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1.
Rev Med Chil ; 149(6): 899-905, 2021 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-34751349

RESUMO

Cancer related pain is one of the most frequent and relevant symptoms in patients with malignant tumors, causing a huge impact in their quality of life. According to the Chilean Public Health System Technical Report of the Cancer Pain Control and Palliative Care Program 2013-2014, 90% of cancer patients admitted to the Program experienced pain, being moderate or intense in 34%. International and local standards recommend the use of strong opioids (morphine, methadone, or fentanyl) associated with adjuvants such as paracetamol as an initial strategy for pain management. This recommendation assumes that the use of combined analgesics could allow the use of lower opioid doses to obtain similar analgesic effect, decreasing the occurrence of opioid side effects. However, this technical report also describes that there is uncertainty about the impact of paracetamol as an adjuvant in patients with cancer pain who are already receiving strong opioids. This review aims to describe the current state of the art regarding the role of paracetamol as a coadjuvant in cancer pain patients.


Assuntos
Analgésicos Opioides , Neoplasias , Acetaminofen/uso terapêutico , Analgésicos Opioides/uso terapêutico , Humanos , Morfina , Neoplasias/complicações , Manejo da Dor , Qualidade de Vida
2.
Clin J Pain ; 37(12): 908-913, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34757343

RESUMO

OBJECTIVE: We aimed to evaluate the analgesic efficacy as well as the postoperative quality of recovery of preoperative oral duloxetine a serotonin and norepinephrine reuptake inhibitor for patients undergoing major abdominal cancer surgery. MATERIALS AND METHODS: Sixty-two patients, undergoing major abdominal cancer surgery were divided into 2 equal groups, received oral duloxetine 60 mg (2 h preoperative) or placebo. Postoperative 48 hours morphine consumption, visual analog scale pain score, and quality of recovery were measured. RESULTS: The cumulative 48 hours morphine consumption was significantly reduced in the duloxetine group compared with the placebo group (mean±SD) (5.2±3.2 vs. 12.9±3.4 mg), mean difference (95% confidence interval) 7.6 mg (5.9-9.3) P<0.001. The time to first morphine request was delayed significantly in the duloxetine group, median (interquartile range), 25 (19 to 38) versus 8 (4 to 9) hours, P<0.001. The duloxetine group had lower pain scores than the placebo group at 8, 12, 16, and 24 hours postoperatively, however, nonsignificant changes were observed at 0, 2, 4, 36, and 48 hours postoperatively. Participants in the duloxetine group had a better postoperative quality of recovery than the placebo group. The median (interquartile range) of the global quality of recovery-40 scoring system for the duloxetine group was 185 (180 to 191) compared with 170 (163 to 175) in the placebo group (P<0.001). DISCUSSION: A single preoperative dose of oral duloxetine, 60 mg for patients subjected to major abdominal cancer surgery reduced postoperative pain, decreased opioid consumption, and improved the quality of recovery.


Assuntos
Neoplasias , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego , Cloridrato de Duloxetina/uso terapêutico , Humanos , Morfina , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico
3.
Pol Merkur Lekarski ; 49(293): 379-381, 2021 Oct 22.
Artigo em Polonês | MEDLINE | ID: mdl-34800029

RESUMO

According to International Association for the Study of Pain (IASP) neuropathic pain is defined as a pain caused by a lesion or disease of the somatosensory nervous system. In general population 7-8% adults suffer from chronic pain with neuropathic characteristic. The most common causes include: lumbar radiculopathy, postherpetic neuropathy, HIV infection, autoimmune diseases (multiple sclerosis), metabolic diseases (diabetic neuropathy), stroke or spinal cord injury. Current pharmacotherapy of neuropathic pain has insufficient effectiveness, so comprehension of neuropathic pain mechanism is necessary for research of new therapeutic methods. In the study we verify the analgesic effect of maraviroc (antagonist of the chemokine receptor - CCR5) and its potential role in the treatment of neuropathic pain. In the study we focused on dependency between opioid and chemokine receptors, because of similar structure between this receptors occurs cross-desensitization phenomenon. Chemokine antagonist maraviroc belongs to a group of entry inhibitors, antiretroviral drug. It enhances analgesic properties of opioids by inhibition of crossdesensitization of opioid's receptor. Application of maraviroc with morphine can reduce effective dosage of morphine 2,3 fold. Moreover, research show that prophylactic administration of maraviroc without opioid analgesics suppresses development of neuropathic pain symptoms. It has influence on glial phenotype, decreases secretion of proinflammatory cytokines and increases anti-inflammatory cytokine secretion. Furthermore it decreases expression of chemikine receptor mRNA and chemikine ligand's secreted by microglia and astrocytes as a result of nerve injury. We conclude that maraviroc has immunomodulatory properties, potentiates opioid analgesics effect, and can be used in neuropathic pain therapy as a potential co-analgesic.


Assuntos
Infecções por HIV , Neuralgia , Analgésicos Opioides , Infecções por HIV/complicações , Humanos , Maraviroc , Morfina , Neuralgia/tratamento farmacológico , Neuralgia/etiologia
4.
J Zoo Wildl Med ; 52(3): 1018-1023, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34687519

RESUMO

This study is aimed at evaluating the efficacy of two protocols for the immobilization of mouflon (Ovis orientalis musimon). Six mouflon were immobilized twice using IM medetomidine 0.07 ± 0.01 mg/kg, ketamine 2.88 ± 0.48 mg/kg, and morphine 0.57 ± 0.09 mg/kg (MKM) or dexmedetomidine 0.04 ± 0.01 mg/kg, ketamine 3.01 ± 0.6 mg/kg, and morphine 0.60 ± 0.12 mg/kg (DKM). Anesthetic times were recorded from injection to initial drug effects, sternal recumbency, lateral recumbency, unresponsiveness to external stimuli, and recovery following atipamezole IM administration. Cardiopulmonary variables (HR in beats/min, RR in breaths/min, mean, systolic, and diastolic noninvasive blood pressure [MAP, SAP, DAP] in mm Hg, oxygen hemoglobin saturation [SpO2)], expired end tidal carbon dioxide [PECO2]), and rectal temperature in °C were monitored and recorded. No statistically significant differences were detected between protocols at any time point and no significant differences were detected in any measured variables at any time point between protocols. However, a significant decrease in the noninvasive blood pressure variables (SAP, MAP, and DAP) and in the RR were detected over time. Both chemical immobilization protocols provided at least 50 min of immobilization in mouflon, allowing minor procedures and tracheal intubation.


Assuntos
Dexmedetomidina , Ketamina , Anestésicos Dissociativos/farmacologia , Animais , Dexmedetomidina/farmacologia , Frequência Cardíaca , Hipnóticos e Sedativos/farmacologia , Imobilização/veterinária , Ketamina/farmacologia , Medetomidina/farmacologia , Morfina/farmacologia , Carneiro Doméstico
5.
J Coll Physicians Surg Pak ; 31(11): 1375-1377, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34689504

RESUMO

This study was conducted to investigate the influence of µ-opioid receptor gene (OPRM1) A118G polymorphism on dosage of morphine in advanced liver cancer patients. Seventy patients with advanced liver cancer at Changyi People's Hospital, Shandong Province, China, were included from February 2019 to December 2020. The dosage of morphine in patients with OPRM1 A118G different genotypes was compared. Thirty patients (42.86%) were of AA genotype, 35 (50.00%) were AG genotype and 5 (7.14%) were GG genotype. There was a significant difference in morphine dosage within the first 24 hours in patients with AA, AG and GG genotypes (all p <0.001), and morphine dosage in patients with GG genotype was the highest. In conclusion, OPRM1 A118G genotype may affect the dosage of morphine in advanced liver cancer patients. More dosages of morphine are needed for pain control in patients with G allele. Key Words: µ-opioid receptor gene (OPRM1), Gene polymorphism, Liver cancer, Morphine.


Assuntos
Neoplasias Hepáticas , Morfina , Analgésicos Opioides/uso terapêutico , Genótipo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Morfina/uso terapêutico , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Receptores Opioides mu/genética
6.
Pediatrics ; 148(5)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34610948

RESUMO

BACKGROUND: Midazolam is a benzodiazepine sedative used in NICUs. Because benzodiazepine's effects include respiratory depression and potential detrimental developmental effects, minimizing exposure could benefit neonates. Dexmedetomidine is routinely used for sedation in older pediatric populations. We implemented a quality improvement initiative with the aim of decreasing midazolam infusions by 20% through use of dexmedetomidine. METHODS: A multidisciplinary committee created a sedation guideline that included standardized dexmedetomidine dosing escalation and weaning. Baseline data collection occurred from January 2015 to February 2018, with intervention from March 2018 to December 2019. Percentage of sedation episodes with dexmedetomidine initiated was followed as a process measure. Outcomes measures were percentage of eligible infants receiving midazolam infusions and midazolam-free days per sedation episode. Bradycardia with dexmedetomidine, unplanned extubation rates, and morphine dosage were monitored as balancing measures. RESULTS: Our study included 434 episodes of sedation in 386 patients. Dexmedetomidine initiation increased from 18% to 49%. The intervention was associated with a significant reduction in midazolam initiation by 30%, from 95% to 65%, with special cause variation on statistical process control chart analysis. Midazolam-free days per sedation episode increased from 0.3 to 2.2 days, and patients receiving dexmedetomidine had lower midazolam doses (1.3 mg/kg per day versus 2.2 mg/kg per day, P = 5.97 × 10-04). Bradycardia requiring discontinuation of dexmedetomidine, unplanned extubation rates, and morphine doses were unchanged. CONCLUSIONS: Implementation of a quality improvement initiative was successful in reducing the percentage of patients receiving midazolam infusions and increased midazolam-free days per sedation episode, revealing an overall reduction in benzodiazepine exposure while maintaining adequate sedation.


Assuntos
Dexmedetomidina/administração & dosagem , Substituição de Medicamentos , Hipnóticos e Sedativos/administração & dosagem , Midazolam/administração & dosagem , Extubação , Analgésicos Opioides/administração & dosagem , Bradicardia/induzido quimicamente , Dexmedetomidina/efeitos adversos , Esquema de Medicação , Idade Gestacional , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipotensão/induzido quimicamente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Midazolam/efeitos adversos , Morfina/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde , Melhoria de Qualidade , Fatores de Tempo
7.
J Opioid Manag ; 17(5): 405-416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34714541

RESUMO

OBJECTIVE: Morphine is a potent analgesic used to manage the pain following total knee arthroplasty (TKA). We aim to assess the safety and efficacy of intrathecal morphine (ITM) compared with placebo following TKA. METHODS: We systematically searched four databases for trials that study the safety and efficacy of ITM in TKA. From relevant studies, data were extracted and pooled as mean difference (MD) or standardized mean difference (SMD) with 95 percent confidence interval (CI) using Review Manager software (Version 5.3). RESULTS: We included six randomized controlled trials in our study. ITM significantly reduced pain scores at 4 hours (SMD = -0.82, 95 percent CI [-1.52, -0.12], p = 0.02) and 24 hours (MD = -2.01, 95 percent CI [-2.93, -1.09], p = 0.0001) after surgery compared to placebo. No statistically significant difference in cumulative morphine use or nausea episodes was observed after 24 hours. ITM in-creased the risk of pruritus more than placebo (relative risk [RR] = 4.82, 95 percent CI [2.34, 9.93], p < 0.0001). CONCLUSION: ITM reduces pain at 4 and 24 hours post-operatively with no effect on cumulative morphine consumption. The only feared side effect is pruritus.


Assuntos
Artroplastia do Joelho , Morfina , Analgésicos , Analgésicos Opioides/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Humanos , Morfina/efeitos adversos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Life Sci ; 285: 120014, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34619167

RESUMO

AIMS: We have shown that chemokines injected into the periaqueductal gray region of the brain blocks opioid-induced analgesia in the rat cold-water tail flick test (CWTF). The present experiments tested whether chemokine receptor antagonists (CRAs), in combination with sub-analgesic doses of morphine, would provide maximal analgesia in the CWTF test and the mouse formalin pain assay. The effect of CRAs on respiratory depression was also evaluated. MAIN METHODS: One, two or four CRAs (AMD3100/CXCR4, maraviroc/CCR5, RS504393/CCR2 orAZD8797/CX3CR1) were used in combination with sub-analgesic doses of morphine, all given systemically. Pain was assessed using the rat CWTF test or formalin injection into the paw of mice scored by licking. Respiration and oxygen saturation were measured in rats using a MouseOX® Plus - pulse oximeter. KEY FINDINGS: In the CWTF test, a sub-maximal dose of morphine in combination with maraviroc alone, maraviroc plus AMD3100, or with the four chemokine receptor antagonists, produced synergistic increases in antinociception. In the formalin test, the combination of four CRAs plus a sub-maximal dose of morphine resulted in increased antinociception in both male and female mice. AMD3100 had an additive effect with morphine in both sexes. Coadministration of CRAs with morphine did not potentiate the opioid respiratory depressive effect. SIGNIFICANCE: These results support the conclusion that combinations of CRAs can increase the potency of sub-analgesic doses of morphine analgesia without increasing respiratory depression. The results support an "opioid sparing" strategy for alleviation of pain using reduced doses of opioids in combination with CRAs to achieve maximal analgesia.


Assuntos
Analgesia/métodos , Analgésicos Opioides/farmacologia , Morfina/farmacologia , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/tratamento farmacológico , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Benzilaminas/administração & dosagem , Benzilaminas/farmacologia , Ciclamos/administração & dosagem , Ciclamos/farmacologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Masculino , Maraviroc/administração & dosagem , Maraviroc/farmacologia , Morfina/administração & dosagem , Morfina/efeitos adversos , Dor Nociceptiva/fisiopatologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/induzido quimicamente , Tiazóis/administração & dosagem , Tiazóis/farmacologia
9.
J Opioid Manag ; 17(7): 109-118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34520032

RESUMO

Opioids are an important tool in the treatment of pain, but opioid overdose has become a serious health issue. Most opioid-related deaths are caused by respiratory depression, and the risk of respiratory depression is compounded because of the risks of abuse and diversion, which makes the need for safer opioids even more urgent. However, the atypical opioids (buprenorphine, tramadol, and tapentadol), with mechanisms of action not purely driven by µ-opioid receptor agonism, may be safer than conventional opioids, eg, morphine, oxycodone, and fentanyl. The purpose of this narrative review is to describe the clinical and experimental evidence regarding opioid-induced respiratory depression in the context of the mechanisms of action of the atypical opioids. Among the atypical opioids, tramadol has an advantage of being a Schedule IV drug, and thus having a relatively low abuse potential-but its effects, including its effect on respiratory drive, are dependent on cytochrome P450 2D6 metabolizer status. Tapentadol appears to affect respiratory drive, but this has not been well investigated. Buprenorphine is a Schedule III drug, thus having less abuse potential than the majority of opioids. Experimentally, a ceiling effect on the respiratory depression has been reported with intravenous buprenorphine. In addition, experimental hypercapnic stress in healthy volunteers demonstrated no respiratory depression following the administration of a single dose of the buccal film formulation of buprenorphine when compared with placebo. Overall, the data suggest that atypical opioids may be a safer option than conventional opioids for the treatment of pain.


Assuntos
Analgésicos Opioides , Buprenorfina , Analgésicos Opioides/efeitos adversos , Fentanila , Humanos , Morfina , Oxicodona
10.
Ned Tijdschr Tandheelkd ; 128(9): 441-450, 2021 Sep.
Artigo em Holandês | MEDLINE | ID: mdl-34490769

RESUMO

To alleviate acute dental pain, dentists and dental specialists frequently prescribe analgesics to patients, either on prescription or not. In order to effectively manage dental pain, it is advisable to follow a step-by-step plan based on the WHO analgesic ladder: step 1, start with acetaminophen step 2, add an NSAID (e.g. ibuprofen, diclofenac, naproxen); step 3, add a weak opioid (e.g. tramadol) in combination with acetaminophen or an NSAID; step 4, replace a weak opioid with a strong opioid (e.g. morphine or oxycodone). A dentist in general practice or a dental specialist needs to know, the mechanism of action and the most important interactions, contraindications and adverse effects of each of these groups of medications. Attention is needed when prescribing analgesics to risk groups such as frail elderly, pregnant and lactating women, and children.


Assuntos
Lactação , Tramadol , Idoso , Analgésicos , Analgésicos Opioides/efeitos adversos , Criança , Feminino , Humanos , Morfina , Gravidez
11.
Trials ; 22(1): 632, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530881

RESUMO

OBJECTIVES: We aim to study the effect of epidural morphine as a means to reduce high respiratory drive in COVID 19 patients on non-invasive ventilation (NIV)-primary end point-and to study its effect on respiratory parameters, subjective patient comfort, rates of endotracheal intubation, duration of mechanical ventilation and mortality. TRIAL DESIGN: Parallel group, randomised, double blind, single centre placebo control trial. Allocation ratio 1:1, superiority trial PARTICIPANTS: Trial site and population-COVID ICU patients in the All India Institute of Medical Sciences (AIIMS) Bhubaneswar, Odisha, India Inclusion and exclusion criteria Inclusion criteria Adult patients on NIV with COVID-19 Exclusion criteria Metabolic acidosis HCO3-< 16 and pH < 7.2. Severe hypoxemia warranting cessation of NIV and intubation, non-acceptance of NIV and proven sepsis. Technical difficulty for epidural catheterization, coagulation abnormalities, low respiratory drive and EOL orders. Sources or methods of recruitment-daily discussion at 8 am of new admissions to COVID ICU on NIV-consenting adult patients with COVID19 on NIV and high respiratory drive; not meeting exclusion criteria will be recruited for the trial and randomised. INTERVENTION AND COMPARATOR: Patients of both groups will be turned to a lateral or sitting position (as comfortable), and an injection of local anaesthetic be given at lumbar 2-3/3-4 space. In the intervention group, an epidural catheter will be inserted using aseptic technique and fixed to the skin. The control group will have a sham catheter fixed exactly like in the intervention group, but not entering the epidural space. The intervention group will be administered injection morphine sulphate once every 18-24 h into the epidural space. The doses will be escalated daily (5-10 mg), titrated to effect: escalation limited by hypoventilation resulting in respiratory acidosis (pH < 7.2). The intervention will continue for a minimum of 2 doses and a maximum of 5 doses (96 h) of morphine. It will be stopped if the epidural catheter gets dislodged before the second dose or the patient is weaned off non-invasive ventilation to high flow mask for a continuous period of 24 h or requires endotracheal intubation. The patient will be followed up till death or 28 days after ICU discharge. MAIN OUTCOMES: Primary outcome-diaphragm thickening index fraction (average of minimum 3 readings) Secondary outcomes-ventilator parameters, sedation and pain scores, subjective comfort and dyspnoea scores, time to intubation, length of stay on NIV and 28-day mortality Timing of outcome assessment-every 8th hour assessment for 24 h after the last dose of epidural morphine or 120 h whichever is greater RANDOMISATION: A central random number list will be kept with the study research assistant. She will randomise according to the numbers available in the list using an allocation ratio of 1:1. An opaque sealed envelope concealing the allotted randomisation code will be dispatched to the ICU team. BLINDING (MASKING): The assessor, patient, nurses and physicians will be blind to group allocation. One member of the team not involved in research will administer the intervention. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Twenty-five patients per group; 50 patients total TRIAL STATUS: Protocol version 1. Not recruiting yet. Recruitment to begin by 24 July 2021 and end by 31 August 2022 TRIAL REGISTRATION: Central Trials Registry India CTRI CTRI/2021/07/035093 . Registered on 23 July 2021. Prospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Adulto , Espaço Epidural , Humanos , Morfina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
12.
Rev Cardiovasc Med ; 22(3): 865-872, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34565084

RESUMO

Intravenous morphine is a controversial treatment for acute heart failure (AHF). This study aimed to evaluate and compare the efficacy of intravenous morphine treatment vs. no morphine treatment in AHF patients. Relevant research conducted before June 2020 was retrieved from electronic databases. One unpublished study of our own was also included. Studies were eligible for inclusion if they compared AHF patients treated with intravenous morphine and patients who did not receive morphine. This meta-analysis included three propensity-matched cohorts and two retrospective analyses, involving a total of 149,967 patients (intravenous-morphine group, n = 22,072; no-morphine group, n = 127,895). There was a non-significant increase in the in-hospital mortality in the morphine group (combined odds ratio [OR] = 2.14, 95% confidence interval [CI]: 0.88-5.23, p = 0.095, I2 = 97.1%). However, subgroup analyse showed that the rate of in-hospital mortality with odds of 1.41 times more likely (95% CI: 1.11-1.80, p = 0.005, I2 = 0%) in those receiving vs. not receiving intravenous morphine. No significant correlation was found between intravenous morphine and invasive mechanical ventilation (OR = 2.19, 95% CI: 0.84-5.73, p = 0.10, I2 = 94.2%; subgroup analysis: OR = 2.24, 95% CI: 0.70-7.21, p = 0.176, I2 = 95.1%) or long-term mortality (hazard ratio = 1.15, 95% CI: 0.96-1.34, p = 0.335; I2 = 8.6%). The administration of intravenous morphine to patients with AHF may be related to in-hospital mortality, but not to invasive mechanical ventilation and long-term mortality.


Assuntos
Insuficiência Cardíaca , Morfina , Doença Aguda , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Mortalidade Hospitalar , Humanos , Morfina/efeitos adversos , Estudos Retrospectivos
13.
Alkaloids Chem Biol ; 86: 145-342, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34565506

RESUMO

This chapter provides a short overview of the history of morphine since it's isolation by Sertürner in 1805. The biosynthesis of the title alkaloid as well as all total and formal syntheses of morphine and codeine published after 1996 are discussed in detail. The last section of this chapter provides a detailed overview of medicinally relevant derivatives of the title alkaloid.


Assuntos
Alcaloides , Morfina , Biologia , Codeína
14.
Anesthesiology ; 135(5): 864-876, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34520520

RESUMO

BACKGROUND: Intrathecal morphine decreases postoperative pain in standard cardiac surgery. Its safety and effectiveness have not been adequately evaluated in minimally invasive cardiac surgery. The authors hypothesized that intrathecal morphine would decrease postoperative morphine consumption after minimally invasive cardiac surgery. METHODS: In this randomized, placebo-controlled, double-blinded clinical trial, patients undergoing robotic totally endoscopic coronary artery bypass received either intrathecal morphine (5 mcg/kg) or intrathecal saline before surgery. The primary outcome was postoperative morphine equivalent consumption in the first 24 h after surgery; secondary outcomes included pain scores, side effects, and patient satisfaction. Pain was assessed via visual analog scale at 1, 2, 6, 12, 24, and 48 h after intensive care unit arrival. Opioid-related side effects (nausea/vomiting, pruritus, urinary retention, respiratory depression) were assessed daily. Patient satisfaction was evaluated with the Revised American Pain Society Outcome Questionnaire. RESULTS: Seventy-nine patients were randomized to receive intrathecal morphine (n = 37) or intrathecal placebo (n = 42), with 70 analyzed (morphine 33, placebo 37). Intrathecal morphine patients required significantly less median (25th to 75th percentile) morphine equivalents compared to placebo during first postoperative 24 h (28 [16 to 46] mg vs. 59 [41 to 79] mg; difference, -28 [95% CI, -40 to -18]; P < 0.001) and second postoperative 24 h (0 [0 to 2] mg vs. 5 [0 to 6] mg; difference, -3.3 [95% CI, -5 to 0]; P < 0.001), exhibited significantly lower visual analog scale pain scores at rest and cough at all postoperative timepoints (overall treatment effect, -4.1 [95% CI, -4.9 to -3.3] and -4.7 [95% CI, -5.5 to -3.9], respectively; P < 0.001), and percent time in severe pain (10 [0 to 40] vs. 40 [20 to 70]; P = 0.003) during the postoperative period. Mild nausea was more common in the intrathecal morphine group (36% vs. 8%; P = 0.004). CONCLUSIONS: When given before induction of anesthesia for totally endoscopic coronary artery bypass, intrathecal morphine decreases use of postoperative opioids and produces significant postoperative analgesia for 48 h.


Assuntos
Analgesia/métodos , Analgésicos Opioides/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Morfina/uso terapêutico , Idoso , Analgésicos Opioides/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem
15.
Anesthesiology ; 135(5): 829-841, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34525173

RESUMO

BACKGROUND: There is need to identify perioperative interventions that decrease chronic opioid use. The authors hypothesized that receipt of a peripheral nerve block would be associated with a lower incidence of persistent postoperative opioid prescription fulfillment. METHODS: This was a retrospective population-based cohort study examining ambulatory shoulder surgery patients in Ontario, Canada. The main outcome measure was persistent postoperative opioid prescription fulfillment. In opioid-naive patients (no opioid prescription fulfillment in 90 days preoperatively), this was present if an individual fulfilled an opioid prescription of at least a 60-day supply during postoperative days 90 to 365. In opioid-exposed (less than 60 mg oral morphine equivalent dose per day within 90 days preoperatively) or opioid-tolerant (60 mg oral morphine equivalent dose per day or above within 90 days preoperatively) patients, this was classified as present if an individual experienced any increase in opioid prescription fulfillment from postoperative day 90 to 365 relative to their baseline use before surgery. The authors' exposure was the receipt of a peripheral nerve block. RESULTS: The authors identified 48,523 people who underwent elective shoulder surgery from July 1, 2012, to December 31, 2017, at one of 118 Ontario hospitals. There were 8,229 (17%) patients who had persistent postoperative opioid prescription fulfillment. Of those who received a peripheral nerve block, 5,008 (16%) went on to persistent postoperative opioid prescription fulfillment compared to 3,221 (18%) patients who did not (adjusted odds ratio, 0.90; 95% CI, 0.83 to 0.97; P = 0.007). This statistically significant observation was not reproduced in a coarsened exact matching sensitivity analysis (adjusted odds ratio, 0.85; 95% CI, 0.71 to 1.02; P = 0.087) or several other subgroup and sensitivity analyses. CONCLUSIONS: This retrospective analysis found no association between receipt of a peripheral nerve block and a lower incidence of persistent postoperative opioid prescription fulfillment in ambulatory shoulder surgery patients.


Assuntos
Procedimentos Cirúrgicos Ambulatórios/métodos , Analgésicos Opioides/uso terapêutico , Bloqueio Nervoso/estatística & dados numéricos , Dor Pós-Operatória/tratamento farmacológico , Prescrições/estatística & dados numéricos , Ombro/cirurgia , Administração Oral , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/uso terapêutico , Bloqueio Nervoso/métodos , Ontário , Nervos Periféricos/efeitos dos fármacos , Estudos Retrospectivos
16.
Can J Anaesth ; 68(12): 1802-1810, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34585366

RESUMO

PURPOSE: Approximately one in five women will experience severe postoperative pain after Cesarean delivery (CD). Previously, a bedside three-item questionnaire (3-IQ) has shown to predict women experiencing higher evoked pain intensity after CD, with an area under the receiver operator characteristics (ROC) curve of 0.72. We hypothesized that the addition of psychophysical pain tests to the existing 3-IQ would improve the ability to predict severe pain in women undergoing elective CD under spinal anesthesia METHODS: This was a prospective cohort study on women undergoing elective CD under spinal anesthesia. Women were assessed preoperatively using the 3-IQ, pressure algometry (PA) and mechanical temporal summation (TS) response. All women received standard perioperative care, including a multimodal analgesia regimen that included intrathecal fentanyl and morphine. A 0-100 mm visual analogue scale (VAS) was used to assess the severity of pain at rest (VASr) and on movement (VASm) at 24 and 48 hr after surgery. Patient satisfaction and opioid consumption were also recorded. We performed ROC curve analyses to assess whether we could improve the ability to predict our primary outcome of severe pain on movement at 24 hr (VASm24 ≥ 70). RESULTS: We studied 195 women. Median [interquartile range] VASm24 was 53 [32-72] and 28% of patients experienced a VASm24 ≥ 70. The ability to predict a VASm24 ≥ 70 assessed by the area under the ROC curve was 0.64 using the 3-IQ and 0.67 using the 3-IQ combined with TS and PA. CONCLUSION: The addition of PA and TS to the 3-IQ model resulted in a predictive model that performed similarly to the 3-IQ model alone. Further research is warranted in this area to better predict women at risk of severe pain post CD.


Assuntos
Cesárea , Dor Pós-Operatória , Analgésicos Opioides , Cesárea/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Morfina , Dor Pós-Operatória/diagnóstico , Gravidez , Estudos Prospectivos , Inquéritos e Questionários
17.
PLoS One ; 16(9): e0256870, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34520454

RESUMO

Although they represent the cornerstone of analgesic therapy, opioids, such as morphine, are limited in efficacy by drug tolerance, hyperalgesia and other side effects. Activation of microglia and the consequent production of proinflammatory cytokines play a key pathogenic role in morphine tolerance, but the exact mechanisms are not well understood. This study aimed to investigate the regulatory mechanism of epidermal growth factor receptor (EGFR) on microglial activation induced by morphine in mouse microglial BV-2 cells. In this research, BV-2 cells were stimulated with morphine or pretreated with AG1478 (an inhibitor of EGFR). Expression levels of cluster of differentiation molecule 11b (CD11b), EGFR, and phospho-EGFR were detected by immunofluorescence staining. Cell signaling was assayed by Western blot. The migration ability of BV-2 cells was tested by Transwell assay. The production of interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) in the cell supernatant was determined by ELISA. We observed that the expression of CD11b induced by morphine was increased in a dose- and time- dependent manner in BV-2 cells. Phosphorylation levels of EGFR and ERK1/2, migration of BV-2 cells, and production of IL-1ß and TNFα were markedly enhanced by morphine treatment. The activation, migration, and production of proinflammatory cytokines in BV-2 cells were inhibited by blocking the EGFR signaling pathway with AG1478. The present study demonstrated that the EGFR/ERK signaling pathway may represent a novel pharmacological strategy to suppress morphine tolerance through attenuation of microglial activation.


Assuntos
Tolerância a Medicamentos/genética , Receptores ErbB/genética , Microglia/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Morfina/farmacologia , Animais , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Regulação da Expressão Gênica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Microglia/citologia , Microglia/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Quinazolinas/farmacologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Tirfostinas/farmacologia
18.
J Neurochem ; 159(3): 590-602, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34499746

RESUMO

Morphine is a potent opioid analgesic with high propensity for the development of antinociceptive tolerance. Morphine antinociception and tolerance are partially regulated by the midbrain ventrolateral periaqueductal gray (vlPAG). However, the majority of research evaluating mu-opioid receptor signaling has focused on males. Here, we investigate kinase activation and localization patterns in the vlPAG following acute and chronic morphine treatment in both sexes. Male and female mice developed rapid antinociceptive tolerance to morphine (10 mg/kg i.p.) on the hot plate assay, but tolerance did not develop in males on the tail flick assay. Quantitative fluorescence immunohistochemistry was used to map and evaluate the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), protein kinase-C (PKC), and protein kinase-A (PKA). We observed significantly greater phosphorylated ERK 1/2 in the vlPAG of chronic morphine-treated animals which co-localized with the endosomal marker, Eea1. We note that pPKC is significantly elevated in the vlPAG of both sexes following chronic morphine treatment. We also observed that although PKA activity is elevated following chronic morphine treatment in both sexes, there is a significant reduction in the nuclear translocation of its phosphorylated substrate. Taken together, this study demonstrates increased activation of ERK 1/2, PKC, and PKA in response to repeated morphine treatment. The study opens avenues to explore the impact of chronic morphine treatment on G-protein signaling and kinase nuclear transport.


Assuntos
Indução Enzimática/efeitos dos fármacos , Morfina/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/enzimologia , Proteínas Quinases/biossíntese , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Tolerância a Medicamentos , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/efeitos dos fármacos , Proteína Quinase C/metabolismo , Transporte Proteico , Caracteres Sexuais , Proteínas de Transporte Vesicular/biossíntese , Proteínas de Transporte Vesicular/genética
19.
PLoS One ; 16(9): e0253902, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34500453

RESUMO

BACKGROUND: É£-aminobutyric acid (GABA) facilitator valproic acid may be able to curb memory disruption induced by morphine exposure. OBJECTIVE: The effects of the GABA facilitator valproic acid on the behavioral tolerance induced by morphine were investigated. Then hippocampal-dependent tasks named spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Finally, the changes in the expression of hippocampal GABA-A receptors underlying morphine tolerance were also examined. METHODS: Rats were treated with daily morphine injections, with or without distinct contextual pairing. To examine the effect of valproic acid on morphine tolerance expression, valproic acid was pretreated an hour before morphine. Spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Afterwards the changes in the expression of hippocampal GABAα receptors using the quantitative real-time PCR and western blot techniques to detect GABArα subunits mRNAs and protein level were studied. RESULTS: Our results showed that both learned and non-associative morphine tolerance influence short-term memory and the subjacent expression of GABArα mRNAs and protein level. Despite its attenuating effects on the development and expression of both learned and non-associative morphine tolerance, only associative morphine tolerance-induced memory dysfunction was ameliorated by valproic acid pretreatment. We also found that the expression of GABArα1, α2, α5 subunits mRNAs and GABAα protein level were affected heavier in associative morphine tolerant rats. CONCLUSION: Our data supports the hypothesis that unconditioned and learned morphine tolerance influences short-term memory and the expression of GABArα 1, α2, α5 mRNAs and GABArα protein level differently, and adds to our understanding of the behavioral and molecular aspects of the learned tolerance to morphine effects.


Assuntos
Tolerância a Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Morfina/farmacologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Analgésicos Opioides/farmacologia , Animais , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Wistar , Receptores de GABA-A/genética
20.
Cells ; 10(9)2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34571832

RESUMO

HIV enters the CNS early after peripheral infection, establishing reservoirs in perivascular macrophages that contribute to development of HIV-associated neurocognitive disorders (HAND) in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy (ART). Opioid use may contribute to dysregulated macrophage functions resulting in more severe neurocognitive symptoms in PWH taking opioids. Macroautophagy helps maintain quality control in long-lived cell types, such as macrophages, and has been shown to regulate, in part, some macrophage functions in the CNS that contribute to HAND. Using Western blotting and confocal immunofluorescence in primary human macrophages, we demonstrated that morphine and a commonly prescribed ART regimen induce bulk autophagy. Morphine and ART also inhibited completion of autophagy. HIV infection increased these inhibitory effects. We also examined two types of selective autophagy that degrade aggregated proteins (aggrephagy) and dysfunctional mitochondria (mitophagy). Morphine and ART inhibited selective autophagy mediated by p62 regardless of HIV infection, and morphine inhibited mitophagic flux in HIV-infected cells demonstrating potential mitotoxicity. These results indicate that inhibition of autophagy, both in bulk and selective, in CNS macrophages may mediate neurocognitive dysfunction in PWH using opioids. Increasing autophagic activity in the context of HIV may represent a novel therapeutic strategy for reducing HAND in these individuals.


Assuntos
Antirretrovirais/farmacologia , Autofagia/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Morfina/farmacologia , Transtornos Neurocognitivos/tratamento farmacológico , Células Cultivadas , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Mitofagia/efeitos dos fármacos , Transtornos Neurocognitivos/virologia
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