	0.026 ^{^c c Significant difference.} a Different from Day 1.	1.615
Placebo + tDCS	27.82 ± 0.76	27.68 ± 1.02	28.27 ± 1.00	1.000	-
Placebo + tDCS Sham	27.40 ± 0.94	28.10 ± 1.21	27.25 ± 0.71	0.607	-
STAI - Trait
LDN + tDCS	24.86 ± 0.65	23.52 ± 0.75	21.86 ± 1.26^a a Different from Day 1.	0.003 ^{^c c Significant difference.} a Different from Day 1.	2.992
LDN + tDCS Sham	25.67 ± 0.63	25.24 ± 0.75	25.43 ± 0.61	0.607	‒
Placebo + tDCS	25.45 ± 0.66	24.64 ± 0.65	24.27 ± 0.72	0.277	‒
Placebo + tDCS Sham	24.60 + 0.74	24.75 + 0.78	23.95 + 0.74	0.520	‒
PCS - Total
LDN + tDCS	36.57 + 2.13	33.71 + 2.34	30.62 + 2.88^a a Different from Day 1.	0.027 ^{^c c Significant difference.} a Different from Day 1.	2.349
LDN + tDCS Sham	35.10 + 2.42	32.43 + 3.13	33.19 + 2.91	0.645	‒
Placebo + tDCS	37.09 + 2.41	32.00 + 1.79	31.23 + 2.56	0.071	‒
Placebo + tDCS Sham	37.10 + 2.12	31.75 + 2.81	30.20 + 3.41^a a Different from Day 1.	0.032 ^{^c c Significant difference.} a Different from Day 1.	2.430
PCS - Hopelessness
LDN + tDCS	16.19 + 1.03	14.62 + 1.10	12.67 + 1.42^a a Different from Day 1.	0.029 ^{^c c Significant difference.} a Different from Day 1.	2.837
LDN + tDCS Sham	15.14 + 1.35	14.14 + 1.50	14.95 + 1.39	0.681	‒
Placebo + tDCS	16.77 + 1.09	14.59 + 0.86	13.82 + 1.22	0.170	‒
Placebo + tDCS Sham	16.85 + 0.99	14.05 + 1.30	12.70 + 1.62^a a Different from Day 1.	0.003 ^{^c c Significant difference.} a Different from Day 1.	3.091
PCS - Magnification
LDN + tDCS	8.05 + 0.65	7.62 + 0.62	7.05 + 0.73	0.638	‒
LDN + tDCS Sham	8.10 + 0.56	7.29 + 0.85	7.29 + 0.77	0.520	‒
Placebo + tDCS	7.86 + 0.70	6.82 + 0.57	7.05 + 0.72	0.326	‒
Placebo + tDCS Sham	8.10 + 0.62	6.90 + 0.81	6.45 + 0.94	0.050	‒
PCS - Rumination
LDN + tDCS	12.33 + 0.64	11.48 + 0.77	10.90 + 0.84	0.067	‒
LDN + tDCS Sham	11.86 + 0.63	11.00 + 0.87	10.95 + 0.90	0.513	‒
Placebo + tDCS	12.45 + 0.87	10.59 + 0.63	10.36 + 0.83	0.058	‒
Placebo + tDCS Sham	12.15 + 0.77	10.80 + 0.92	11.05 + 0.92	0.348	‒

Sociedade Brasileira de Anestesiologia (SBA) Rua Professor Alfredo Gomes, 36, Botafogo , cep: 22251-080 - Rio de Janeiro - RJ / Brasil , tel: +55 (21) 97977-0024 - Rio de Janeiro - RJ - Brazil
E-mail: editor.bjan@sbahq.org

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[1] * Corresponding author. E-mail:andressasz@gmail.com (A.d. Souza).