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1.
Medicine (Baltimore) ; 98(41): e17503, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593120

RESUMO

BACKGROUND: The local injection of multimodal cocktail is currently commonly used in the treatment of postoperative pain after total knee arthroplasty (TKA). It is still inconclusive whether the morphine added to the intraoperative injection mixture could make some difference. This meta-analysis aimed to evaluate the efficacy and safety of additional morphine injection on postoperative analgesia in TKA, and provide some useful information on morphine usage in clinical practice. METHODS: The randomized controlled trials (RCTs) in databases including PubMed, Web of Science, Embase, Cochrane Library, Chinese biomedical literature database (CBM), and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched. Of 623 records identified, 8 RCTs involving 1093 knees were eligible for data extraction and meta-analysis according to criteria included. RESULTS: Meta-analysis showed that the use of local morphine injection was not associated with significant pain relief within 48 hours postoperatively at rest and on motion (P > .05, all). The use of morphine reduced postoperative total systemic opioids consumption (P < .05). This study found no significant differences in other outcomes including knee flexion range of motion (ROM) (P > .05), extension ROM (P > .05), The Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores (P > .05), Post-operative nausea and vomiting occurrence (P > .05) regardless of the presence of morphine or not in the injections. CONCLUSION: Additional morphine added to multimodal cocktail did not decrease the postoperative pain scores significantly based on our outcomes, but it reduced the systemic postoperative opioids consumption in total knee arthroplasty.


Assuntos
Analgesia/métodos , Artroplastia do Joelho/efeitos adversos , Morfina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Analgesia/efeitos adversos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Anestesia Local/métodos , Artroplastia do Joelho/métodos , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Náusea e Vômito Pós-Operatórios/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Amplitude de Movimento Articular/efeitos dos fármacos
2.
Georgian Med News ; (292-293): 11-16, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31560655

RESUMO

The goal: to study the influence of various methods of analgesia on the state of postoperative anesthesia in patients after thoracotomy; compare the quantity of narcotic analgesics (morphine) used in different types of anesthesia and anesthesia related complications. In 85 patients after thoracotomy, anesthesia was performed by prolonged paravertebral analgesia (PVA) (19 patients), by prolonged epidural analgesia (EDA) (36 patients) with 0.2% solution of rapamycain and by an intravenous patient-controlled analgesia (PCA) with a morphine solution in the control group (30 patients). In all three groups, the nonsteroidal anti-inflammatory drug (NSAIDs) ketorolac tromethamine was used intramuscularly. The evaluation was performed within 3 days after surgery using the visual analog scale (VAS). In the PVA group, the pain level was 29.1 points four hours after surgery to 18.7 points at the end of the third day; in the EDA group - from 24.2 to 20.3 points, respectively; in the control group - from 48.8 to 38.0 points, respectively. The need for morphine administration within the first day after surgery was the highest in the control group and was 42.83±13.23 mg/day. In experimental groups, the need for morphine was 15.0±5.0 mg/day in the EDA group and 16.15±5.38 mg/day in the PVA group. The greatest number of complications was observed in the control group and was associated with the use of morphine. The method of anesthesia associated with the use of PVA was accompanied by the least amount of complications. In terms of the effectiveness of analgesia and the amount of narcotic analgesic used, it was comparable to EDA. Patients of this group least often developed chronic postoperative pain syndrome. PVA may be a priority for postoperative pain management in patients after thoracotomy.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Morfina/administração & dosagem , Morfina/uso terapêutico , Alcaloides Opiáceos/administração & dosagem , Alcaloides Opiáceos/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Dor/prevenção & controle , Toracotomia , Analgesia Epidural , Analgesia Controlada pelo Paciente , Analgésicos Opioides/efeitos adversos , Humanos , Pulmão/cirurgia , Morfina/efeitos adversos , Alcaloides Opiáceos/efeitos adversos , Medição da Dor/efeitos dos fármacos , Complicações Pós-Operatórias
3.
BMC Neurosci ; 20(1): 36, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366324

RESUMO

BACKGROUND: Postoperative pain (POP) is a severe acute pain encountered in patients suffering from an operation, and is less than adequately controlled by the currently available analgesics. Phosphatidylinositol 3-kinase (PI3K) has been reported to have an important role in neuropathic and inflammatory pain. Our previous research revealed that pre-surgical inhibition of spinal PI3K alleviated the pain behavior induced by plantar incision in mice. The aim of this study was to clarify whether post-surgical inhibition of PI3K would attenuate the POP and the underlying mechanisms. METHODS: A POP model was established by plantar incision in Kunming mice. A behavioral test was performed to determine mechanical allodynia, thermal hyperalgesia, and cumulative pain scores. The spinal Fos was detected by immunohistochemistry. The spinal expression of protein kinase B (Akt) or phosphorylated Akt (pAkt) was explored using western blot. The cellular location of pAkt was determined by immunofluorescence. RESULTS: Post-surgical inhibition of PI3K attenuated mechanical allodynia, thermal hyperalgesia, and cumulative pain scores induced by plantar incision significantly in male mice, and mildly in female mice. Post-surgical inhibition of PI3K attenuated the expression of spinal Fos in male mice. Plantar incision induced a time-dependent expression of spinal pAkt in male mice, which was primarily expressed in the spinal dorsal horn, and localized with the neuron and microglia's marker. Post-surgical inhibition of PI3K attenuated the activation of Akt induced by plantar incision in male mice as well. CONCLUSIONS: We concluded that post-surgical inhibition of PI3K could attenuate the pain-related behaviors induced by plantar incision, by suppressing the activation of spinal Akt in male mice. This finding might be used in clinical studies to reach a better understanding of POP mechanisms and optimal treatment.


Assuntos
Cromonas/farmacologia , Hiperalgesia/fisiopatologia , Morfolinas/farmacologia , Dor Pós-Operatória/prevenção & controle , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Wortmanina/farmacologia , Animais , Feminino , Traumatismos do Pé/complicações , Hiperalgesia/complicações , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Dor Pós-Operatória/complicações , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Caracteres Sexuais , Medula Espinal/metabolismo
4.
Psychopharmacology (Berl) ; 236(11): 3341-3352, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31201479

RESUMO

RATIONALE: Dozens of preclinical studies have reported cannabinoid agonist potentiation of the analgesic effects of µ-opioid agonists. OBJECTIVES: The aim of this study was to determine if a cannabinoid agonist could potentiate opioid analgesia in humans using several laboratory pain models. METHODS: Healthy participants (n = 10) with/out current drug use/pain conditions completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Nine 8-h sessions were completed during which dronabinol (0, 2.5, 5 mg, p.o.) was administered 1 h before oxycodone (0, 5, 10 mg, p.o.) for a total of 9 test conditions. Outcomes included sensory threshold and tolerance from four experimental pain models (cold pressor, pressure algometer, hot thermode, cold hyperalgesia), along with participant- and observer-rated, performance and physiological effects. RESULTS: Oxycodone produced miosis (p < 0.05) and analgesic responses (e.g., pressure algometer [p < 0.05]), while dronabinol did not (p > 0.05). Depending on the dose combination, dronabinol attenuated or did not alter oxycodone analgesia; for example, dronabinol (2.5 mg) decreased the analgesic effects of oxycodone (10 mg) on pressure tolerance. Conversely, dronabinol increased oxycodone subjective effects (e.g., drug liking) (p < 0.05); oxycodone (5 mg) ratings of "high" were potentiated by 5 mg dronabinol (p < 0.05; placebo = 1.1 [± 0.7]; 5 mg oxycodone = 4.7 [± 2.2]; 5 mg dronabinol = 9.9 [± 8.4]; 5 mg oxycodone + 5 mg dronabinol = 37.4 [± 11.3]). CONCLUSIONS: This study indicates that dronabinol did not enhance the analgesic effects of oxycodone and increased abuse- and impairment-related subjective effects. These data suggest that dronabinol may not be an effective or appropriate opioid adjuvant; it could potentially increase opioid dose requirements, while increasing psychoactive opioid effects.


Assuntos
Analgesia/métodos , Analgesia/psicologia , Analgésicos Opioides/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/psicologia , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Estudos Cross-Over , Autoavaliação Diagnóstica , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Dor/psicologia , Medição da Dor/métodos , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Adulto Jovem
5.
Lancet Psychiatry ; 6(8): 667-674, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31248841

RESUMO

BACKGROUND: Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to continue the course of treatment. Mechanistic studies might help advance the pharmacology of depression by identifying pathways through which treatments exert their effects. Toward this goal, we aimed to identify the effects of antidepressant treatment on neural connectivity, the relationship with symptom improvement, and to test whether these effects were reproducible across two studies. METHODS: We completed two double-blind, placebo-controlled trials of SNRI antidepressant medications with MRI scans obtained before and after treatment. One was a 10-week trial of duloxetine (30-120 mg daily; mean 92·1 mg/day [SD 30·00]) and the other was a 12-week trial of desvenlafaxine (50-100 mg daily; 93·6 mg/day [16·47]). Participants consisted of adults with persistent depressive disorder. Adjusting for sex and age, we examined the effect of treatment on whole-brain functional connectivity. We also examined correlations between change in functional connectivity and improvement in symptoms of depression (24-item Hamilton Depression Rating Scale) and pain symptom severity (Symptom Checklist-90-Revised). FINDINGS: Participants were enrolled between Jan 26, 2006, and Nov 22, 2011, for the duloxetine RCT and Aug 5, 2012, and Jan 28, 2016, for the desvenlafaxine RCT. Before and after treatment MRI scans were collected in 32 participants for the duloxetine RCT and 34 participants for the desvenlafaxine RCT. In both studies, antidepressants decreased functional connectivity compared with placebo (duloxetine study: ß=-0·06; 95% CI -0·08 to -0·03; p<0·0001, ηp2=0·44; desvenlafaxine study: -0·06, -0·09 to -0·03; p<0·0001, ηp2=0·35) within a thalamo-cortico-periaqueductal network that has previously been associated with the experience of pain. Within the active drug groups, reductions in functional connectivity within this network correlated with improvements in depressive symptom severity in both studies (duloxetine study: r=0·38, 95% CI 0·01-0·65; p=0·0426; desvenlafaxine study: 0·44, 0·10-0·69; p=0·0138) and pain symptoms in the desvenlafaxine study (0·39, 0·04 to 0·65; p=0·0299). INTERPRETATION: The findings suggest the thalamo-cortico-periaqueductal network associated with the experience of pain is a new and potentially important target for novel antidepressant therapeutics. FUNDING: National Mental Health Institute, Eli Lilly and Company, Pfizer Pharmaceuticals, and the Edwin S Webster Foundation.


Assuntos
Antidepressivos/administração & dosagem , Encéfalo/diagnóstico por imagem , Conectoma/métodos , Transtorno Depressivo/tratamento farmacológico , Succinato de Desvenlafaxina/administração & dosagem , Cloridrato de Duloxetina/administração & dosagem , Adulto , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Transtorno Depressivo/diagnóstico por imagem , Succinato de Desvenlafaxina/farmacologia , Método Duplo-Cego , Esquema de Medicação , Cloridrato de Duloxetina/farmacologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Resultado do Tratamento
6.
Mar Drugs ; 17(5)2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083641

RESUMO

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA's ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.


Assuntos
Analgésicos/farmacocinética , Barreira Hematoencefálica/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Proteínas Recombinantes de Fusão/farmacocinética , ômega-Conotoxinas/farmacocinética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacocinética , Analgésicos/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Feminino , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/efeitos dos fármacos , Peptídeos/administração & dosagem , Peptídeos/química , Proteína FUS de Ligação a RNA , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/biossíntese , Tremor/tratamento farmacológico , Tremor/metabolismo , ômega-Conotoxinas/administração & dosagem , Produtos do Gene tat do Vírus da Imunodeficiência Humana/administração & dosagem
7.
J Neuroinflammation ; 16(1): 100, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31109346

RESUMO

BACKGROUND: Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853's lack of interaction with the neuroimmune system reduces the risk of prolonged pain. METHODS: Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund's adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 µl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups. RESULTS: As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain. CONCLUSIONS: ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain.


Assuntos
Analgésicos Opioides/uso terapêutico , Analgésicos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Morfina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Imunomodulação/fisiologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Masculino , Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Dor Pós-Operatória/imunologia , Peptídeos Cíclicos/farmacologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia
8.
Psychopharmacology (Berl) ; 236(9): 2725-2734, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31098655

RESUMO

RATIONALE: Mitragyna speciosa (kratom) may hold promise as both an analgesic and treatment for opioid use disorder. Mitragynine, its primary alkaloid constituent, is an opioid receptor ligand. However, the extent to which the in vivo effects of mitragynine are mediated by opioid receptors, or whether mitragynine interacts with other opioid agonists, is not fully established. OBJECTIVES: The effects of mitragynine and the prototypical opioid agonist morphine were compared for their capacity to decrease operant responding for food delivery, and to increase response latency to a thermal stimulus. METHODS: Male and female Sprague-Dawley rats responded under a multiple cycle fixed ratio 10 schedule of food delivery and were tested on a hot plate (52 °C) immediately after each cycle. Morphine and mitragynine were administered alone, in combination with each other, and in combination with the opioid antagonist naltrexone. RESULTS: Morphine and mitragynine dose-dependently decreased schedule-controlled responding; the ED50 values were 7.3 and 31.5 mg/kg, respectively. Both drugs increased thermal antinociception; the ED50 value for morphine was 18.3. Further, doses of naltrexone that antagonized morphine did not antagonize mitragynine. Mitragynine (17.8 mg/kg) did not alter the rate-decreasing or antinociceptive effects of morphine. CONCLUSIONS: The antinociceptive effects of mitragynine and morphine occur at doses larger than those that disrupt learned behavior. Opioid receptors do not appear to mediate the disruptive effects of mitragynine on learned behavior. Mitragynine had lesser antinociceptive effects than morphine, and these did not appear to be mediated by opioid receptors. The pharmacology of mitragynine includes a substantial non-opioid mechanism.


Assuntos
Analgésicos/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Alcaloides de Triptamina e Secologanina/farmacologia , Analgésicos Opioides/farmacologia , Animais , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Mitragyna , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/agonistas
9.
Exp Clin Psychopharmacol ; 27(4): 338-347, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31120286

RESUMO

Given the use of cannabis as an analgesic by a broadening age range of patients, the aim of this study was to determine whether the antinociceptive effects of Δ9-tetrahydrocannabinol (THC) differ by age. The antinociceptive potency and efficacy of THC (1.0-18 mg/kg ip) was compared in male and female rats aged postnatal day 35-40 (adolescent), 60-70 (young adult), and 291-325 (middle-aged adult), using warm water tail withdrawal and paw pressure tests. Motoric effects of THC were assessed using a locomotor activity test. On the tail withdrawal test, THC was significantly more effective in middle-aged adult than in young adult rats and significantly less effective in adolescent than in young adult rats. Similar but smaller age-related differences were observed on the paw pressure test. Sex differences in THC's antinociceptive effects were consistent across the 3 ages examined, with greater THC effects observed in females than males of each age. Age-related differences in THC's locomotor-suppressing effect were also observed, with the greatest effect in young adult female rats. Serum THC levels were slightly higher in adolescent than in young adult rats, and levels of the active metabolites 11-OH-THC and cannabinol, as well as the inactive metabolite 11-nor-9-carboxy-THC, did not differ between adolescent and young adult rats. These results suggest that the pain-relieving effects of THC may be more limited in adolescents than in adults and that these age-related differences in THC effect are not attributable to differential absorption or metabolism of THC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Dronabinol/farmacologia , Dor/tratamento farmacológico , Caracteres Sexuais , Analgésicos , Animais , Canabinol/farmacologia , Cannabis , Dronabinol/uso terapêutico , Feminino , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Ratos
10.
Physiol Res ; 68(3): 501-510, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-30904013

RESUMO

One of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy for several types of cancers. Our recent study showed that impairment of Nrf2-antioxidant response element (Nrf2-ARE) and upregulation of oxidative signals in the dorsal root ganglion (DRG) of rats with treatment of paclitaxel result in neuropathic pain. The purpose of this study was to examine the beneficial role played by electroacupuncture (EA) in modifying neuropathic pain evoked by paclitaxel via Nrf2-ARE and oxidative mechanisms. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-ARE and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our data showed that paclitaxel increased mechanical and thermal sensitivity and this was accompanied with impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress (i.e. 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). EA treatment largely restored the levels of Nrf2-ARE/SOD and inhibited products of oxidative stress and thereby attenuated mechanical and thermal hypersensitivity induced by paclitaxel. In conclusion, we revealed specific signaling pathways leading to paclitaxel-evoked neuropathic pain, including impairment of Nrf2-ARE and heightened oxidative signals. We further provided evidence for the role of EA in alleviating paclitaxel-neuropathic pain via these molecular mediators.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Antioxidantes , Eletroacupuntura/métodos , Neuralgia/induzido quimicamente , Neuralgia/terapia , Paclitaxel/toxicidade , Animais , Antioxidantes/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Neuralgia/metabolismo , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
11.
Int J Immunopathol Pharmacol ; 33: 2058738419838383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900486

RESUMO

Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological states that determine the onset of neuropathic pain are heterogeneous, such as metabolic disorders, neuropathy caused by viral infections, and autoimmune diseases affecting the central nervous system (CNS). Neuropathic pain in the general population is estimated to have a prevalence ranging between 3% and 17%. Most of the available treatments for neuropathic pain have moderate efficacy and present side effects that limit their use; therefore, other therapeutic approaches are needed for patients. In this article, the current standard of care treatment, the emerging pharmacological approaches from the completed phase III clinical trials, and the preclinical studies on novel promising therapeutic options will be reviewed.


Assuntos
Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Medição da Dor/métodos , Analgésicos/farmacologia , Animais , Ensaios Clínicos Fase I como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Previsões , Humanos , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Medição da Dor/efeitos dos fármacos , Resultado do Tratamento
12.
Clin Drug Investig ; 39(4): 411-418, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30887417

RESUMO

The sufentanil 30 µg sublingual tablet (hereafter referred to as the sufentanil ST) is approved in the EU for acute moderate to severe pain in adults (Dzuveo™) and in the USA for acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate (Dsuvia™). It is a single-strength tablet housed in a single-dose applicator (which may minimize the likelihood of dosing errors) and is strictly for use in medically supervised/monitored settings. It is administered by a healthcare professional and has a minimum re-dose interval of 1 h and no drug delivery setup requirements. In placebo-controlled or noncomparative phase 2 or 3 trials, the sufentanil ST provided effective analgesia for adults with moderate to severe acute pain due to surgery or trauma/injury, reducing the intensity of pain within 15-30 min after the first dose and maintaining analgesic benefit over the 2-24 h study periods. Such short-term use of the sufentanil ST was also generally well tolerated. Studies directly comparing the sufentanil ST with other opioids in terms of efficacy, tolerability, usability and cost effectiveness would be beneficial, as would analyses of its abuse potential, given sufentanil is considerably more potent than fentanyl or morphine. In the meantime, current data indicate that the sufentanil ST is a noninvasive, fast-acting, opioid formulation for managing moderate to severe acute pain in medically supervised/monitored settings that may be of particular use when oral or intravenous opioid analgesia is not possible/feasible.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Manejo da Dor/métodos , Sufentanil/administração & dosagem , Dor Aguda/diagnóstico , Administração Intravenosa , Administração Sublingual , Analgesia Controlada pelo Paciente , Ensaios Clínicos como Assunto/métodos , Método Duplo-Cego , Fentanila/administração & dosagem , Humanos , Morfina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/tratamento farmacológico , Comprimidos
13.
Reg Anesth Pain Med ; 44(5): 595-603, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30886069

RESUMO

BACKGROUND AND OBJECTIVES: Two ultrasound (US)-guided techniques for greater occipital nerve (GON) block have been described for the management of headache disorders: a "proximal or central" technique targeting the GON at the level of the second cervical vertebra and a "distal or peripheral" technique targeting the GON at the level of the superior nuchal line. In this multicenter, prospective, randomized control trial, we compared accuracy, effectiveness, and safety of these two techniques in patients with chronic migraines (CMs). METHODS: Forty patients with refractory CMs were randomized to receive either a proximal or distal US-guided GON block with bupivacaine and methylprednisolone acetate. The primary outcome was the difference in Numerical Rating Score (NRS) for headache intensity at 1 month. Secondary outcomes were effectiveness, performance, and safety-related. Effectiveness-related outcomes included NRS for headache intensity, number of headache days per week, patient satisfaction, quality of life, assessment of sleep quality, and sleep interruption. Performance-related outcomes included procedure time, accuracy of block, and patient discomfort. Safety-related outcomes included an assessment for adverse effects. RESULTS: NRS pain scores were significantly reduced at 24 hours and at 1 week postprocedure in both cohorts and at 1 and 3 months in the proximal group as compared with the baseline. There was no significant difference in NRS pain scores between the two cohorts at any of the follow-up time points. There was a significant reduction in number of headache days per week at 1 month in both groups, and a significant improvement in sleep interruption at 1 week in both groups. There were no significant adverse effects. CONCLUSIONS: This study was designed to compare two different US-guided approaches for blocking the GON. Our results demonstrate that both distal and proximal techniques can provide a short-term improvement in headache intensity, reduction in number of headache days per week, and an improvement in sleep interruption. The proximal GON technique may confer more sustained analgesic benefit compared with the distal approach in patients with CM headaches. TRIAL REGISTRATION NUMBER: NCT02031822.


Assuntos
Anestésicos Locais/administração & dosagem , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Nervos Espinhais/diagnóstico por imagem , Ultrassonografia de Intervenção/métodos , Adulto , Doença Crônica , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Estudos Prospectivos , Nervos Espinhais/efeitos dos fármacos , Resultado do Tratamento
14.
Psychopharmacology (Berl) ; 236(9): 2641-2652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30927021

RESUMO

RATIONALE: Non-medical prescription opioid use and opioid use disorder (OUD) present a significant public health concern. Identifying behavioral mechanisms underlying OUD will assist in developing improved prevention and intervention approaches. Behavioral economic demand has been extensively evaluated as a measure of reinforcer valuation for alcohol and cigarettes, whereas prescription opioids have received comparatively little attention. OBJECTIVES: Utilize a purchase task procedure to measure the incremental validity and test-retest reliability of opioid demand. METHODS: Individuals reporting past year non-medical prescription opioid use were recruited using the crowdsourcing platform Amazon Mechanical Turk (mTurk). Participants completed an opioid purchase task as well as measures of cannabis demand, delay discounting, and self-reported pain. A 1-month follow-up was used to evaluate test-retest reliability. RESULTS: More intense and inelastic opioid demand was associated with OUD and more intense cannabis demand was associated with cannabis use disorder. Multivariable models indicated that higher opioid intensity and steeper opioid delay discounting rates each significantly and uniquely predicted OUD. Increased opioid demand intensity, but not elasticity, was associated with higher self-reported pain, and no relationship was observed with perceived pain relief from opioids. Opioid demand showed acceptable-to-good test-retest reliability (e.g., intensity rxx = .75; elasticity rxx = .63). Temporal reliability was lower for cannabis demand (e.g., intensity rxx = .53; elasticity rxx = .58) and discounting rates (rxx = .42-.61). CONCLUSIONS: Opioid demand was incrementally valid and test-retest reliable as measured by purchase tasks. These findings support behavioral economic demand as a clinically useful measure of drug valuation that is sensitive to individual difference variables.


Assuntos
Analgésicos Opioides/administração & dosagem , Mercantilização , Desvalorização pelo Atraso/efeitos dos fármacos , Economia Comportamental , Medição da Dor/efeitos dos fármacos , Adulto , Analgésicos Opioides/economia , Desvalorização pelo Atraso/fisiologia , Prescrições de Medicamentos/economia , Feminino , Humanos , Masculino , Fumar Maconha/economia , Fumar Maconha/psicologia , Transtornos Relacionados ao Uso de Opioides/economia , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Transtornos Relacionados ao Uso de Opioides/psicologia , Medição da Dor/economia , Medição da Dor/psicologia , Reprodutibilidade dos Testes , Fatores de Risco , Autorrelato , Transtornos Relacionados ao Uso de Substâncias/economia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
15.
Physiol Res ; 68(3): 511-518, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-30904004

RESUMO

Galanin and galanin receptors (GalRs) have been reported to be involved in the transmission and modulation of nociceptive information in the central nervous system (CNS). However, the underlying mechanism of the antinociception of GalRs in neuropathic pain remains unclear. This study investigated the antinociception induced by galanin receptor 1 (GalR1) via protein kinase A (PKA) signaling pathway in the nucleus accumbens (NAc) of rats with neuropathic pain. A mononeuropathy model was replicated by ligation of the left sciatic nerve, following which the expression of phospho-PKA (p-PKA) in the NAc were markedly up-regulated at 14(th) and 28(th) day after ligation of sciatic nerve, and p-PKA expression was down-regulated by intra-NAc injection of GalR1 agonist M617, but the GalR1 antagonist M35 did not have an effect. We also found that M35 in the NAc blocked the M617-induced increase in the hind paw withdrawal latencies (HWLs) of rats with mononeuropathy, but M35 alone had no effect on HWLs, and PKA inhibitor H-89 attenuated the M617-induced an increase in the HWLs. These results suggested that GalR1 induced an antinociception via inhibiting PKA activation, implying that GalR agonists may be potential and potent therapeutic options to treat chronic neuropathic pain.


Assuntos
Analgésicos/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Neuralgia/metabolismo , Neuralgia/prevenção & controle , Núcleo Accumbens/metabolismo , Receptor Tipo 1 de Galanina/biossíntese , Animais , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Galanina/análogos & derivados , Galanina/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Galanina/agonistas , Receptor Tipo 1 de Galanina/antagonistas & inibidores
16.
Biomed Pharmacother ; 112: 108693, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798128

RESUMO

This study evaluated the pharmacological effect of the association of crude extract from the fruits of Pterodon pubescens (Pp) with the essential oil of Cordia verbenacea (Cv) in antinociception and anti-inflammatory experimental models. The effective doses of each extract and the combinations used in the associations of extracts were defined by acetic acid-induced writhing test. The separate extracts were also evaluated on formalin test. Interaction between extracts was assessed by isobologram method. The effects of different concentrations of associations (A50, A100 and A200) were evaluated on formalin test, tail flick and hot plate. The anti-inflammatory activity was evaluated in paw edema induced by carrageenan and PGE2, carrageenan-induced peritonitis and mechanical allodynia induced by Complete Freund's Adjuvant (CFA). The associations were markedly synergistic, as assessed using isobolographic analyses. On formalin and on acetic acid-induced writhing tests, associations demonstrated greater efficacy when compared to extracts separately. In paw edema models, significant reductions of edema were observed. On mechanical allodynia induced by CFA, associations were effective at acute phase with pronounced effect at chronic phase. The associations were not effective in hot plate, tail flick and carrageenan-induced peritonitis tests. Phytochemical analysis by HPLC-DAD and FID showed important concentrations of α-Humulene, trans-Caryophyllene, geranylgeraniol, isomers 6α-hydroxy-7ß-acetoxy-vouacapan-17ßoate methyl ester and 6α-acetoxy-7ß-hydroxy-vouacapan-17ß-oate methyl ester (compounds m/z 404) and 6α,7ß-dihydroxyvouacapan-17ß-oate methyl ester (m/z 362). These findings demonstrate that the associations promote synergistic antinociceptive effect and important anti-inflammatory activities, especially on chronic inflammation conditions, at lower doses than the separate crude extracts, without demonstrating side effects, probably acting in different pharmacological receptors. The inhibition of inflammation suggests a relationship with inflammatory mediators and PGE2 pathway and might be exploited to achieve greater anti-inflammatory efficacy, being considered as a potential phytotherapy.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Cordia , Modelos Animais de Doenças , Fabaceae , Dor/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Masculino , Camundongos , Dor/metabolismo , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Extratos Vegetais/isolamento & purificação
17.
Eur J Pharmacol ; 848: 80-87, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30707956

RESUMO

Opioid and neurotensin (NT) receptors are expressed in both central and peripheral nervous systems where they modulate nociceptive responses. Nowadays, opioid analgesics like morphine remain the most prescribed drugs for the treatment of moderate to severe pain. However, despite their daily used, opioids can produce life-threatening side effects, such as constipation or respiratory depression. Besides, NT analogs exert strong opioid-independent analgesia. Here, we thus hypothesized that the combined use of opioid and NT agonists would require lower doses to produce significant analgesic effects, hence decreasing opioid-induced adverse effects. We used isobologram analyses to determine if the combination of a NT brain-penetrant analog, An2-NT(8-13) with morphine results in an inhibitory, synergistic or additive analgesic response. We found that intravenous administration of An2-NT(8-13) reduced by 90% the nocifensive behaviors induced by formalin injection, at the dose of 0.018 mg/kg. Likewise, subcutaneous morphine reduced pain by 90% at 1.8 mg/kg. Importantly, isobologram analyses revealed that the co-injection of An2-NT(8-13) with morphine induced an additive analgesic response. We finally assessed the effects of morphine and An2-NT(8-13) on the gastrointestinal tract motility using the charcoal meal test. As opposed to morphine which significantly reduced the intestinal motility at the analgesic effective dose of 1.8 mg/kg, An2-NT(8-13) did not affect the charcoal meal intestinal transit at 0.018 mg/kg. Interestingly, at the dose providing 90% pain relief, the co-administration of morphine with An2-NT(8-13) had a reduced effect on constipation. Altogether, these results suggest that combining NT agonists with morphine may improve its analgesic/adverse effect ratio.


Assuntos
Analgésicos Opioides/administração & dosagem , Neurotensina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Peptídeos/administração & dosagem , Receptores de Neurotensina/agonistas , Receptores Opioides mu/agonistas , Animais , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Masculino , Morfina/administração & dosagem , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores de Neurotensina/metabolismo , Receptores Opioides mu/metabolismo
18.
Neurosci Lett ; 699: 54-58, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30708129

RESUMO

Repeated intravesical PAR4 (protease activated receptor 4) activation elicits persistent bladder pain lasting 5 days after the last treatment. Persistent bladder pain was fully reversed by a systemic HMGB1 (high mobility group box 1) inhibitor while a MIF (macrophage migration inhibitory factor) antagonist partly reversed it. Since there is growing evidence that spinal MIF and HMGB1 mediate inflammatory and neuropathic pain we examined whether there were spinal changes occurring during persistent bladder pain that may be responsible for maintaining bladder pain. In addition, we tested whether we could modulate persistent bladder pain with spinal MIF or HMGB1 antagonists. Persistent bladder pain was elicited in female C57 mice by repeated (3x) intravesical instillation of PAR4-activating peptide while control animals received scramble peptide treatment. On day 4, spinal cord (L6-S1) changes in c-fos (non-specific marker of spinal activation) was assessed with immunofluorescence while MIF and HMGB1 were assessed with immunofluorescence, western blotting and real-time PCR. On day 7, mice received an intrathecal injection of a neutralizing MIF monoclonal antibody (15 µg in 5 µl PBS) or a HMGB1 inhibitor glycyrrhizin (25 µg in 5 µl of 5% alcohol in PBS) and abdominal mechanical threshold was tested. On day 9, mice were treated with vehicle or control and abdominal mechanical threshold was tested. Immunofluorescence showed that c-fos and MIF in the dorsal horn, dorsal grey commissure and intermediolateral areas significantly increased in PAR4-treated mice while HMGB1 was decreased. In addition, intrathecal treatment with MIF neutralizing mAb or glycyrrhizin significantly alleviated abdominal mechanical hypersensitivity at 1 and 2 h and the analgesic effect diminished at 6 h. Vehicle or control treatment had no effect. Persistent bladder pain is associated with spinal changes in MIF and HMGB1 levels. Furthermore, spinal treatment with MIF monoclonal antibody and HMGB1 inhibitor temporarily reversed bladder pain. Our findings suggest that spinal MIF and HMGB1 participate in persistent bladder pain induced by repeated intravesical PAR4 and may be potential therapeutic targets in chronic bladder pain conditions.


Assuntos
Proteína HMGB1/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Neuralgia/metabolismo , Bexiga Urinária/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Feminino , Ácido Glicirrízico/farmacologia , Proteína HMGB1/antagonistas & inibidores , Hiperalgesia/induzido quimicamente , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/prevenção & controle , Oligopeptídeos , Medição da Dor/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de Trombina/agonistas , Medula Espinal/metabolismo , Bexiga Urinária/efeitos dos fármacos
19.
Neuroscience ; 404: 246-258, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30794845

RESUMO

Bidirectional selection of mice for high (HA) and low (LA) swim stress-induced analgesia (SSIA) is associated with a divergent response to opioids. In the current study, we investigated whether the genetic divergence in opioid system activity between HA and LA mice also affects cannabinoid sensitivity. Additionally, we also investigated whether the endocannabinoid system mediates SSIA in these lines. Numerous reports support the existence of pharmacological and molecular interactions between the opioid and cannabinoid systems along the pain pathways, as both systems utilize the same G-protein subtype for signal transduction. Mice from both lines were treated with a non-selective CB1/CB2 agonist, WIN55,212-2 and their behavior was evaluated according to the tetrad paradigm assessing antinociception, catalepsy, hypothermia and locomotor activity. Surprisingly, the engagement of CB1 receptors in SSIA was not confirmed. G-protein activation was studied in different brain regions and the spinal cord in the [35S]GTPγS assay. It was shown that WIN55,212-2 produced more potent antinociception in HA than in LA mice. Also, HA mice displayed stronger cannabinoid-induced catalepsy in the bar test. However, LA mice were more sensitive to the hypothermic effect of WIN55,212-2. The intensity of behavioral responses to WIN55,212-2 was correlated with increased G-protein activation in the periaqueductal gray matter, frontal cortex, striatum and thalamus in HA mice. A weak response to WIN55,212-2 in LA mice could depend on impaired CB2 receptor signaling. In conclusion, differences in both opioid and cannabinoid sensitivity between HA and LA mice could stem from alterations in intracellular second messenger mechanisms involving G-protein activation.


Assuntos
Encéfalo/fisiologia , Dor/genética , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/genética , Estresse Psicológico/genética , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Proteínas de Ligação ao GTP/agonistas , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Especificidade da Espécie , Estresse Psicológico/metabolismo
20.
Neurosci Lett ; 699: 140-144, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30716423

RESUMO

The participation of endocannabinoids in central and peripheral antinociception induced by several compounds has been shown by our group. In this study, we investigated the effect of endocannabinoids on the central antinociception induced by ketamine. The nociceptive threshold for thermal stimulation was measured using the tail-flick test in Swiss mice. The drugs were administered intracerebroventricularly. Probabilities less than 5% (p < 0.05) were considered to be statistically significant (Two-way ANOVA/Bonferroni's test). The CB1-selective cannabinoid receptor antagonist AM251 (2 and 4 µg) completely reversed the central antinociception induced by ketamine (4 µg) in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 (2 and 4 µg) did not antagonize this effect. Additionally, the administration of the anandamide amidase inhibitor MAFP (0.2 µg) and anandamide uptake inhibitor VDM11 (4 µg) significantly enhanced the antinociception induced by a low dose of ketamine (2 µg). It was concluded that central antinociception induced by ketamine involves the activation of CB1 cannabinoid receptors. Mobilization of cannabinoids might be required for the activation of those receptors, since inhibitors of the endogenous cannabinoids potentiate the effect of Ketamine.


Assuntos
Analgésicos/farmacologia , Canabinoides/metabolismo , Ketamina/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Ácidos Araquidônicos/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Indóis/farmacologia , Infusões Intraventriculares , Ketamina/administração & dosagem , Ketamina/antagonistas & inibidores , Masculino , Camundongos , Organofosfonatos/farmacologia , Medição da Dor/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores
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