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1.
Eur Rev Med Pharmacol Sci ; 24(24): 13062-13064, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33378059

RESUMO

Cytokine storm in COVID-19 is linked to disease severity and mortality. 40% of patients with severe COVID-19 require mechanical ventilation. Analgesia and sedation are used for treatment of pain, facilitation of mechanical ventilation, or management of acute agitation. Herein, we present the immunomodulating actions of morphine that may either improve or worsen the clinical course of COVID-19 once cytokine storm develops. A literature search was performed to find articles on potential immunomodulatory effects of morphine. Taken together, the results of in vitro and in vivo models in non-COVID-19 conditions suggest that morphine could have a beneficial effect by mitigating the cytokine storm in the early stages of severe COVID-19. In contrast, it could be potentially harmful in late stages of severe COVID-19, especially in the presence of septic shock.


Assuntos
Analgésicos Opioides/efeitos adversos , Síndrome da Liberação de Citocina/imunologia , Imunomodulação , Morfina/efeitos adversos , Analgésicos Opioides/uso terapêutico , Citocinas/imunologia , Humanos , Morfina/uso terapêutico , Respiração Artificial , Choque Séptico/imunologia
2.
Medicine (Baltimore) ; 99(36): e22070, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899074

RESUMO

BACKGROUND: A number of recent studies have investigated the optimal dosage and timing of dexamethasone in total hip arthroplasty (THA) but have inconsistent findings. Therefore, we designed the randomized controlled research to look for the optimal intravenous dexamethasone dose for the treatment of early postoperative pain after the THA. METHODS: The Declaration of Helsinki principles was followed and the Consolidated Standards of Reporting Trials guidelines for randomized controlled trials was adhered in this study. The First Medical Center in People's Liberation Army General Hospital approved the study (2020-089). After written informed consent was obtained, patients aged between 18 and 80 years with Physical Status I to III of American Society of Anesthesiologists, scheduled for primary unilateral THA, were included in this present work. Randomization is the use of a computer-formed list via a secretary, at a ratio of 1:1:1. The major end points were pain scores at 24 hours, 48 hours, and 72 hours after surgery, with visual analog scale (VAS) utilized at rest, and at 45 degrees passive hip flexion. The secondary outcomes involved the total consumption of morphine, opioid-related side effects, hip range of motion, inflammation markers, and the length of hospital stay. RESULTS: We assumed that the patients who received 3 doses of dexamethasone intravenously possessed the best postoperative results compared to those who received 1 or 2 doses of the dexamethasone. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry5864).


Assuntos
Anti-Inflamatórios/administração & dosagem , Artroplastia de Quadril/efeitos adversos , Dexametasona/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Estudos de Casos e Controles , Dexametasona/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Tempo de Internação , Pessoa de Meia-Idade , Morfina/efeitos adversos , Entorpecentes/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Amplitude de Movimento Articular , Escala Visual Analógica , Adulto Jovem
3.
Br J Anaesth ; 125(5): 811-817, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32900508

RESUMO

BACKGROUND: Intrathecal morphine prolongs analgesia after surgery, but has been implicated in postoperative respiratory depression or apnoeic episodes. However, this has not been investigated in a prospective trial using respiratory polygraphy. This randomised controlled triple-blinded trial tested the hypothesis that intrathecal morphine increases sleep apnoea severity, measured using respiratory polygraphy. METHODS: Sixty subjects undergoing hip arthroplasty under spinal anaesthesia received either 15 mg isobaric bupivacaine 0.5% with 0.5 ml normal saline 0.9% (control group) or 15 mg isobaric bupivacaine 0.5% with 0.5 ml intrathecal morphine 100 µg (intrathecal morphine group). Respiratory polygraphy was performed before surgery and on the first and third postoperative nights. The primary outcome was the apnoea-hypopnoea index in the supine position (supine AHI) on the first postoperative night. Secondary outcomes included supine AHI on the third postoperative night, oxygen desaturation index (ODI), and ventilatory frequency during the first and third postoperative nights. RESULTS: On the first postoperative night, mean (95% confidence interval) values for supine AHI were 20.6 (13.9-27.3) and 21.2 (12.4-30.0) events h-1 in the control and intrathecal morphine groups, respectively (P=0.90). There were no significant between-group differences for any of the secondary outcomes, except for a significantly higher central and mixed apnoea index preoperatively and significantly lower mean SpO2 on the third postoperative night in the control group. CONCLUSIONS: Intrathecal morphine did not increase sleep apnoea severity when measured using respiratory polygraphy. Of note, all patients had an increased number of apnoeic episodes on the third postoperative night. CLINICAL TRIAL REGISTRATION: NCT02566226.


Assuntos
Analgésicos Opioides/efeitos adversos , Artroplastia de Quadril/métodos , Morfina/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Síndromes da Apneia do Sono/induzido quimicamente , Síndromes da Apneia do Sono/epidemiologia , Idoso , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Raquianestesia/métodos , Anestésicos Locais , Bupivacaína , Método Duplo-Cego , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Morfina/uso terapêutico , Oxigênio/sangue , Polissonografia , Decúbito Dorsal , Resultado do Tratamento
4.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913133

RESUMO

BACKGROUND: Despite the standardization of care, formula feeding varied across sites of the Ohio Perinatal Quality Collaborative (OPQC). We used orchestrated testing (OT) to learn from this variation and improve nonpharmacologic care of infants with neonatal abstinence syndrome (NAS) requiring pharmacologic treatment in Ohio. METHODS: To test the impact of formula on length of stay (LOS), treatment failure, and weight loss among infants hospitalized with NAS, we compared caloric content (high versus standard) and lactose content (low versus standard) using a 22 factorial design. During October 2015 to June 2016, OPQC sites joined 1 of 4 OT groups. We used response plots to examine the effect of each factor and control charts to track formula use and LOS. We used the OT results to revise the nonpharmacologic bundle and implemented it during 2017. RESULTS: Forty-seven sites caring for 546 NAS infants self-selected into the 4 OT groups. Response plots revealed the benefit of high-calorie formula (HCF) on weight loss, treatment failure, and LOS. The nonpharmacologic treatment bundle was updated to recommend HCF when breastfeeding was not possible. During implementation, HCF use increased, and LOS decreased from 17.1 to 16.4 days across the OPQC. CONCLUSIONS: OT revealed that HCF was associated with shorter LOS in OPQC sites. Implementation of a revised nonpharmacologic care bundle was followed by additional LOS improvement in Ohio. Despite some challenges in the implementation of OT, our findings support its usefulness for learning in improvement networks.


Assuntos
Ingestão de Energia , Fórmulas Infantis , Tempo de Internação/estatística & dados numéricos , Síndrome de Abstinência Neonatal/terapia , Feminino , Humanos , Recém-Nascido , Lactose/administração & dosagem , Metadona/administração & dosagem , Metadona/efeitos adversos , Morfina/administração & dosagem , Morfina/efeitos adversos , Ohio , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Melhoria de Qualidade/organização & administração , Ganho de Peso
5.
Anesthesiology ; 133(3): 559-568, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788558

RESUMO

BACKGROUND: To improve understanding of the respiratory behavior of oliceridine, a µ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the ß-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. METHODS: Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) - P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. RESULTS: The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. CONCLUSIONS: These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Insuficiência Respiratória/induzido quimicamente , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Adulto , Analgésicos Opioides/efeitos adversos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Valores de Referência , Medição de Risco , Compostos de Espiro/efeitos adversos , Tiofenos/efeitos adversos , Adulto Jovem
7.
Proc Natl Acad Sci U S A ; 117(32): 19556-19565, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694207

RESUMO

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.


Assuntos
Encéfalo/fisiopatologia , Dependência de Morfina/fisiopatologia , Rede Nervosa/fisiopatologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Conectoma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Morfina/administração & dosagem , Morfina/efeitos adversos , Dependência de Morfina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
8.
Life Sci ; 257: 118048, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622946

RESUMO

AIMS: Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORAs) indicated for the treatment of opioid-induced constipation (OIC). We investigated the preventive effect of naldemedine on morphine-induced nausea and vomiting in ferrets and conducted a pharmacokinetic/pharmacodynamic (PK/PD) analysis. MAIN METHODS: The antiemetic effect of naldemedine was evaluated as the frequency and time of retching (rhythmic abdominal contractile motion) and vomiting (throwing up vomit or similar reactions) caused by morphine in ferrets. After a single oral administration of naldemedine to ferrets, the plasma concentrations of naldemedine and morphine were measured by liquid chromatography-tandem mass spectrometry. KEY FINDINGS: Naldemedine showed a potent and dose-dependent anti-emetic effects against morphine-induced emetic responses, for up to 6 h. The dose of naldemedine that produced half the maximal effect (ED50) value for anti-emetic effect of naldemedine in the morphine-treated ferrets was 0.033 mg/kg. The PK/PD analysis revealed that the antiemetic effect was related to the plasma naldemedine concentration, with a half maximal effective concentration that produces half the maximal effect (EC50) of 3.51 ng/mL. The plasma concentration producing an antiemetic effect was almost 200-fold lower than that inducing an anti-analgesic effect in rats. SIGNIFICANCE: Naldemedine showed potent inhibition of morphine-induced vomiting for up to 6 h after dosing. These data suggest that naldemedine possesses antiemetic properties and could be effective against opioid-induced nausea and vomiting (OINV).


Assuntos
Naltrexona/análogos & derivados , Náusea/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Animais , Constipação Intestinal/induzido quimicamente , Furões , Masculino , Morfina/efeitos adversos , Naltrexona/metabolismo , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Vômito/induzido quimicamente
9.
Clin Drug Investig ; 40(8): 755-764, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583295

RESUMO

BACKGROUND AND OBJECTIVE: Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective µ-agonist with limited activity on ß-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. METHODS: Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. RESULTS: Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Compostos de Espiro/efeitos adversos , Tiofenos/efeitos adversos , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Manejo da Dor , Medição da Dor , Insuficiência Respiratória/tratamento farmacológico , Compostos de Espiro/administração & dosagem , Tiofenos/administração & dosagem
10.
J Pharmacol Exp Ther ; 374(2): 331-341, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32434943

RESUMO

Treating chronic pain by using opioids, such as morphine, is hampered by the development of opioid-induced hyperalgesia (OIH; increased pain sensitivity), antinociceptive tolerance, and withdrawal, which can contribute to dependence and abuse. In the central nervous system, the purine nucleoside adenosine has been implicated in beneficial and detrimental actions of morphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphine-induced OIH and antinociceptive tolerance in rats is associated with a twofold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord. Blocking ADK activity in the spinal cord provided greater than 90% attenuation of OIH and antinociceptive tolerance through A3 adenosine receptor (A3AR) signaling. Supplementing adenosine signaling with selective A3AR agonists blocked OIH and antinociceptive tolerance in rodents of both sexes. Engagement of A3AR in the spinal cord with an ADK inhibitor or A3AR agonist was associated with reduced dorsal horn of the spinal cord expression of the NOD-like receptor pyrin domain-containing 3 (60%-75%), cleaved caspase 1 (40%-60%), interleukin (IL)-1ß (76%-80%), and tumor necrosis factor (50%-60%). In contrast, the neuroinhibitory and anti-inflammatory cytokine IL-10 increased twofold. In mice, A3AR agonists prevented the development of tolerance in a model of neuropathic pain and reduced naloxone-dependent withdrawal behaviors by greater than 50%. These findings suggest A3AR-dependent adenosine signaling is compromised during sustained morphine to allow the development of morphine-induced adverse effects. These findings raise the intriguing possibility that A3AR agonists may be useful adjunct to opioids to manage their unwanted effects. SIGNIFICANCE STATEMENT: The development of hyperalgesia and antinociceptive tolerance during prolonged opioid use are noteworthy opioid-induced adverse effects that reduce opioid efficacy for treating chronic pain and increase the risk of dependence and abuse. We report that in rodents, these adverse effects are due to reduced adenosine signaling at the A3AR, resulting in NOD-like receptor pyrin domain-containing 3-interleukin-1ß neuroinflammation in spinal cord. These effects are attenuated by A3AR agonists, suggesting that A3AR may be a target for therapeutic intervention with selective A3AR agonist as opioid adjuncts.


Assuntos
Analgésicos/efeitos adversos , Tolerância a Medicamentos , Hiperalgesia/induzido quimicamente , Morfina/efeitos adversos , Receptor A3 de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/etiologia , Adenosina/metabolismo , Animais , Feminino , Hiperalgesia/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/biossíntese , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
11.
PLoS One ; 15(4): e0231721, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294144

RESUMO

Opioid addiction is recognized as a chronic relapsing brain disease resulting from repeated exposure to opioid drugs. Cellular and molecular mechanisms underlying the ability of organism to return back to the physiological norm after cessation of drug supply are not fully understood. The aim of this work was to extend our previous studies of morphine-induced alteration of rat forebrain cortex protein composition to the hippocampus. Rats were exposed to morphine for 10 days and sacrificed 24 h (groups +M10 and -M10) or 20 days after the last dose of morphine (groups +M10/-M20 and -M10/-M20). The six altered proteins (≥2-fold) were identified in group (+M10) when compared with group (-M10) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). The number of differentially expressed proteins was increased to thirteen after 20 days of the drug withdrawal. Noticeably, the altered level of α-synuclein, ß-synuclein, α-enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also determined in both (±M10) and (±M10/-M20) samples of hippocampus. Immunoblot analysis of 2D gels by specific antibodies oriented against α/ß-synucleins and GAPDH confirmed the data obtained by 2D-DIGE analysis. Label-free quantification identified nineteen differentially expressed proteins in group (+M10) when compared with group (-M10). After 20 days of morphine withdrawal (±M10/-M20), the number of altered proteins was increased to twenty. We conclude that the morphine-induced alteration of protein composition in rat hippocampus after cessation of drug supply proceeds in a different manner when compared with the forebrain cortex. In forebrain cortex, the total number of altered proteins was decreased after 20 days without morphine, whilst in hippocampus, it was increased.


Assuntos
Analgésicos Opioides/efeitos adversos , Hipocampo/efeitos dos fármacos , Morfina/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/patologia , Síndrome de Abstinência a Substâncias/patologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Humanos , Masculino , Proteômica , Ratos , Ratos Wistar , Fatores de Tempo
12.
Aust J Gen Pract ; 49(3): 116-120, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32113200

RESUMO

BACKGROUND: High-dose opioid prescribing is associated with an increased risk of harms, including death. OBJECTIVE: The aim of this article is to discuss the concept of high-risk opioid prescribing, as well as relevant management strategies for patients on >100 mg oral morphine equivalent daily dose (OMEDD). The six 'Rs' approach to managing high-risk opioid prescribing (Rotation of opioids; Reduction; Replacement pharmacotherapy; Reversal with naloxone; Referral; Restriction of supply) is discussed. DISCUSSION: The six Rs is an aide-memoire that summarises the management options available to mitigate the risk of high OMEDDs. However, an effective therapeutic alliance between clinician and patient remains the foundation of all risk mitigation strategies.


Assuntos
Analgésicos Opioides/uso terapêutico , Morfina/uso terapêutico , Padrões de Prática Médica/normas , Analgésicos Opioides/efeitos adversos , Humanos , Morfina/efeitos adversos , Padrões de Prática Médica/estatística & dados numéricos
13.
Sci China Life Sci ; 63(9): 1-9, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32180109

RESUMO

Ultrasound stimulation is an emerging noninvasive option in treating neuropsychiatric disorders. The present study investigates the behavioral alterations resulting from ultrasound stimulation on the nucleus accumbens (NAc) in freely moving mice. Our results show that an acute ultrasound stimulation on the NAc, rather than the visual cortex or auditory cortex, led to a pronounced avoidance behavior, while repeated NAc ultrasound stimulation resulted in an obvious conditioned place aversion with changes in synaptic protein (GluA1/2 subunit) expression. Notably, NAc ultrasound stimulation suppressed the morphine-induced conditioned place preference. The results provide evidence that NAc ultrasound stimulation can be applied as a potential noninvasive therapeutic option in treating psychiatric disorders.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Dependência de Morfina/metabolismo , Morfina/efeitos adversos , Núcleo Accumbens/efeitos dos fármacos , Ondas Ultrassônicas/efeitos adversos , Animais , Condicionamento Psicológico/efeitos dos fármacos , Estimulação Encefálica Profunda , Cinética , Masculino , Camundongos Endogâmicos C57BL , Morfina/administração & dosagem
14.
PLoS One ; 15(3): e0230563, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210470

RESUMO

Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/ß-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit ß-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to ß-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of ß-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of ß-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect ß-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.


Assuntos
Analgésicos Opioides/efeitos adversos , Infecções por HIV/complicações , HIV-1/efeitos dos fármacos , Morfina/efeitos adversos , Transtornos Neurocognitivos/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologia , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/virologia , Linhagem Celular , Células Cultivadas , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Transtornos Neurocognitivos/imunologia , Transtornos Neurocognitivos/virologia , Transtornos Relacionados ao Uso de Substâncias/imunologia , beta Catenina/imunologia
15.
Am J Emerg Med ; 38(5): 1046.e5-1046.e7, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31952869

RESUMO

BACKGROUND: Local anesthetic systemic toxicity characteristically occurs after inadvertent intravascular injection of local anesthetics; however, it is unclear if similar symptoms arise after intrathecal adminstration. Intrathecal use of local anesthetics for chronic pain is increasing and carries a potential risk of toxicity. Experience with the presenting symptoms and appropriate treatment for intrathecal local anesthetic toxicity is limited. CASE STUDY: A 74-year-old woman with an intrathecal bupivacaine/morphine pump developed lower extremity sensory neuropathy followed by obtundation, hypotension, and lower extremity flaccidity after an intrathecal pump refill. Her condition evolved to status epilepticus (SE) refractory to standard treatment. Intravenous fat emulsion (IFE) was administered, but was not immediately effective thus necessitating phenobarbital loading and propofol infusion. Despite significant bupivacaine neurotoxicity, no cardiotoxicity developed. DISCUSSION: The patient developed intrathecal local anesthetic and opioid toxicity after a malfunction of her intrathecal pump during a refill. We hypothesize that no cardiotoxicity developed secondary to sequestration of bupivacaine within the central nervous system. Likewise, poor CNS penetration of intravenous lipid emulsion may have negated or delayed any antidotal effect. CONCLUSION: We present a case of intrathecal toxicity leading to prolonged spinal anesthesia, progressive encephalopathy, and SE refractory to intravenous lipid emulsion. Management of SE with benzodiazepines and barbiturates may be more effective than lipids in cases of toxicity from intrathecal administration of bupivacaine.


Assuntos
Bupivacaína/efeitos adversos , Hipotensão/induzido quimicamente , Morfina/efeitos adversos , Estado Epiléptico/induzido quimicamente , Idoso , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Raquianestesia/efeitos adversos , Anestésicos Locais/administração & dosagem , Anestésicos Locais/efeitos adversos , Barbitúricos/uso terapêutico , Benzodiazepinas/uso terapêutico , Bupivacaína/administração & dosagem , Emulsões Gordurosas Intravenosas , Feminino , Humanos , Hipotensão/tratamento farmacológico , Injeções Espinhais , Morfina/administração & dosagem , Estado Epiléptico/tratamento farmacológico
16.
Eur J Pharmacol ; 871: 172918, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31958457

RESUMO

Mu opioid receptor (MOPr) agonists are thought to produce analgesia via modulation of G-protein-coupled intracellular signalling pathways whereas the ß-arrestin2 pathway is proposed to mediate opioid-related adverse effects. Here, we report the antinociception, constipation and respiratory depressant profile of CYX-6, a potent MOPr agonist that is also a delta and a kappa opioid receptor (DOPr/KOPr) antagonist and that lacks ß-arrestin2 recruitment at each of the MOPr, DOPr and the KOPr. In anaesthetised male Sprague Dawley rats, an intracerebroventricular (i.c.v.) guide cannula was stereotaxically implanted. After 5-7 days post-surgical recovery, rats received a single i.c.v. bolus dose of CYX-6 (3-30 nmol), morphine (100 nmol) or vehicle. Antinociception was assessed using the warm water tail flick test (52.5 ± 0.5 °C). Constipation was assessed using the charcoal meal gut motility test and the castor oil-induced diarrhoea test. Respiratory depression was measured by whole-body plethysmography in awake, freely moving animals, upon exposure to a hypercapnic gas mixture (8% CO2, 21% O2 and 71% N2). The intrinsic pharmacology of CYX-6 given by the i.c.v. route in rats showed that it produced dose-dependent antinociception. It also produced respiratory stimulation rather than depression and it had a minimal effect on intestinal motility in contrast to the positive control, morphine. CYX-6 is an endomorphin-2 analogue that dissociates antinociception from constipation and respiratory depression in rats. Our findings provide useful insight to inform the discovery and development of novel opioid analgesics with a superior tolerability profile compared with morphine.


Assuntos
Analgésicos Opioides/farmacologia , Constipação Intestinal/induzido quimicamente , Morfina/farmacologia , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/agonistas , Insuficiência Respiratória/induzido quimicamente , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/metabolismo , Animais , Infusões Intraventriculares , Ligantes , Masculino , Morfina/efeitos adversos , Peptídeos Opioides/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo
17.
J Am Coll Cardiol ; 75(3): 289-300, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31976867

RESUMO

BACKGROUND: Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial. OBJECTIVES: This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls. METHODS: Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days. RESULTS: In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; pinteraction = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; pinteraction = 0.46). CONCLUSIONS: When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895).


Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Analgésicos Opioides/administração & dosagem , Angiografia Coronária/métodos , Morfina/administração & dosagem , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico por imagem , Síndrome Coronariana Aguda/tratamento farmacológico , Idoso , Analgésicos Opioides/efeitos adversos , Clopidogrel/administração & dosagem , Angiografia Coronária/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Infarto do Miocárdio sem Supradesnível do Segmento ST/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Resultado do Tratamento
18.
Anesthesiology ; 132(4): 702-712, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31977522

RESUMO

BACKGROUND: Intrathecal morphine is commonly and effectively used for analgesia after joint arthroplasty, but has been associated with delayed respiratory depression. Patients with obstructive sleep apnea may be at higher risk of postoperative pulmonary complications. However, data is limited regarding the safety of intrathecal morphine in this population undergoing arthroplasty. METHODS: This retrospective cohort study aimed to determine the safety of intrathecal morphine in 1,326 patients with documented or suspected obstructive sleep apnea undergoing hip or knee arthroplasty. Chart review was performed to determine clinical characteristics, perioperative events, and postoperative outcomes. All patients received neuraxial anesthesia with low-dose (100 µg) intrathecal morphine (exposure) or without opioids (control). The primary outcome was any postoperative pulmonary complication including: (1) respiratory depression requiring naloxone; (2) pneumonia; (3) acute respiratory event requiring consultation with the critical care response team; (4) respiratory failure requiring intubation/mechanical ventilation; (5) unplanned admission to the intensive care unit for respiratory support; and (6) death from a respiratory cause. The authors hypothesized that intrathecal morphine would be associated with increased postoperative complications. RESULTS: In 1,326 patients, 1,042 (78.6%) received intrathecal morphine. The mean age of patients was 65 ± 9 yr and body mass index was 34.7 ± 7.0 kg/m. Of 1,326 patients, 622 (46.9%) had suspected obstructive sleep apnea (Snoring, Tired, Observed, Pressure, Body Mass Index, Age, Neck size, Gender [STOP-Bang] score greater than 3), while 704 of 1,326 (53.1%) had documented polysomnographic diagnosis. Postoperatively, 20 of 1,322 (1.5%) patients experienced pulmonary complications, including 14 of 1,039 (1.3%) in the exposed and 6 of 283 (2.1%) in the control group (P = 0.345). Overall, there were 6 of 1 322 (0.5%) cases of respiratory depression, 18 of 1,322 (1.4%) respiratory events requiring critical care team consultation, and 4 of 1,322 (0.3%) unplanned intensive care unit admissions; these rates were similar between both groups. After adjustment for confounding, intrathecal morphine was not significantly associated with postoperative pulmonary complication (adjusted odds ratio, 0.60 [95% CI, 0.24 to 1.67]; P = 0.308). CONCLUSIONS: Low-dose intrathecal morphine, in conjunction with multimodal analgesia, was not reliably associated with postoperative pulmonary complications in patients with obstructive sleep apnea undergoing joint arthroplasty.


Assuntos
Analgésicos Opioides/administração & dosagem , Artroplastia de Quadril/tendências , Artroplastia do Joelho/tendências , Morfina/administração & dosagem , Complicações Pós-Operatórias/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Idoso , Analgésicos Opioides/efeitos adversos , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/prevenção & controle , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/etiologia , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/etiologia , Estudos Retrospectivos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/cirurgia
19.
BMC Vet Res ; 16(1): 19, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959188

RESUMO

BACKGROUND: Epidural administration of morphine has been shown to be an effective analgesic strategy in horses; however, the possible occurrence of side effects limits its usage. In order to decrease their frequency, it is important to target the minimal effective plasma concentration and avoid overdosing. As to date species-specific pharmacokinetics data are not available for epidural morphine, the dosing regimen is usually established on the basis of clinical reports and personal experience. In certain physiological conditions, like gestation, the outcome of an empirical dosing scheme can be unpredictable. The aim of this case report is to describe the pharmacological profile of morphine and its metabolites after prolonged epidural administration in a pregnant mare and her foal. CASE PRESENTATION: A 20 years old pregnant mare was presented to our hospital because of severe lameness, 2 months before delivery. Following an ineffective systemic pain treatment, an epidural catheter was inserted and morphine administered (initial dose 0.1 mg/kg every 8 h). Due to its efficacy in controlling pain, it was continued until end of gestation. Plasmatic concentration of morphine and its metabolites were assessed in the mare 6 weeks after starting the treatment, and in both the mare and foal during the first days after delivery. Plasmatic values similar to those previously reported in the literature following morphine short term administration through various routes and not accompanied by side effects were found in the mare, except during an excitatory period. Moreover, no evidence of dangerous drug accumulation or significant milk passage was noticed in the foal. Mild reduction of feces production with no signs of colic and two self-limiting episodes of excitement occurred during treatment in the mare. No side effects occurred during gestation and first phases of life in the foal. CONCLUSION: Prolonged epidural administration of morphine in a pregnant mare allowed good pain control in absence of clinically relevant side effects, in both the mare and her foal. Sudden increase in morphine plasmatic concentration can occur and side effects appear; careful treatment to the lowest effective dose and continuous monitoring of the clinical condition of the treated horse should be performed.


Assuntos
Analgésicos Opioides/uso terapêutico , Cavalos , Morfina/uso terapêutico , Analgésicos Opioides/administração & dosagem , Animais , Animais Recém-Nascidos/sangue , Feminino , Injeções Epidurais/veterinária , Coxeadura Animal/tratamento farmacológico , Morfina/administração & dosagem , Morfina/efeitos adversos , Morfina/sangue , Derivados da Morfina/sangue , Dor/prevenção & controle , Dor/veterinária , Gravidez , Tendinopatia/veterinária
20.
Am J Surg ; 219(6): 969-975, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31280840

RESUMO

Understanding variation in perioperative opioid exposure and its effect on patients' outcomes is critical for pain management. This study characterized perioperative exposure to morphine and its association with postoperative pain and 30-day readmissions. We utilized nationwide Veterans Healthcare Administration (VHA) data on four high-volume surgical procedures, 2007-2014. We identified 235,239 Veterans undergoing orthopedic, general, or vascular surgery; 5.4% high trajectories (116.1 OME/Day), 53.2% medium trajectories (39.7 OME/Day), and 41.4% low trajectories (19.1 OME/Day). Modeled estimates suggest that patients in the high OME group had higher risk of a pain-related readmission (OR: 1.59; CI: 1.39, 1.83) compared to the low OME trajectory. Yet when stratified by pain trajectory, patients with high pain and high OME had lower risk of a pain-related readmission compared to patients in the high pain low OME group (OR: 0.76, CI: 0.62, 0.94). In conclusion, patients receiving high perioperative OME are more likely to return to care for pain-related problems. This study highlights opportunities to reduce the amount of prescriptions opioids in the communities.


Assuntos
Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/complicações , Manejo da Dor , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/etiologia , Readmissão do Paciente/estatística & dados numéricos , Saúde dos Veteranos , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Estudos Retrospectivos , Estados Unidos , United States Department of Veterans Affairs
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