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1.
J Refract Surg ; 37(9): 582-589, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34506240

RESUMO

PURPOSE: To compare the efficacy of oral codeine plus acetaminophen versus oxycodone plus acetaminophen for severe pain control following photorefractive keratectomy (PRK). METHODS: This single-center trial randomized 200 patients to receive codeine 30 mg/acetaminophen 325 mg (codeine group) or oxycodone 5 mg/acetaminophen 325 mg (oxycodone group)every 4 hours as needed for severe pain for 4 days following PRK. Patients recorded postoperative pain, tablet consumption, and tetracaine use. Patients were monitored at postoperative 1 day, 1 week, and 1, 3, and 6 months for visual acuity and follow-up. Study outcomes were mean postoperative pain, treatment and tetracaine use, and visual acuity. RESULTS: Analysis of 197 patients who completed the trial (97 codeine group and 100 oxycodone group) showed mean pain scores were lower in the codeine group throughout the intervention period. Mean pain scores were higher in the oxycodone group than the codeine group on postoperative days 2 and 4 (P = .017 and P = .034, respectively). The oxycodone group consumed more tablets than the codeine group, with a difference on postoperative day 2 (P = .019), and used a greater number of tetracaine drops (P = .015). Repeated measures analysis of variance showed significant improvement in visual acuity in both groups with no difference in visual outcomes (P = .81). CONCLUSIONS: Codeine/acetaminophen is as effective and safe as oxycodone/acetaminophen for pain control following PRK, with no clinical difference in overall pain control and long-term visual outcomes. This implies that treating postoperative pain after PRK with a Schedule III opioid (codeine) is effective and potentially decreases the risk of misuse by a higher regulated Schedule II opioid (oxycodone), lowering the potential for abuse and dependence. [J Refract Surg. 2021;37(9):582-589.].


Assuntos
Oxicodona , Ceratectomia Fotorrefrativa , Codeína , Método Duplo-Cego , Humanos , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico , Estudos Prospectivos
2.
Clin Drug Investig ; 41(10): 875-883, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34524651

RESUMO

BACKGROUND AND OBJECTIVES: Current evidence shows that tapentadol hydrochloride prolonged-release is more cost effective than other opioids. However, the introduction into the market of generic formulations of traditional comparators, leading to potential savings due to their lower price, creates space for further research. The objective of this study is to evaluate and compare the efficacy of tapentadol versus oxycodone/naloxone and the economic impact of the two alternatives in both branded and generic formulations. METHODS: A cost-effectiveness analysis was performed using the third-payer perspective (TPP), with specific reference to the Italian National Health Service. A Markov model was implemented to simulate transitions between states, comparing two arms: The first arm simulated the administration of tapentadol, while the second simulated the administration of oxycodone/naloxone, both branded and generic. The results were reported in terms of net monetary benefit (NMB). The willingness to pay (WPT) was estimated at €35,000/quality-adjusted life year. RESULTS: Tapentadol was dominant in all scenarios, assuming a population of 1000 individuals over a 1-year time horizon. In all cases, although the prices of oxycodone/naloxone generic formulations were lower, the costs associated with treatment discontinuation were always higher than those associated with tapentadol. The comparison with the branded formulation of oxycodone/naloxone was associated with the highest savings of €431.77 per patient, and with the highest NMB of €1943.77 per patient. CONCLUSION: The results of this pharmacoeconomic evaluation promote the use of tapentadol in comparison with oxycodone/naloxone, confirming the results obtained in previous studies with reference to the generic formulations.


Assuntos
Dor Musculoesquelética , Oxicodona , Analgésicos Opioides/uso terapêutico , Análise Custo-Benefício , Preparações de Ação Retardada , Humanos , Dor Musculoesquelética/tratamento farmacológico , Naloxona/uso terapêutico , Fenóis , Medicina Estatal , Tapentadol
3.
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
4.
J Opioid Manag ; 17(7): 179-182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34520040

RESUMO

This case report demonstrates using buprenorphine 32 mg to achieve adequate pain control after a total knee replacement. The patient stopped buprenorphine 48 hours before surgery. He was prescribed 150 tablets of oxycodone 5 mg. After finishing oxycodone, he experienced significant pain that was relieved by 32 mg of buprenorphine daily. Urine drug screens were negative perioperatively. Patients with opioid use disorder require careful discharge planning to avoid opioid relapses or misuses of pain medications. Buprenorphine offers many unique advantages in acute pain control, including lower risk of respiratory depression, abuse potential, and lower risk of nephrotoxicity.


Assuntos
Artroplastia do Joelho , Buprenorfina , Analgésicos Opioides/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Buprenorfina/efeitos adversos , Humanos , Masculino , Oxicodona/efeitos adversos , Dor
5.
Ned Tijdschr Tandheelkd ; 128(9): 435-439, 2021 Sep.
Artigo em Holandês | MEDLINE | ID: mdl-34490768

RESUMO

Oral care providers frequently prescribe analgesics for the management of dental pain. To get an overview of the analgesics prescribed in the Netherlands from 2016 through 2020, we collected data from the Stichting Farmaceutische Kengetallen (foundation [for] pharmaceutical indicators). Annually, more than 300,000 analgesics are prescribed by dentists in general practice and dental specialists. The largest group concerns NSAIDs (88%), followed by weak opioids (9%), acetaminophen (2%) and strong opioids (1%). Of the NSAIDs, ibuprofen is the most prescribed by all groups of oral care providers (84-91%). Of the weak opioids, dentists and oral and maxillofacial surgeons mainly prescribe codeine and codeine/ acetaminophen (64% and 78%, respectively), while orthodontists mainly prescribe tramadol (53%). Of the strong opioids, oxycodone is the most frequently prescribed by all groups of oral care providers (77-87%). Analgesics are a large part of the prescription medications in Dutch oral care and mainly concern NSAIDs (ibuprofen) and weak opioids (codeine/ acetaminophen). There are no major differences in prescription behaviour among different oral care providers.


Assuntos
Oxicodona , Tramadol , Analgésicos , Analgésicos Opioides , Humanos , Países Baixos
6.
Obstet Gynecol ; 138(2): 253-259, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237764

RESUMO

OBJECTIVE: To evaluate whether viewing an educational video on pain management reduces opioid use after cesarean delivery. METHODS: We conducted a randomized, controlled trial of women aged 18 years or older who underwent cesarean delivery at a tertiary care center. Eligible women were randomized in a 1:1 ratio to usual discharge pain medication instructions plus an educational video on pain management or to usual discharge pain medication instructions alone. All women received the same opioid prescription at discharge: Twenty 5-mg oxycodone tablets. Participants were contacted at 7 days and at 14 days after delivery to assess the number of oxycodone tablets used, adjunct medication (acetaminophen and ibuprofen) use, pain scores, and overall satisfaction of pain control. The primary outcome was the number of oxycodone tablets used from discharge through postpartum day 14. A sample size of 23 per group (n=46) was planned to detect a 25% difference in mean number of oxycodone tablets used between groups, as from 20 to 15. RESULTS: From July 2019 through December 2019, 61 women were screened and 48 were enrolled-24 in each group. Women who viewed the educational video used significantly fewer opioid tablets from discharge through postpartum day 14 compared with women who received usual pain medication instructions (median 1.5, range 0-20 vs median 10, range 0-24, P<.001). Adjunct medication use, pain scores, and satisfaction with pain control did not differ significantly between groups. CONCLUSION: Among women who underwent cesarean delivery, viewing an educational video on pain management reduced postdischarge opioid use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03959969.


Assuntos
Analgésicos Opioides/administração & dosagem , Cesárea/métodos , Oxicodona/administração & dosagem , Manejo da Dor/métodos , Educação de Pacientes como Assunto/métodos , Gravação de Videoteipe , Acetaminofen/administração & dosagem , Adulto , Feminino , Humanos , Ibuprofeno/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Dor Pós-Operatória/tratamento farmacológico , Período Pós-Parto , Gravidez
8.
BMJ Open ; 11(6): e044157, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193479

RESUMO

OBJECTIVES: Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone. DESIGN: Retrospective cohort study. SETTING: Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study. PARTICIPANTS: The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1-Q3)=58 (47-66). PRIMARY AND SECONDARY OUTCOME MEASURES: Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient's medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity. RESULTS: From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004). CONCLUSIONS: These findings support the importance of sex as a biological variable to be factored into pain management studies.


Assuntos
Analgésicos Opioides , Caracteres Sexuais , Analgésicos Opioides/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Masculino , Oxicodona/efeitos adversos , Estudos Retrospectivos
9.
J Immunol ; 207(3): 860-867, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281999

RESUMO

Vaccines and mAbs offer promising strategies to treat substance use disorders (SUDs) and prevent overdose. Despite vaccines and mAbs against SUDs demonstrating proof of efficacy, selectivity, and safety in animal models, it is unknown whether the mechanism of action of these immunotherapeutics relies exclusively on the formation of Ab/drug complexes, or also involves Ab-mediated effector functions. Hence, this study tested whether the efficacy of active and passive immunization against drugs of abuse requires phagocytosis, the intact Fc portion of the anti-drug Ab, FcγRs, or the neonatal FcR (FcRn). The efficacy of a lead vaccine against oxycodone was not diminished in mice after depletion of macrophages or granulocytes. Anti-oxycodone F(ab')2 fragments resulted in lower serum levels of F(ab')2 compared with intact mAbs, and F(ab')2s were not as effective as the parent mAbs in reducing distribution of oxycodone to the brain. The efficacy of vaccines and mAbs against oxycodone was preserved in either FcγIII or FcγI-IV ablated mice, suggesting that FcγRs are not required for Ab efficacy. Finally, both active and passive immunization against oxycodone in FcRn-/- mice yielded reduced efficacy compared with wild-type control mice. These data identified a role for FcRn, but not for phagocytosis or Fc-dependent effector functions, in mediating the efficacy of vaccines and mAbs against SUD. This study supports rational design of vaccines and mAbs engineered for maximal neutralization activity and optimal FcRn binding.


Assuntos
Transtornos Relacionados ao Uso de Opioides , Vacinas , Animais , Anticorpos Monoclonais , Camundongos , Oxicodona
10.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203972

RESUMO

Opioid abuse has become a major public health crisis that affects millions of individuals across the globe. This widespread abuse of prescription opioids and dramatic increase in the availability of illicit opioids have created what is known as the opioid epidemic. Pregnant women are a particularly vulnerable group since they are prescribed for opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta and potentially impact the developing fetus. Limited information exists regarding the effect of oxycodone (oxy) on synaptic alterations. To fill this knowledge gap, we employed an integrated system approach to identify proteomic signatures and pathways impacted on mixed neuroglial cultures treated with oxy for 24 h. Differentially expressed proteins were mapped onto global canonical pathways using ingenuity pathway analysis (IPA), identifying enriched pathways associated with ephrin signaling, semaphorin signaling, synaptic long-term depression, endocannabinoid signaling, and opioid signaling. Further analysis by ClueGO identified that the dominant category of differentially expressed protein functions was associated with GDP binding. Since opioid receptors are G-protein coupled receptors (GPCRs), these data indicate that oxy exposure perturbs key pathways associated with synaptic function.


Assuntos
Neuroglia/metabolismo , Oxicodona/farmacologia , Proteoma/metabolismo , Análise de Sistemas , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Ontologia Genética , Neuroglia/efeitos dos fármacos , Proteômica , Ratos Sprague-Dawley
11.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34312305

RESUMO

Opioid drugs are increasingly being prescribed to pregnant women. Such compounds can also bind and activate opioid receptors in the fetal brain, which could lead to long-term brain and behavioral disruptions. We hypothesized that maternal treatment with oxycodone (OXY), the primary opioid at the center of the current crisis, leads to later neurobehavioral disorders and gene expression changes in the hypothalamus and hippocampus of resulting offspring. Female mice were treated daily with 5 mg OXY/kg or saline solution (control; CTL) for two weeks before breeding and then throughout gestation. Male and female offspring from both groups were tested with a battery of behavioral and metabolic tests to measure cognition, exploratory-like, anxiety-like, voluntary physical activity, and socio-communication behaviors. qPCR analyses were performed for candidate gene expression patterns in the hypothalamus and hippocampus of OXY and CTL derived offspring. Developmental exposure to OXY caused socio-communication changes that persisted from weaning through adulthood. Such offspring also showed cognitive impairments, reduced voluntary physical activity, and weighed more than CTL counterparts. In the hippocampus, prenatal exposure to OXY caused sex-dependent differences in expression of genes encoding opioid receptors and those involved in serotonin signaling. OXY exposure induced changes in neuropeptide hormone expression and the epigenetic modulator, Dnmt3a, in the hypothalamus, which could result in epigenetic changes in this brain region. The findings suggest cause for concern that consumption of OXY by pregnant mothers may result in permanent neurobehavioral changes in their offspring. Further work is needed to determine the potential underpinning epigenetic mechanisms.


Assuntos
Oxicodona , Efeitos Tardios da Exposição Pré-Natal , Animais , Ansiedade , Epigênese Genética , Feminino , Hipocampo , Hipotálamo , Masculino , Camundongos , Oxicodona/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética
12.
Brasília; CONITEC; jul. 2021.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1292539

RESUMO

O QUE É DOR CRÔNICA?: A dor crônica é aquela que persiste por um período igual ou superior a três meses. No Brasil, de todas as pessoas que buscam atendimento ambulatorial por causa de dor, entre 28% e 76% se referem a quadros de dor crônica. Essa dor acaba trazendo não apenas sofrimento físico, mas também psicológico, podendo comprometer a qualidade de vida, gerar incapacitação, ansiedade e depressão. COMO OS PACIENTES COM DOR CRÔNICA SÃO TRATADOS NO SUS? O PCDT (Protocolo Clínico e Diretrizes Terapêuticas) da Dor Crônica, publicado em 2012, indica o tratamento farmacológico para os diferentes tipos de dores de acordo com uma escala em degraus numéricos, que correspondem a uma determinada combinação de medicamentos. MEDICAMENTOS ANALISADOS: OPIOIDES FORTES (FENTANILA, OXICODONA E BUPRENORFINA): Os opioides são substâncias químicas que atuam em uma área do cérebro chamada sistema nervoso central e possuem potentes propriedades analgésicas. Os opioides fortes atualmente disponíveis no SUS são a morfina e a metadona. Motivada pela atualização do PCDT da Dor Crônica, a Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde, do Ministério da Saúde (SCTIE/MS), demandou a incorporação dos opioides fortes fentanila, oxicodona e buprenorfina para o tratamento de pacientes com dor crônica no Sistema Único de Saúde (SUS). PERSPECTIVA DO PACIENTE: As chamadas públicas para participar da Perspectiva do Paciente sobre os temas de dor crônica foram abertas em dois períodos distintos: de 13/01/2021 a 17/01/2021 e de 19/01/2021 a 02/02/2021. As quatro chamadas públicas abertas tiveram um total de 32 inscrições. A indicação dos representantes titular e suplente foi feita a partir de consenso entre o grupo de inscritos. RECOMENDAÇÃO INICIAL DA CONITEC: A Conitec recomendou inicialmente a não incorporação dos opioides fortes fentanila, oxicodona e buprenorfina no SUS para o tratamento de dor crônica. Esse tema foi discutido durante a 97ª reunião ordinária da Comissão, realizada nos dias 05 e 06 de maio de 2021. Na ocasião, o Plenário considerou que os resultados das análises não mostraram diferença significante entre os medicamentos mencionados e aqueles disponíveis atualmente no SUS, seja em termos de eficácia ou de segurança. O assunto esteve disponível na consulta pública nº 44, durante 20 dias, no período de 27/05/2021 a 15/06/2021, para receber contribuições da sociedade (opiniões, sugestões e críticas) sobre o tema. RESULTADO DA CONSULTA PÚBLICA: Foram recebidas 65 contribuições, sendo 30 de natureza técnico-científica e 35 de experiência ou opinião. As contribuições abordaram principalmente a necessidade de incorporação dos opióides fortes para dor oncológica. Os resultados da consulta pública, no entanto, não foram suficientes para alterar o entendimento do plenário e a recomendação inicial, desfavorável à incorporação, foi mantida. RECOMENDAÇÃO FINAL DA CONITEC: O Plenário da Conitec, em sua 99ª Reunião Ordinária, no dia 01 de julho de 2021, deliberou por unanimidade recomendar a não incorporação dos opioides fortes (fentanila, oxicodona e buprenorfina) para o tratamento de dor crônica, pois entendeu que as contribuições da consulta pública não trouxeram elementos suficientes para promover a mudança da recomendação preliminar, que ficou mantida. DECISÃO FINAL: Com base na recomendação da Conitec, o secretário de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde do Ministério da Saúde, no uso de suas atribuições legais, decidiu pela não incorporação, no âmbito do Sistema Único de Saúde - SUS, dos opioides fortes (fentanila, oxicodona e buprenorfina) para o tratamento de dor crônica.


Assuntos
Humanos , Oxicodona/uso terapêutico , Buprenorfina/uso terapêutico , Fentanila/uso terapêutico , Dor Crônica/tratamento farmacológico , Sistema Único de Saúde , Brasil , Análise Custo-Benefício
13.
Psychopharmacology (Berl) ; 238(9): 2503-2514, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34106317

RESUMO

AIMS: Intravenous (IV) misuse of the µ opioid analgesic oxymorphone has caused significant public health harms; however, no controlled data on its IV abuse potential are available. The primary aims of this pilot study were to directly compare IV oxymorphone to IV oxycodone, morphine, and hydromorphone on a subjective measure of drug liking and to assess relative potency. METHODS: Participants (n = 6) with opioid use disorder, physical dependence, and current IV use completed this two-site, within-subject, double-blind, placebo-controlled, inpatient pilot study. During each session, one IV dose (mg/70 kg) was administered: oxymorphone (1.8, 3.2, 5.6, 10, 18, 32), hydromorphone (1.8, 3.2, 5.6, 10, 18), oxycodone (18, 32, 56), morphine (18, 32), and placebo. Data were collected before and for 6 h after dosing. Primary outcomes included safety/physiological effects, subjective reports of drug liking, and relative potency estimates. RESULTS: All active test drugs produced prototypical, dose-related µ opioid agonist effects (e.g., miosis). Oxymorphone was more potent than the comparator opioids on several measures, including drug liking and respiratory depression (p < 0.05). Across abuse-related subjective outcomes, oxymorphone was 2.3-2.8-fold more potent than hydromorphone and 12.5-14-fold more potent than oxycodone (p < 0.05). CONCLUSIONS: Despite the relatively small sample size, this pilot study detected robust oxymorphone effects. Oxymorphone was far more potent than the comparator opioids, particularly on abuse potential outcomes. Overall, these findings may help explain surveillance reports that demonstrate, after adjusting for prescription availability, oxymorphone is injected at the highest frequency, relative to other prescription opioids.


Assuntos
Transtornos Relacionados ao Uso de Opioides , Oximorfona , Analgésicos Opioides/efeitos adversos , Humanos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona , Oximorfona/efeitos adversos , Projetos Piloto
14.
J Pharm Biomed Anal ; 203: 114171, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087551

RESUMO

INTRODUCTION: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method. AIMS: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices. METHODS: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM). RESULTS: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84-124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83-122%. CONCLUSION: A LC-MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS.


Assuntos
Oximorfona , Tramadol , Idoso , Cromatografia Líquida , Fentanila/análogos & derivados , Humanos , Morfinanos , Oxicodona , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Tramadol/análogos & derivados
15.
ACS Chem Neurosci ; 12(10): 1777-1790, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33950681

RESUMO

Opioids and benzodiazepines have complex drug-drug interactions (DDIs), which serve as an important source of adverse drug effects. In this work, we predicted the DDI between oxycodone (OXY) and diazepam (DZP) in the human body by applying in silico pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation. First, we studied the PK interaction between OXY and DZP with a physiologically based pharmacokinetic (PBPK) model. Second, we applied molecular modeling techniques including molecular docking, molecular dynamics (MD) simulation, and the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) free energy method to predict the PD-DDI between these two drugs. The PK interaction between OXY and DZP predicted by the PBPK model was not obvious. No significant interaction was observed between the two drugs at normal doses, though very high doses of DZP demonstrated a non-negligible inhibitory effect on OXY metabolism. On the contrary, the molecular modeling study shows that DZP has potential to compete with OXY at the same binding pocket of the active µ-opioid receptor (MOR) and κ-opioid receptor (KOR). MD simulation and MM-PBSA calculation results demonstrated that there is likely a synergetic effect between OXY and DZP binding to opioid receptors, as OXY is likely to target the active MOR while DZP selectively binds to the active KOR. Thus, pharmacokinetics contributes slightly to the DDI between OXY and DZP although an overdose of DZP has been brought to attention. Pharmacodynamics is likely to play a more important role than pharmacokinetics in revealing the mechanism of DDI between OXY and DZP.


Assuntos
Oxicodona , Preparações Farmacêuticas , Simulação por Computador , Diazepam/farmacologia , Interações Medicamentosas , Humanos , Modelos Biológicos , Simulação de Acoplamento Molecular
16.
Clin Pharmacol Ther ; 110(4): 1004-1010, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34032277

RESUMO

Opioids are commonly prescribed following childbirth, but data are lacking on trends in postpartum opioid prescribing over time. We examined whether a highly publicized 2006 case report questioning the safety of codeine during lactation was associated with changes in postpartum opioid prescribing. We conducted a cross-sectional time series analysis of all publicly funded prescriptions for opioids to postpartum women in Ontario, Canada, from April 1, 2000, to March 31, 2017. The intervention was the publication of a case report in 2006 attributing the death of a breastfeeding neonate to maternal codeine use. The primary outcome was the rate of opioid prescribing to postpartum women. Among postpartum women eligible for prescription drug coverage, 17.5% filled an opioid prescription in the third quarter of 2006 (immediately prior to the intervention), with codeine representing 89.8% of all prescriptions. By the fourth quarter of 2010, only 12.2% of postpartum women filled an opioid prescription, representing a decline of 30% (P < 0.01), with codeine representing 71.9% of all prescriptions. During this period, we observed sizeable relative increases in the proportion of opioid prescriptions filled for morphine, hydromorphone, and oxycodone. By 2017, among women prescribed opioids post partum, 39.0% filled a prescription for codeine, while the remainder filled prescriptions for oxycodone (18.6%), morphine (25.5%), and hydromorphone (16.9%). A highly publicized case report questioning the safety of maternal codeine use during breastfeeding was associated with significant changes in opioid prescribing to postpartum women, including a decline in overall opioid prescribing and a shift from codeine to stronger opioids.


Assuntos
Analgésicos Opioides/uso terapêutico , Codeína/uso terapêutico , Lactação , Período Pós-Parto , Padrões de Prática Médica/tendências , Adulto , Aleitamento Materno , Feminino , Humanos , Hidromorfona/uso terapêutico , Recém-Nascido , Análise de Séries Temporais Interrompida , Morfina/uso terapêutico , Ontário , Oxicodona/uso terapêutico , Gravidez , Adulto Jovem
17.
Nihon Yakurigaku Zasshi ; 156(3): 128-133, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33952838

RESUMO

In Japan, 14 opioids with a variety of dosage forms, such as oral preparation, injection, transdermal patch, transmucosal and suppository are clinically available as analgesics, and their use properly depends on the type and degree of pain and patient condition. Fundamentally, strong opioids are restricted to only treatment of cancer pain, while the indication of fentanyl transdermal patch and oxycodone tamper resistant tablet has been expanded for the treatment of non-cancer chronic pain. In US, the additional indication of opioids to chronic pain has led to prolongation and generalization of opioid use, which may contribute to "opioid crisis" in which opioid-related death strikingly increased due to opioid abuse and overdose-induced respiratory depression. Currently, opioid-related abuse and death have not been evident in Japan, while abuse of antitussive opioids (codeine and dihydrocodeine) are recently seen as a problem, which may suggest the sense of guilt to abuse legally-uncontrolled drugs (ex. weak opioids, antitussives or hypnotics) may be low in Japanese. In this review, I will summarize current status and issues in clinical use of opioid analgesics, and will talk about the necessity and expectation for development of novel analgesics without serious adverse reactions such as addiction and respiratory depression.


Assuntos
Analgésicos Opioides , Dor Crônica , Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Humanos , Japão , Oxicodona/efeitos adversos
18.
Psychopharmacology (Berl) ; 238(7): 1857-1866, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33988725

RESUMO

RATIONALE: Preclinical studies demonstrate that the NK1 receptor is involved in opioid reinforcement and withdrawal expression. Few studies have examined the impact of treatment with NK1 antagonists on opioid response in humans. OBJECTIVE: To explore the potential for a selective NK1 antagonist, tradipitant, to attenuate the abuse liability and reinforcing and analgesic effects of oxycodone in opioid-experienced individuals. METHODS: Participants with recreational opioid use, but without opioid physical dependence, were enrolled as inpatients for ~6 weeks (n = 8). A within-subject, double-blind, randomized, placebo-controlled, crossover design was employed. The pharmacodynamic response to intranasal oxycodone across a range of doses (0 to 30 mg) was examined during two counterbalanced maintenance periods (tradipitant 0 or 85 mg/bid). Oxycodone self-administration was assessed with a modified progressive ratio procedure, and analgesia was assessed with the cold pressor test. RESULTS: Oxycodone produced significant and dose-related increases on a broad array of prototypic opioid measures, including subjective ratings related to abuse liability (e.g., liking) and physiological outcomes (i.e., expired CO2). Oxycodone self-administration increased with increasing dose, as did analgesia. Tradipitant largely did not alter any of these effects of oxycodone, with the exception of producing a reduction in ratings of desire for opioids. CONCLUSIONS: Given that the vast majority of oxycodone effects were unchanged by tradipitant, these data do not provide support for the utility of NK1 antagonists as a potential treatment for opioid use disorder.


Assuntos
Analgésicos Opioides/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/administração & dosagem , Medição da Dor/efeitos dos fármacos , Receptores da Neurocinina-1 , Administração Intranasal , Adolescente , Adulto , Analgesia/métodos , Analgesia/psicologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/psicologia , Medição da Dor/métodos , Medição da Dor/psicologia , Reforço Psicológico , Autoadministração , Resultado do Tratamento , Adulto Jovem
19.
Pain Res Manag ; 2021: 2542010, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055117

RESUMO

Background: Acute postoperative pain delays recovery and increases morbidity and mortality. Opioid therapy is effective but is accompanied by adverse reactions. Patient-controlled analgesia (PCA) enables self-administration of analgesics. Oral-PCA is a safe and beneficial alternative to intravenous (IV) PCA. We have developed a novel Oral-PCA device, which enables self-administration of solid pills to the patient's mouth. This is a retrospective study comparing the effectiveness and usability of this novel Oral-PCA with those of IV-PCA. Methods: Medical records of patients who received PCA following gynecology and orthopedic surgeries were analyzed. The control cohort (n = 61) received oxycodone by IV-PCA. The test cohort (n = 44) received oxycodone by Oral-PCA via the PCoA Acute device. Outcome measures include the Numeric Rating Scale (NRS) score at rest and movement, side effects, technical difficulties, bolus dose administered, and bolus dose requested. Results: Patient demographics, initial NRS, and PCA duration were comparable between cohorts. NRS reduction in rest and movement was stronger in the Oral-PCA cohort (rest: 1.61 and 2.27, P = 0.077; movement: 2.05 and 2.84, P = 0.039), indicating better pain control and mobility for Oral-PCA. Side effect rates were comparable between cohorts (9% and 11% of patients who experienced side effects, P = 1.000). The rate of technological difficulties was higher in the Oral-PCoA cohort (19.7% and 36.4%, P = 0.056). The mean total bolus dose administered to patients was comparable in both cohorts (18.32 mg and 21.14 mg oxycodone, P = 0.270). However, the mean total boluses requested by patients during lockout intervals were lower in the Oral-PCA cohort (12.8 mg and 6.82 mg oxycodone, P = 0.004), indicating better pain control. Conclusions: Oral-PCA by using PCoA® Acute provides pain control and usability which is noninferior to the IV-PCA, as well as superior to pain reduction in rest and movement. These results, along with the noninvasiveness, medication flexibility, and reduced cost, suggest the potential of Oral-PCA, by using PCoA Acute, to replace IV-PCA for postoperative analgesia.


Assuntos
Administração Intravenosa , Administração Oral , Analgesia Controlada pelo Paciente/instrumentação , Analgésicos Opioides/administração & dosagem , Oxicodona/administração & dosagem , Manejo da Dor/instrumentação , Dor Pós-Operatória/tratamento farmacológico , Administração Intravenosa/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
20.
Viruses ; 13(5)2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946474

RESUMO

Human immunodeficiency virus (HIV) is associated with neuroendocrine dysfunction which may contribute to co-morbid stress-sensitive disorders. The hypothalamic-pituitary-adrenal (HPA) or -gonadal (HPG) axes are perturbed in up to 50% of HIV patients. The mechanisms are not known, but we have found the HIV-1 trans-activator of transcription (Tat) protein to recapitulate the clinical phenotype in male mice. We hypothesized that HPA and/or HPG dysregulation contributes to Tat-mediated interactions with oxycodone, an opioid often prescribed to HIV patients, in females. Female mice that conditionally-expressed the Tat1-86 protein [Tat(+) mice] or their counterparts that did not [Tat(-) control mice] were exposed to forced swim stress (or not) and behaviorally-assessed for motor and anxiety-like behavior. Some mice had glucocorticoid receptors (GR) or corticotropin-releasing factor receptors (CRF-R) pharmacologically inhibited. Some mice were ovariectomized (OVX). As seen previously in males, Tat elevated basal corticosterone levels and potentiated oxycodone's psychomotor activity in females. Unlike males, females did not demonstrate adrenal insufficiency and oxycodone potentiation was not regulated by GRs or CRF-Rs. Rather OVX attenuated Tat/oxycodone interactions. Either Tat or oxycodone increased anxiety-like behavior and their combination increased hypothalamic allopregnanolone. OVX increased basal hypothalamic allopregnanolone and obviated Tat or oxycodone-mediated fluctuations. Together, these data provide further evidence for Tat-mediated dysregulation of the HPA axis and reveal the importance of HPG axis regulation in females. HPA/HPG disruption may contribute vulnerability to affective and substance use disorders.


Assuntos
Infecções por HIV/complicações , Infecções por HIV/virologia , HIV-1/fisiologia , Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/fisiopatologia , Oxicodona/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Ciclo Estral , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Camundongos , Atividade Motora , Sistemas Neurossecretores/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Pregnanolona/sangue , Pregnanolona/metabolismo , Esteroides/sangue
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