[Low-dose naltrexone (LDN): consumption trend in Brazilian capitals and the Federal District, 2014-2020]. / Naltrexona em baixa dose (LDN): tendência de consumo nas capitais brasileiras e Distrito Federal, 2014-2020.

The scope of this paper is an ecological study to determine the consumption of low-dose naltrexone (LDN) in the 26 Brazilian capitals and the Federal District and monitor the trend between the years 2014 to 2020. Data collection on the dispensation of manipulated naltrexone was done through the National Management System of Controlled Products, published in 2020, considering low-dose prescriptions of up to 5 mg. The calculation of the dispensation coefficients used the population estimates of the Brazilian Institute of Geography and Statistics. Descriptive statistical analysis and generalized Prais-Winsten regression analysis were used for the time series analysis. The trends observed were classified as increasing, stable, or decreasing, with a 95% confidence interval and 5% significance level. The results showed higher LDN consumption coefficients in the Mid-West, South and Southeast regions and lower coefficients in the North and Northeast. Increasing dispensation of LDN was observed in 55.6% of the capitals, being stationary in 44.4%, with no decreasing coefficients. Despite the limited evidence regarding LDN pharmacotherapy and its off-label prescription, the data show that prescription, dispensing, and consumption have been on the increase in Brazil, with emphasis on the central-south regions of the country.

Estudo ecológico com objetivo de determinar o consumo de naltrexona em baixa dose (LDN) nas 26 capitais brasileiras e Distrito Federal e acompanhar a tendência entre os anos de 2014 e 2020. A coleta de dados da dispensação de naltrexona manipulada, se deu por meio do Sistema Nacional de Gerenciamento de Produtos Controlados, publicizado em 2020, considerando-se baixa dose prescrições de até 5 mg. O cálculo dos coeficientes de dispensação utilizou as estimativas populacionais do Instituto Brasileiro de Pesquisa Geografia e Estatística. Utilizou-se análise estatística descritiva e de regressão generalizada de Prais-Winsten para a série temporal. As tendências observadas foram classificadas em crescentes, estáveis ou decrescentes, com intervalo de confiança de 95% e nível de significância de 5%. Os resultados demonstraram maiores coeficientes de consumo de LDN nas regiões Centro-Oeste, Sul e Sudeste e menores nas Norte e Nordeste. Observou-se dispensação de LDN crescente em 55,6% das capitais, estacionária em 44,4% e ausência de coeficientes decrescentes. Apesar das evidências limitadas quanto à farmacoterapia de LDN e da sua prescrição off-label, os dados demonstram que a prescrição, dispensação e consumo vem crescendo no Brasil, com ênfase nas regiões centro-sul do país.

Naltrexona em baixa dose (LDN): tendência de consumo nas capitais brasileiras e Distrito Federal, 2014-2020 / Low-dose naltrexone (LDN): consumption trend in Brazilian capitals and the Federal District, 2014-2020

Resumo Estudo ecológico com objetivo de determinar o consumo de naltrexona em baixa dose (LDN) nas 26 capitais brasileiras e Distrito Federal e acompanhar a tendência entre os anos de 2014 e 2020. A coleta de dados da dispensação de naltrexona manipulada, se deu por meio do Sistema Nacional de Gerenciamento de Produtos Controlados, publicizado em 2020, considerando-se baixa dose prescrições de até 5 mg. O cálculo dos coeficientes de dispensação utilizou as estimativas populacionais do Instituto Brasileiro de Pesquisa Geografia e Estatística. Utilizou-se análise estatística descritiva e de regressão generalizada de Prais-Winsten para a série temporal. As tendências observadas foram classificadas em crescentes, estáveis ou decrescentes, com intervalo de confiança de 95% e nível de significância de 5%. Os resultados demonstraram maiores coeficientes de consumo de LDN nas regiões Centro-Oeste, Sul e Sudeste e menores nas Norte e Nordeste. Observou-se dispensação de LDN crescente em 55,6% das capitais, estacionária em 44,4% e ausência de coeficientes decrescentes. Apesar das evidências limitadas quanto à farmacoterapia de LDN e da sua prescrição off-label, os dados demonstram que a prescrição, dispensação e consumo vem crescendo no Brasil, com ênfase nas regiões centro-sul do país.

Abstract The scope of this paper is an ecological study to determine the consumption of low-dose naltrexone (LDN) in the 26 Brazilian capitals and the Federal District and monitor the trend between the years 2014 to 2020. Data collection on the dispensation of manipulated naltrexone was done through the National Management System of Controlled Products, published in 2020, considering low-dose prescriptions of up to 5 mg. The calculation of the dispensation coefficients used the population estimates of the Brazilian Institute of Geography and Statistics. Descriptive statistical analysis and generalized Prais-Winsten regression analysis were used for the time series analysis. The trends observed were classified as increasing, stable, or decreasing, with a 95% confidence interval and 5% significance level. The results showed higher LDN consumption coefficients in the Mid-West, South and Southeast regions and lower coefficients in the North and Northeast. Increasing dispensation of LDN was observed in 55.6% of the capitals, being stationary in 44.4%, with no decreasing coefficients. Despite the limited evidence regarding LDN pharmacotherapy and its off-label prescription, the data show that prescription, dispensing, and consumption have been on the increase in Brazil, with emphasis on the central-south regions of the country.

A3 receptor agonist modulates IL-1ß hippocampus levels in a rat model of neuropathic pain

Introduction: Considering the lack of specific treatments for neuropathic pain, this study aimed to evaluate the effect of a single dose of adenosine A3 receptor IB-MECA on inflammatory and neurotrophic parameters in rats subjected to a neuropathic pain model. Methods: 64 adult male Wistar rats were used. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve and the treatment consisted of a 0.5 µmol/kg dose of IB-MECA, a selective A3 adenosine receptor agonist, dissolved in 3% DMSO; vehicle groups received DMSO 3% in saline solution, and morphine groups received 5 mg/kg. Cerebral cortex and hippocampus IL-1ß, BDNF, and NGF levels were determined by Enzyme-Linked Immunosorbent assay. Results: The main outcome was that a single dose of IB-MECA was able to modulate the IL-1ß hippocampal levels in neuropathic pain induced by CCI and the DMSO increased IL-1ß and NGF hippocampal levels in sham-operated rats. However, we did not observe this effect when the DMSO was used as vehicle for IB-MECA, indicating that IB-MECA was able to prevent the effect of DMSO. Conclusions: Considering that the IL-1ß role in neuropathic pain and the contributions of the hippocampus are well explored, our result corroborates the relationship between the A3 receptor and the process of chronic pain maintenance.

Transcranial Direct Current Stimulation in Patients with Anxiety: Current Perspectives.

Anxiety is one of the most prevalent and debilitating psychiatric conditions worldwide. Pharmaco- and psycho-therapies have been employed in the treatment of human anxiety to date. Yet, either alone or in combination, unsatisfactory patient outcomes are prevalent, resulting in a considerable number of people whose symptoms fail to respond to conventional therapies with symptoms remaining after intervention. The demand for new therapies has given birth to several noninvasive brain stimulation techniques. Transcranial direct current stimulation (tDCS) has arisen as a promising tool and has been proven to be safe and well tolerated for the treatment of many diseases, including chronic pain, depression, and anxiety. Here, reports of the use of tDCS in anxiety disorders in human patients were reviewed and summarized. A literature search was conducted in mid-2019, to identify clinical studies that evaluated the use of tDCS for the treatment of anxiety behavior. The PubMed, Web of Science, and Scielo and PsycInfo databases were explored using the following descriptors: "anxiety", "anxious behavior", "tDCS", and "transcranial direct current stimulation". Among the selected articles, considerable variability in the type of tDCS treatment applied in interventions was observed. Evidence shows that tDCS may be more effective when used in combination with drugs and cognitive behavioral therapies; however future large-scale clinical trials are recommended to better clarify the real effects of this intervention alone, or in combination with others.

The Fear of Pain Questionnaire: psychometric properties of a Brazilian version for adolescents and its relationship with brain-derived neurotrophic factor (BDNF).

OBJECTIVES: The primary aim was to assess the psychometric properties (including internal consistency, construct validity, criterion validity, criterion-group validity and responsiveness) of the Fear of Pain Questionnaire (FOPQ) for adolescents (FOPQ-A) and parents (FOPQ-P) translated to Brazilian Portuguese (BrP). The secondary aim was to analyze the factor structures and their ability to identify subjects with chronic pain conditions and identify the relationship of the BrP FOPQ-A with saliva brain-derived neurotrophic-factor (BDNF). METHODS: A cross-sectional study was conducted with 286 adolescents aged 11 to 18 (257 healthy adolescents [157 females] and 29 adolescents with chronic pain [16 females]). Parents and adolescents completed the BrP-FOPQ. A team of experts translated the FOPQ according to international guidelines. Convergent validity and factor analysis were performed. Later, a subsample (n=146) was used to correlate the BrP-FOPQ-A with saliva BDNF. RESULTS: The BrP-FOPQ for adolescents and parents presented strong psychometric properties (Cronbach's α equal to 0.92 and 0.91, respectively). BrP-FOPQ-A confirmatory factor analysis yielded a two-factor structure while the factorial analyses of BrP-FOPQ-P demonstrated that the best solution was a three-structure factorial. The BrP-FOPQ-P scores in healthy adolescents and those in chronic pain conditions was 34.13 (16.71) vs 43.14 (18.08), respectively. A generalized mixed model demonstrated that the scores in the BrP-FOPQ-A are higher in those with chronic pain conditions compared to healthy subjects (29.20 [12.77] vs 33.80 [10.76], respectively; Wald χ2= 17.80; df=1, P<0.0001). The model revealed that the BDNF was positively correlated with the score of BrP-FOPQ-A and subjects with chronic pain showed higher levels of BDNF. CONCLUSION: The BrP-FOPQ scores for adolescents and parents were found to be psychometrically robust and reliable instruments, with primary evidence of validity. Higher scores on the BrP-FOPQ-A were correlated positively with saliva BDNF and permitted the identification of subjects with chronic pain conditions.

Intramuscular electrical stimulus potentiates motor cortex modulation effects on pain and descending inhibitory systems in knee osteoarthritis: a randomized, factorial, sham-controlled study.

BACKGROUND: Neuroplastic changes in nociceptive pathways contribute to severity of symptoms in knee osteoarthritis (KOA). A new look at neuroplastic changes management includes modulation of the primary motor cortex by transcranial direct current stimulation (tDCS). OBJECTIVES: We investigated whether tDCS combined with intramuscular electrical stimulation (EIMS) would be more efficacious than a sham (s) intervention (s-tDCS/s-EIMS) or a single active(a)-tDCS/s-EIMS intervention and/or s-tDCS/a-EIMS in the following domains: pain measures (visual analog scale [VAS] score and descending pain modulatory system [DPMS], and outcomes, and analgesic use, disability, and pain pressure threshold (PPT) for secondary outcomes. REGISTRATION: The trial is registered in Clinicaltrials.gov: NCT01747070. METHODS: Sixty women with KOA, aged 50-75 years old, randomly received five sessions of one of the four interventions (a-tDCS/a-EIMS, s-tDCS/s-EIMS, a-tDCS/s-EIMS, and s-tDCS/a-EIMS). tDCS was applied over the primary motor cortex (M1), for 30 minutes at 2 mA and the EIMS paraspinal of L1-S2. RESULTS: A generalized estimating equation model revealed the main effect of the a-tDCS/a-EIMS in the VAS pain scores at end treatment compared with the other three groups (P<0.0001). There existed a significant effect of time and a significant interaction between group and time (P<0.01 for both). The delta-(Δ) pain score on VAS in the a-tDCS/a-EIMS group was -3.59, 95% CI: -4.10 to -2.63. The (Δ) pain scores on VAS in the other three groups were: a-tDCS/s-EIMS=-2.13, 95% CI: -2.48 to -1.64; s-tDCS/a-EIMS=-2.25, 95% CI: -2.59 to -1.68; s-tDCS/s-EIMS MR =-1.77, 95% CI: -2.08 to -1.38. The a-tDCS/a-EIMS led to better effect in DPMS, PPT, analgesic use, and disability related to pain. CONCLUSION: This study provides additional evidence regarding additive clinical effects to improve pain measures and descending pain inhibitory controls when the neuromodulation of the primary motor cortex with tDCS is combined with a bottom-up modulation with EIMS in KOA. Also, it improved the ability to walk due to reduced pain and reduced analgesic use.

The Central Sensitization Inventory validated and adapted for a Brazilian population: psychometric properties and its relationship with brain-derived neurotrophic factor.

OBJECTIVES: The primary aim was to assess the psychometric properties (including internal consistency, construct validity, reproducibility, and factor structure) of the Central Sensitization Inventory (CSI), adapted and validated for a Brazilian population (CSI-BP). Additionally, we evaluated the relationship between the CSI-BP and the serum brain-derived neurotrophic factor (BDNF) and determined if the symptoms elicited by the CSI-BP discriminate between subjects who do/do not respond to the conditioned pain modulation (CPM) task, as assessed by change in numeric pain scale (0-10) score. PATIENTS AND METHODS: A cross-sectional study was conducted in a pain clinic in a tertiary teaching hospital. A total of 222 adults with chronic musculoskeletal pain and 63 healthy control subjects completed the CSI-BP and the Brazilian Portuguese pain-catastrophizing scale (BP-PCS). A team of experts translated the CSI according to the international guidelines. Test-retest, item analysis, convergent validity, and factor analysis were performed. Later, a random subsample (n=77) was used to correlate the CSI-BP adjusted index with change in numeric pain-scale score during the CPM task and a BDNF blood sample. RESULTS: The CSI-BP presented strong psychometric properties (test-retest reliability 0.91, Cronbach's α=0.91). Confirmatory factor analysis yielded a four-factor structure, supporting the original English version. The CSI-BP adjusted index showed moderate positive correlation with the BP-PCS, and classified more than 80% of patients correctly vs healthy controls. Serum BDNF levels explained 27% of the variation in the CSI-BP adjusted index. Subjects with impairment in the descending modulatory system had higher CSI-BP adjusted index scores than subjects who responded normally to the CPM task: 49.35 (12.1) vs 39.5 (12.33), respectively (P<0.05). CONCLUSION: The CSI-BP was found to be a psychometrically strong and reliable instrument, with primary evidence of validity. Higher scores on the CSI-BP were correlated positively with serum BDNF and with greater dysfunction of the descending pain-modulatory system.

Melatonin administration reduces inflammatory pain in rats.

In view of the broad range of effects attributed to melatonin, this study evaluated its analgesic effect on inflammatory pain induced by complete Freund's adjuvant (CFA) in Wistar rats. Inflammation was induced by intradermal CFA injection in the hind paw of all animals, which were then divided into two groups that received either 60 mg/kg of melatonin or vehicle (1% alcohol in saline), intraperitoneally, for three days. The analgesic effect of melatonin was assessed by the hot-plate test, immediately and thereafter at 30, 60, 90, and 120 minutes after the first administration and 24 hours after once-daily administration for 2 more days. After CFA injection, melatonin administration increased withdrawal latency at 60 minutes after the first dose. After the end of treatment, melatonin showed a significant analgesic effect on inflammatory pain. This study paves the way for exploration of how brief courses of treatment could improve this analgesic effect in the late phases of inflammatory pain.

Morphine treatment alters nucleotidase activities in rat blood serum.

Morphine has been widely used in neonatal pain management. However, this treatment may produce adaptive changes in several physiologic systems. Our laboratory has demonstrated that morphine treatment in neonate rats alters nucleoside triphosphate diphosphohydrolase (NTPDase) activity and gene expression in central nervous system structures. Considering the relationship between the opioid and purinergic systems, our aim was to verify whether treatment with morphine from postnatal days 8 (P8) through 14 (P14) at a dose of 5 µg per day alters NTPDase and 5'-nucleotidase activities in rat serum over the short, medium, and long terms. After the in vivo assay, the morphine group showed increased hydrolysis of all nucleotides at P30, and a decrease in adenosine 5'-diphosphate hydrolysis at P60. Moreover, we found that nucleotidase activities change with age; adenosine 5'-triphosphate hydrolysis activity was lower at P16, and adenosine 5'-monophosphate hydrolysis activity was higher at P60. These changes are very important because these enzymes are the main regulators of blood nucleotide levels and, consequently, nucleotide signaling. Our findings showed that in vivo morphine treatment alters nucleotide hydrolysis in rat blood serum, suggesting that purine homeostasis can be influenced by opioid treatment during the neonatal period.

Effects of restraint stress on the daily rhythm of hydrolysis of adenine nucleotides in rat serum.

BACKGROUND: Adenosine 5-triphosphate (ATP) and its breakdown products ADP and adenosine can act as extracellular messengers in a range of biological processes. Extracellular adenine nucleotides are metabolized by a number of enzymes including NTPDases and 5'-nucleotidase, which are considered to be the major regulators of purinergic signaling in the blood. Previous work by our group demonstrated that ATPase and ADPase activities in rat serum exhibit a 24-h temporal pattern, with higher enzyme activity during the dark (activity) phase. It was found that stress can cause disruptions in biological circadian rhythms and in the cardiovascular system. Therefore, the aim of the present study was to examine the influence of acute stress exposure upon temporal patterns of NTPDase and 5-nucleotidase enzyme activities in rat blood serum. METHODS: Adult male Wistar rats were divided into 4 groups: ZT0, ZT6, ZT12 and ZT18. Each group was subdivided in 4 groups: control, immediately, 6 h and 24 h after one hour of restraint stress. ATP, ADP and AMP hydrolysis were assayed in the serum. RESULTS: All stressed groups showed significant decreases in all enzyme activities at ZT 12 and ZT 18 when compared with control. CONCLUSION: Acute stress provokes a decrease in nucleotidase activities dependent on the time that this stress occurs and this effect appears to persist for at least 24 hours. Stress can change levels of nucleotides, related to increased frequency of cardiovascular events during the activity phase. Altered levels of nucleotides in serum may be involved in cardiovascular events more frequent during the activity phase in mammals, and with their etiology linked to stress.