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1.
Medicine (Baltimore) ; 99(44): e22919, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126353

RESUMO

RATIONALE: Pain is the fifth vital sign of human beings. Morphine is the first choice for relieving moderate to severe cancer pain. Most of the previous studies merely focused on the analgesic effect of high-dose or ultra-high-dose morphine in patients with advanced cancers but did not report any cases related to successful morphine withdrawal. PATIENT CONCERNS: A 42-year-old woman was admitted to our hospital in March 2019. DIAGNOSIS: She was diagnosed with progressive aggravation of headache for 1 month, which was meningeal metastasis of lung cancer. INTERVENTIONS: Symptomatic treatments like dehydration, hormone, intrathecal injection chemotherapy and an increased dose of osimertinib to 160 mg/day were applied but showed poor curative effects. The patient refused whole-brain radiotherapy. Pain intensity level was re-evaluated and the patient scored 9 based on numerical rating scale, which suggested that the patient suffered from severer cancerous pain. Thus, the patient started to receive morphine for treating headache. OUTCOMES: The patient's headache was alleviated after receiving high-dose morphine treatment, and she continued to undergo anti-cancer treatment. After tumor remission, the patient's morphine dose gradually decreased and eventually stopped, without any withdrawal symptoms. In addition, the quality of life of the patient was greatly improved with performance status scored 2 and limb muscle strength increased from Grade 2 to Grade 5. LESSONS: For patients with advanced cancers, the application of ultra-high-dose morphine may significantly relieve cancerous pain, improve survival and quality of life, and overcome their fear for death and desperation, which contributes to the establishment of a basis for subsequent anticancer treatments. Thus, timely effective pain management and routine anticancer treatments are the key to addressing the cancer pain problem.


Assuntos
Adenocarcinoma de Pulmão , Dor do Câncer , Cefaleia , Neoplasias Pulmonares , Neoplasias Meníngeas , Manejo da Dor/métodos , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/terapia , Administração Intravenosa , Adulto , Analgésicos Opioides/administração & dosagem , Dor do Câncer/diagnóstico , Dor do Câncer/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Cefaleia/diagnóstico , Cefaleia/tratamento farmacológico , Cefaleia/etiologia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Meníngeas/fisiopatologia , Neoplasias Meníngeas/secundário , Neoplasias Meníngeas/terapia , Morfina/administração & dosagem , Medição da Dor , Resultado do Tratamento
2.
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
3.
PLoS One ; 15(9): e0239896, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986770

RESUMO

INTRODUCTION: Pain management is the pillar of caring for patients with traumatic rib fractures. Intravenous lidocaine (IVL) is a well-established non-opioid analgesic for post-operative pain, yet its efficacy has yet to be investigated in trauma patients. We hypothesized that IVL is associated with decreased inpatient opioid requirements among patients with rib fractures. METHODS: We retrospectively evaluated adult patients presenting to our Level 1 trauma center with isolated chest wall injuries. After 1:1 propensity score matching patients who received vs did not receive IVL, we compared the two groups' average daily opioid use, opioid use in the last 24 hours of admission, and pain scores during admissions hours 24-48. We performed multivariable linear regression for these outcomes (with sensitivity analysis for the opioid use outcomes), adjusting for age as a moderating factor and controlling for hospital length of stay and injury severity. RESULTS: We identified 534 patients, among whom 226 received IVL. Those who received IVL were older and had more serious injury. Compared to propensity-score matched patients who did not receive IVL, patients who received IVL had similar average daily opioid use and pain scores, but 40% lower opioid use during the last 24 hours of admission (p = 0.002). Multivariable regression-with and without sensitivity analysis-did not show an effect of IVL on any outcomes. CONCLUSION: IVL was crudely associated with decreased opioid requirements in the last 24 hours of admission, the time period associated with opioid use at 90 days post-discharge. However, we did not observe beneficial effects of IVL on multivariable adjusted analyses; we are conducting a randomized control trial to further evaluate IVL's opioid-sparing effects for patients with rib fractures.


Assuntos
Administração Intravenosa , Assistência ao Convalescente/métodos , Analgésicos não Entorpecentes/uso terapêutico , Lidocaína/uso terapêutico , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Fraturas das Costelas/cirurgia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Feminino , Humanos , Escala de Gravidade do Ferimento , Lidocaína/administração & dosagem , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Morfina/uso terapêutico , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento
4.
Medicine (Baltimore) ; 99(33): e21670, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872033

RESUMO

BACKGROUND: Total knee arthroplasty (TKA) is an established and successful surgical procedure which is the major treatment for degenerative knee joint diseases. A novel technique to address posterior knee joint pain is the infiltration of local anesthetic between the interspace between the popliteal artery and capsule of the knee (IPACK). The goal of this randomized clinical trial was to assess the efficacy and safety of adding IPACK to adductor canal block (ACB) after TKA. METHODS: This was a prospectively randomized trial that investigated the effectiveness and safety of the IPACK after TKA. Approval from Clinical Studies Ethical Committee in Qilu Hospital of Shandong University was obtained. The inclusion criteria were adult patients undergoing primary unilateral TKA and American Society of Anesthesiologists grade 1 or 2 with normal cognitive function. The patients were randomized to 1 of 2 treatment options: ACB-alone group and ACB + IPACK group. The primary outcome was the total morphine consumption during postoperative 24 hours. Secondary outcomes included postoperative pain score, time to first and total dosage of rescue morphine in postoperative 48 hours, early and late postoperative period (from postoperative day 0-3 months follow-up) performance-based test (Timed-Up and Go test, and quadriceps strength). Postoperative nausea and vomiting, length of hospital stay, patient satisfaction, and other adverse events were also evaluated. RESULTS: It was hypothesized that when combined with a control group, the IPACK block would result in a lower morphine consumption and pain score after TKA. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry5765).


Assuntos
Artroplastia do Joelho/métodos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/prevenção & controle , Analgésicos Opioides/administração & dosagem , Anestésicos Locais/administração & dosagem , Humanos , Morfina/administração & dosagem , Artéria Poplítea , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego
5.
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
6.
Medicine (Baltimore) ; 99(36): e21971, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899035

RESUMO

BACKGROUND: The purpose of this meta-analysis was to comprehensively collect randomized controlled trials (RCTs) to assess the clinical efficacy of intrathecal morphine (ITM) versus local infiltration analgesia (LIA) in the treatment of total knee and hip arthroplasty patients. METHODS: Relevant studies were identified from the Embase, PubMed, Cochrane Library, Web of Science, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases. We also reviewed the references of all identified articles to identify additional studies. For each study, we assessed the risk ratio (RR), weighted mean difference (WMD), and corresponding 95% confidence interval (95% CI) to synthesize outcomes. Meta-analysis was performed with Stata 12.0 software. RESULTS: We included 13 studies with 942 patients for meta-analysis. LIA significantly decreased the pain value with rest or mobilization until 72 hours (P < .05). LIA significantly decreased cumulative morphine consumption by 13.52 mg. Moreover, the length of hospital stay was lower in the LIA group than in the ITM analgesia group. Finally, LIA significantly reduced morphine-related complications (nausea and vomiting, pruritus, and respiration depression). CONCLUSIONS: LIA was an effective approach for relieving postoperative pain and reducing postoperative consumption of morphine compared with ITM in total knee and hip arthroplasty patients.


Assuntos
Analgesia/métodos , Analgésicos Opioides/administração & dosagem , Artroplastia de Quadril , Artroplastia do Joelho , Morfina/administração & dosagem , Anestesia Local , Humanos , Injeções Espinhais , Tempo de Internação , Dor Pós-Operatória/prevenção & controle
7.
Medicine (Baltimore) ; 99(37): e21956, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925729

RESUMO

BACKGROUND: Several studies reported short-term analgesic efficacy of obturator nerve block (ONB), as in comparison with the femoral nerve block (FNB) in the treatment of postoperative pain after the total knee replacement (TKR). The optimal method remains under debate. The purpose of our current work is to compare the safety and efficacy of FNB and ONB for postoperative analgesia after TKR. METHODS: This prospective, randomized, and controlled study was performed from January 2018 to December 2019. It was authorized via the Institutional Review Committee in NO.971 Hospital of the People's Liberation Army Navy (2019-PLAN-132).Two hundred patients were divided randomly into 2 groups, the control group (n = 100) and study group (n = 100). The experimental group received FNB and control groups received ONB. Primary outcome included pain at different time point (Visual Analogue Scale score of anterior knee pain at rest and in motion). The Visual Analogue Scale scores were marked by patients themselves on a paper with a graduated line starting at 0 (no pain) and ending at 10 (the most painful). Opioid consumption was converted to equivalents of oral morphine uniformly for statistical analysis. Secondary outcomes included the knee range of motion, the hospital stay length as well as the postoperative complications such as pulmonary embolism and deep vein thrombosis. RESULTS: Table 1 will show the clinical outcomes between the 2 groups. CONCLUSION: This trial would provide an evidence for the use of different types of peripheral nerve blocks in TKR.


Assuntos
Artroplastia do Joelho/efeitos adversos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/prevenção & controle , Administração Oral , Analgésicos Opioides/administração & dosagem , Nervo Femoral , Humanos , Pessoa de Meia-Idade , Morfina/administração & dosagem , Debilidade Muscular/etiologia , Bloqueio Nervoso/efeitos adversos , Nervo Obturador , Manejo da Dor/métodos , Medição da Dor , Complicações Pós-Operatórias , Estudos Prospectivos , Músculo Quadríceps
8.
Medicine (Baltimore) ; 99(39): e22394, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991462

RESUMO

OBJECTIVE: We perform this protocol for randomized controlled trial to compare the efficacy of intrathecal morphine and local infiltration anesthesia (LIA) in the treatment of the postoperative pain after total knee replacement (TKR). METHODS: This is a randomized controlled, single center trial which was performed from March 2019 to March 2020. This trial is conducted according to the SPIRIT Checklist of randomized researches. It is authorized via the Ethics Committee of Beijing Friendship Hospital (2019-P2-050-01). Eighty participants who undergo TKR were randomized into 2 groups. Intrathecal morphine group: 0.1 mg of the morphine was intrathecally injected, and the spinal anesthetic was injected at the same time in the group LIA; In the LIA group: the knee joint was infiltrated with epinephrine, ketorologic acid and ropivacaine in the process of operation, and the identical mixture was injected 2 bolus through the intraarticular catheter after operation. The main outcome variables were the visual analog scale and the consumption amount of opioid every 6-hour interval within 2 days postoperatively. The secondary outcome variables were the side effects associated with opioid, the length of hospital stay, motion range, and the loss of blood collected by the closed suction drainage. All the required analyses were carried out via applying the SPSS for Windows Version 19.0. RESULTS: The clinical outcome variables between groups were shown in . CONCLUSION: This protocol will provide the evidence on which technique can achieve better analgesia after TKR.


Assuntos
Analgésicos Opioides/administração & dosagem , Anestesia Local , Artroplastia do Joelho/efeitos adversos , Morfina/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Humanos , Injeções Espinhais , Dor Pós-Operatória/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
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
11.
J Pharmacol Sci ; 144(1): 9-15, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32586692

RESUMO

Since 2015 slow-release oral morphine (SROM) is approved for opioid substitution treatment (OST) in Germany. The SROMOS study (efficacy and tolerability of slow-release oral morphine in opioid substitution treatment) evaluates the efficacy and safety of SROM in routine care. This article describes the switching process from racemic methadone, levomethadone and buprenorphine to SROM. Between July 2016 and November 2017 180 patients in 23 study centers in Germany were included in the prospective, non-interventional, naturalistic observational study. Patients were already in OST and switched from a previous medication to SROM. The switching process was analyzed during a period of fourteen days. Data were available for 169 participants. The switching process had a different progression depending on premedication and pre dosage. On the fourteenth day of SROM treatment patients switched from racemic methadone took an average dosage of 922.2 mg/day, from levomethadone 801.0 mg/day and from buprenorphine 626.7 mg/day. Average conversion ratio racemic methadone to SROM was 1:11.8, levomethadone to SROM 1:17.4 and buprenorphine to SROM 1:58.0. This study provides the first data on the switching process from buprenorphine to SROM. Average dose ratio racemic methadone to SROM on the fourteenth day of treatment was considerably higher than recommended in the prescribing information.


Assuntos
Buprenorfina/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Substituição de Medicamentos/métodos , Metadona/administração & dosagem , Morfina/administração & dosagem , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Administração Oral , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
12.
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
14.
Rev Med Suisse ; 16(694): 1022-1025, 2020 May 20.
Artigo em Francês | MEDLINE | ID: mdl-32432418

RESUMO

New technologic devices are presented: insulin pumps and continuous glucose monitoring (CGM) devices as well as morphine pumps to help general practitioners to deal different intensive situations. Insulin pumps and CGM devices are revolutionary for the management of diabetes. However, their use requires strong patient involvement, the opposite of automated diabetes management. Morphine pumps are a great help when patients in end-of-life stage cannot swallow oral morphine anymore. This article summarizes the main principles of use of these technological devices, common problems and situations at risk primary care practice.


Assuntos
Automonitorização da Glicemia/métodos , Glicemia/análise , Medicina de Família e Comunidade/métodos , Morfina/administração & dosagem , Glicemia/metabolismo , Automonitorização da Glicemia/instrumentação , Diabetes Mellitus/metabolismo , Diabetes Mellitus/terapia , Humanos , Morfina/uso terapêutico
16.
Mol Pharmacol ; 98(4): 497-507, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32362586

RESUMO

Based on studies using mutations of the µ-opioid receptor (MOR), phosphorylation of multiple sites on the C-terminus has been recognized as a critical step underlying acute desensitization and the development of cellular tolerance. The aim of this study is to explore which kinases mediate desensitization of MOR in brain slices from drug-naïve and morphine-treated animals. Whole-cell recordings from locus coeruleus neurons were made, and the agonist-induced increase in potassium conductance was measured. In slices from naïve animals, pharmacological inhibition of G-protein receptor kinase (GRK2/3) with compound 101 blocked acute desensitization. Following chronic treatment with morphine, compound 101 was less effective at blocking acute desensitization. Compound 101 blocked receptor internalization in tissue from both naïve and morphine-treated animals, suggesting that GRK2/3 remained active. Kinase inhibitors aimed at blocking protein kinase C and c-Jun N-terminal kinase had no effect on desensitization in tissue taken from naïve animals. However, in slices taken from morphine-treated animals, the combination of these blockers along with compound 101 was required to block acute desensitization. Acute desensitization of the potassium conductance induced by the somatostatin receptor was also blocked by compound 101 in slices from naïve but not morphine-treated animals. As was observed with MOR, it was necessary to use the combination of kinase inhibitors to block desensitization of the somatostatin receptor in slices from morphine-treated animals. The results show that chronic treatment with morphine results in a surprising and heterologous adaptation in kinase-dependent desensitization. SIGNIFICANCE STATEMENT: The results show that chronic treatment with morphine induced heterologous adaptations in kinase regulation of G protein coupled receptor (GPCR) desensitization. Although the canonical mechanism for acute desensitization through phosphorylation by G protein-coupled receptor kinase is supported in tissue taken from naïve animals, following chronic treatment with morphine, the acute kinase-dependent desensitization of GPCRs is disrupted such that additional kinases, including protein kinase C and c-Jun N-terminal kinase, contribute to desensitization.


Assuntos
Locus Cerúleo/metabolismo , Morfina/administração & dosagem , Receptores Opioides mu/metabolismo , Quinases de Receptores Adrenérgicos beta/metabolismo , Animais , Tolerância a Medicamentos , Feminino , Locus Cerúleo/efeitos dos fármacos , Masculino , Morfina/farmacologia , Técnicas de Patch-Clamp , Fosforilação , Potássio/metabolismo , Ratos
17.
Can J Surg ; 63(3): E250-E253, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32386476

RESUMO

Background: Postoperative opioid analgesia may cause respiratory depression. We assessed whether following total hip arthroplasty, placebo-adjusted reductions in morphine consumption at 48 hours with parecoxib (47.0%), propacetamol (35.1%) or parecoxib plus propacetamol (67.9%) translated into a reduction in hypoxemic events. Methods: This was a post hoc analysis of a randomized, placebo-controlled, noninferiority study. Patients were randomly assigned to receive intravenous parecoxib (40 mg twice daily), propacetamol (2 g 4 times daily), parecoxib plus propacetamol (40 mg twice daily + 2 g 4 times daily) or placebo. Dose, date and time of morphine administration via patient-controlled analgesia were monitored throughout the study. In patients not receiving supplemental oxygen, peripheral blood oxygenation was assessed continuously for 48 hours after surgery. Hypoxemia was defined as peripheral oxygen saturation less than 90%. The times and oximeter readings of hypoxemic events were recorded. Pearson correlation coefficient was used to assess for correlations between cumulative morphine consumption at 48 hours and mean number of hypoxemic events. Results: A significantly smaller proportion of patients who received the combined treatment with parecoxib and propacetamol had hypoxemia versus placebo (2.8% v. 13.2%, p < 0.05), and the mean number of hypoxemic events was significantly smaller for parecoxib (0.12), propacetamol (0.06) and parecoxib plus propacetamol (0.03) versus placebo (0.36; all p < 0.05). There was no correlation between the reduction in cumulative morphine consumption at 48 hours and the mean number of hypoxemic events in any treatment group (all p > 0.1). Conclusion: Following total hip arthroplasty, a greater than 70% reduction in morphine consumption may be necessary to translate into a corresponding reduction in hypoxemic events.


Assuntos
Acetaminofen/análogos & derivados , Analgesia Controlada pelo Paciente/métodos , Artroplastia de Quadril/efeitos adversos , Hipóxia/epidemiologia , Isoxazóis/administração & dosagem , Morfina/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Acetaminofen/administração & dosagem , Adulto , Idoso , Analgésicos/administração & dosagem , Analgésicos Opioides/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Hipóxia/prevenção & controle , Incidência , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/diagnóstico , Suíça/epidemiologia , Resultado do Tratamento
18.
Scand J Trauma Resusc Emerg Med ; 28(1): 36, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398160

RESUMO

BACKGROUND: Studies have shown disparate results on the consequences of morphine use in ST-segment elevation myocardial infarction (STEMI). No study has evaluated alternative treatments that could be at least non-inferior to morphine without its potentially damaging consequences for myocardial function and platelet reactivity. The aim of this study was to evaluate whether nitrous oxide/oxygen plus intravenous acetaminophen (NOO-A) is non-inferior to morphine to control chest pain in STEMI patients. METHODS: This multicenter, open-label, cluster-randomized, controlled, non-inferiority study compared NOO-A with morphine in 684 prehospital patients with ongoing suspected STEMI of < 12 h duration and a pain rating score ≥ 4. The primary endpoint was the proportion of patients achieving pain relief (numeric rating score ≤ 3) after 30 min. Secondary safety endpoints included serious adverse events and death at 30 days. RESULTS: The median baseline pain score was 7.0 in both groups. The primary endpoint occurred in 51.7% of the NOO-A group and 73.6% of the morphine group (absolute risk difference - 21.7%; 95% confidence interval - 29.6 to - 13.8). At 30 days, the rate of serious adverse events was 16.0 and 18.8% in the NOO-A and morphine groups respectively (p = NS). The rate of death was 1.8% (NOO-A group) and 3.8% (morphine group) (p = NS). CONCLUSION: Analgesia provided by NOO-A was inferior to morphine at 30 min in patients with acute STEMI in the prehospital setting. Rates of serious adverse events did not differ between groups. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02198378.


Assuntos
Acetaminofen/administração & dosagem , Dor no Peito/terapia , Morfina/administração & dosagem , Óxido Nitroso/uso terapêutico , Oxigenoterapia/métodos , Oxigênio/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Administração por Inalação , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos Opioides/administração & dosagem , Dor no Peito/etiologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Resultado do Tratamento
19.
Am J Health Syst Pharm ; 77(Supplement_2): S41-S45, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32426835

RESUMO

PURPOSE: To address the intravenous (i.v.) opioid shortage, computer-based alerts and modifications were implemented over 2 phases beginning in August 2017 and February 2018, respectively. A study was conducted to assess the impact of these interventions on dispenses of intermittent doses of i.v. opioids during a national shortage. METHODS: A retrospective, single-center, pre- and postimplementation study was conducted to compare opioid dispenses from September 2017 through December 2017 (phase 1) and March 2018 through May 2018 (phase 2) with dispenses during the same time periods of the previous year (historical control periods). Dispense data for intermittent doses of i.v. fentanyl, hydromorphone, and morphine and select oral opioids were collected from automated dispensing cabinets (ADCs) located in nonprocedural areas. The primary endpoint was the percentage of total intermittent doses of i.v. and oral opioids that were dispensed for i.v. administration. A subanalysis accounting for unit type was conducted. Key secondary endpoints were the numbers of oral and i.v. opioid dispenses by month. RESULTS: The final analysis included data from 92 ADCs. The percentage of i.v. opioid dispenses significantly decreased, by 9.8% during phase 1 (P < 0.0001) and by 16.8% during phase 2 (P < 0.0001) compared to dispenses during the historical control periods. These decreases were significant across all unit types except pediatric units during phase 1. Average monthly dispenses of i.v. opioids were 49.9% and 74.2% fewer than dispenses during the historical control periods after the phase 1 and phase 2 implementations, respectively. CONCLUSION: Order entry alerts and modifications significantly decreased dispenses of intermittent doses of i.v. opioids during a national shortage, with demonstrated sustainability of decreases over 7 months.


Assuntos
Analgésicos Opioides/administração & dosagem , Sistemas de Registro de Ordens Médicas , Padrões de Prática Médica/estatística & dados numéricos , Administração Intravenosa , Administração Oral , Analgésicos Opioides/provisão & distribução , Relação Dose-Resposta a Droga , Fentanila/administração & dosagem , Humanos , Hidromorfona/administração & dosagem , Morfina/administração & dosagem , Estudos Retrospectivos
20.
Life Sci ; 252: 117676, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32304763

RESUMO

AIMS: Many µ-opioid receptor (MOR)-associated proteins can regulate the MOR signaling pathway. Using a bacterial two-hybrid screen, we found that the C-terminal of the MOR associated with heat shock protein 90 isoform ß (Hsp90ß). Here, we explored the effect of Hsp90ß on MOR signaling transduction and function. MAIN METHODS: The interaction of Hsp90ß with MOR was detected by co-immunoprecipitation and immunofluorescence. The effects of Hsp90ß on MOR signaling induced by opioids were studied in vitro and in vivo. The effects of the Hsp90ß inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) on morphine tolerance and dependence were studied via a hot plate test and CPP test. KEY FINDINGS: Hsp90ß, instead of Hsp90α, interacted with the MOR in HEK293 cells and SH-SY5Y cells, and the interaction was augmented after morphine pretreatment. The interaction of Hsp90ß and MOR increased the inhibition of cAMP and decreased PKA activity under opioid treatment. The functional Hsp90ß-MOR complex also promoted the phosphorylation and internalization of the MOR induced by DAMGO in MOR-CHO cells. 17-AAG blocked Hsp90ß-MOR interactions and decreased the effect of Hsp90ß on the MOR signal transduction. In C57BL/6 mice, 17-AAG decreased morphine-induced acute anti-nociception in the hot plate test, with an increase in phosphorylated PKA and phosphorylated JNK and a decrease in phosphorylated CREB and phosphorylated ERK in murine brains. Chronic morphine treatment induced tolerance, and dependence was inhibited by 17-AAG co-administration. SIGNIFICANCE: Hsp90ß is a positive co-regulator of the MOR via the activation of a G-protein-dependent and ß-arrestin-dependent pathway. Hsp90ß has the potential to improve the pharmacologic profile of existing opiates. It is conceivable that in future clinical treatments, the Hsp90ß inhibitor, 17-AAG, could decrease the tolerance and dependence in cancer patients induced by opioids.


Assuntos
Analgésicos Opioides/farmacologia , Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Lactamas Macrocíclicas/farmacologia , Morfina/farmacologia , Receptores Opioides mu/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Animais , Células CHO , Cricetinae , Cricetulus , Tolerância a Medicamentos , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/administração & dosagem , Nociceptividade/efeitos dos fármacos , Receptores Opioides mu/metabolismo
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