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The current opioid epidemic is one of the most profound public health crises facing the United States. Despite that it has been under the spotlight for years, available treatments for opioid use disorder (OUD) and overdose are limited to opioid receptor ligands such as the agonist methadone and the overdose reversing drugs such as naloxone. Vaccines are emerging as an alternative strategy to combat OUD and prevent relapse and overdose. Most vaccine candidates consist of a conjugate structure containing the target opioid attached to an immunogenic carrier protein. However, conjugate vaccines have demonstrated some intrinsic shortfalls, such as fast degradation and poor recognition by immune cells. To overcome these challenges, we proposed a lipid-PLGA hybrid nanoparticle (hNP)-based vaccine against oxycodone (OXY), which is one of the most frequently misused opioid analgesics. The hNP-based OXY vaccine exhibited superior immunogenicity and pharmacokinetic efficacy in comparison to its conjugate vaccine counterpart. Specifically, the hNP-based OXY vaccine formulated with subunit keyhole limpet hemocyanin (sKLH) as the carrier protein and aluminum hydroxide (Alum) as the adjuvant (OXY-sKLH-hNP(Alum)) elicited the most potent OXY-specific antibody response in mice. The induced antibodies efficiently bound with OXY molecules in blood and suppressed their entry into the brain. In a following dose-response study, OXY-sKLH-hNP(Alum) equivalent to 60 µg of sKLH was determined to be the most promising OXY vaccine candidate moving forward. This study provides evidence that hybrid nanoparticle-based vaccines may be superior vaccine candidates than conjugate vaccines and will be beneficial in treating those suffering from OUD.
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Nanopartículas , Oxicodona , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Oxicodona/farmacocinética , Oxicodona/inmunología , Oxicodona/administración & dosificación , Oxicodona/química , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Lípidos/química , Ratones , Femenino , Vacunas/farmacocinética , Vacunas/inmunología , Vacunas/administración & dosificación , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Recent studies have proposed the use of dual orexin receptor antagonists, such as suvorexant, for the treatment of opioid use disorder (OUD) and opioid-related sleep disturbances because of orexin's role in sleep-wake regulation and addiction. Accumulating evidence suggests that orexin is also an important modulator of respiratory function, raising the possibility of adverse respiratory events when combining orexin antagonists and opioids. The aim of the present study was to investigate the effects of suvorexant, alone or in combination with the opioid oxycodone, on pulmonary ventilation in male rats. METHODS: Adult, male Sprague Dawley rats received treatments with vehicle, oxycodone (3 and 10mg/kg, i.p.) or suvorexant (10 and 18mg/kg, i.p.), and respiratory measures were obtained using whole-body plethysmography. We then tested the effects of a combination of suvorexant (10 and 18mg/kg, i.p.) and the highest dose of oxycodone that did not suppress respiration alone (3mg/kg, i.p). RESULTS: Oxycodone induced respiratory depression at 10mg/kg, but not 3.0mg/kg; as evident by significant decreases in minute volume (mls/min) and tidal volume (mls). Suvorexant alone did not alter any respiratory measures at the doses tested. When combined, 18mg/kg (but not 10mg/kg) suvorexant plus an ineffective dose of oxycodone significantly decreased minute and tidal volume compared with vehicle and either drug alone, whereas respiratory frequency was significantly decreased compared with vehicle. CONCLUSIONS: Our findings show that suvorexant, at a dose associated with sleep promotion and blockade of oxycodone self-administration, robustly enhanced oxycodone-induced respiratory depression in male rats.
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Background: Multimodal analgesia plays a key role in enhanced recovery after surgery. Herein, we describe a trial protocol investigating the effects of oxycodone-vs. sufentanil-based patient-controlled analgesia in combination with quadratus lumborum block (QLB) vs. transverse abdominis plane block (TAPB) on quality of recovery following major laparoscopic gastrointestinal surgery. Methods: and analysis: This is a prospective, randomized, controlled clinical trial with a 2 × 2 factorial design. A total of 120 adult patients undergoing laparoscopic major gastrointestinal surgery will be randomized, in a 1:1:1:1 ratio, to receive one of two patient-controlled analgesia regimens (based on oxycodone or sufentanil) and one of two regional blocks (QLB or TAPB). The primary outcome measure of this trial is the quality of recovery at 24 h after surgery, assessed using the 15-item quality of recovery (QoR-15) scale. The secondary outcomes include QoR-15 scores at 48 and 72 h after surgery; visceral and incisional pain at rest and while coughing at 1, 6, 24 and 48 h postoperatively; analgesic consumption within 0-24 h and 24-48 h postoperatively; need for rescue analgesia; postoperative flatus time; postoperative adverse events (sedation, nausea and vomiting, use of antiemetics, respiratory depression, and dizziness); and length of postoperative hospital stay. Discussion: The results of this trial will provide evidence for the optimal multimodal analgesic strategy to improve the quality of recovery for patients undergoing laparoscopic major gastrointestinal surgery. Trial registration: This trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn, identifier: ChiCTR2400080766).
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Oxycodone is widely used for pain management and acts via binding to mu- and kappa opioid receptors. It was shown that extended oxycodone usage can result from the demyelination and degeneration of neurons through the stress response, which triggers apoptotic signaling pathways. The striatum and cerebellum are recognized as significant contributors to addiction; however, there is no report on the effect of oxycodone on the cerebellum and striatum and motor coordination. We treated rats daily with oxycodone at 15 mg/kg doses for thirty days. Motor performance and electromyography activity were then evaluated. Stereological methods were performed to assess the number of neurons in the cerebellum and striatum as well as immunohistochemistry for microgliosis and astrogliosis. Furthermore, the Sholl analysis method was utilized to evaluate the cellular structure of both microglia and astrocytes. Results of the rotarod test for motor coordination show no significant (P < 0.05) difference between the oxycodone subjects and those in the control group. In addition, open-field assessments indicated that the application of oxycodone did not alter the amount of distance covered (as an indicator of locomotion) or time spent in the central area (as an indicator of anxiety) (P < 0.001). The electromyography (EMG) test result showed that oxycodone caused a delay in the reaction of the muscular nerves (P < 0.001). Data and results from our experiment revealed that administering oxycodone did not affect astrogliosis and the number of neurons in the cerebellum and striatum (P < 0.05). In contrast, it altered neuromuscular function. In addition, oxycodone administration activated microglia in the cerebellum and striatum. In conclusion, we encourage more research on the adverse effects of oxycodone on the brain.
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This case report describes the novel use of oxybutynin and acetaminophen as a substitution for oxycodone for the express purpose of diverting oxycodone in a hospital-based post-anesthesia care unit (PACU). The report outlines how the physical properties and pharmacologic effects of non-controlled medications in the PACU, like oxybutynin, can be visually mistaken and even mimic the side effects of controlled substances like oxycodone. Substituting oxybutynin for controlled substances can circumvent diversion surveillance software. The authors describe how the diversion was identified and the process improvements that should be implemented for proactive identification moving forward.
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A single-blind, randomized controlled trial comparing oxycodone and fentanyl for patient-controlled intravenous analgesia (PCIA) after laparoscopic hysteromyomectomy found comparable pain relief between the two groups. The study included 60 participants, with NRS scores for pain at rest and when moving showing no significant differences between oxycodone and fentanyl groups at various time points postoperatively. Self-rating depression scale scores were also similar between the groups at 48 h. However, patients' satisfaction with PCIA was higher in the oxycodone group, with 73.3% reporting being very satisfied compared to 36.7% in the fentanyl group. Additionally, the oxycodone group had fewer incidences of headaches within 48 h postoperatively compared to the fentanyl group. These findings suggest that oxycodone may offer comparable pain relief, higher patient satisfaction, and fewer headaches for patients undergoing laparoscopic hysteromyomectomy compared to fentanyl, making it a suitable option for postoperative pain management in this population.Clinical trial registration number The study was registered with CHICTR.org, ChiCTR2100051924.
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Analgesia Controlada por el Paciente , Analgésicos Opioides , Fentanilo , Laparoscopía , Oxicodona , Dolor Postoperatorio , Humanos , Fentanilo/administración & dosificación , Fentanilo/uso terapéutico , Oxicodona/administración & dosificación , Oxicodona/uso terapéutico , Femenino , Analgesia Controlada por el Paciente/métodos , Laparoscopía/efectos adversos , Dolor Postoperatorio/tratamiento farmacológico , Adulto , Método Simple Ciego , Persona de Mediana Edad , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Satisfacción del Paciente , Dimensión del Dolor , Miomectomía Uterina/efectos adversos , Miomectomía Uterina/métodosRESUMEN
Opioid use disorder is marked by a progressive change in the motivation to administer the drug even in the presence of negative consequences. After long periods of abstinence, the urge to return to taking the drug intensifies over time, known as incubation of craving. Conditioned responses to drug-related stimuli, can acquire motivational properties and exert control over motivated behaviors leading to relapse. Although, preclinical data suggest that the behavioral expression of opioid use is similar between male and female rodents, we do not have conclusive results on sex differences on craving and relapse across abstinence periods. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and ex vivo electrophysiology, we assessed synaptic strength and glutamate release probability in this pathway, as well as NAcSh medium spiny neurons (MSN) intrinsic excitability, in slices from rats which were subjected to either 1 (acute) or 14 (prolonged) days of forced abstinence after self-administration. Our results revealed no sex differences in oxycodone self-administration or somatic withdrawal symptoms following acute abstinence. However, we found a sex-specific enhancement in cue-induced relapse after prolonged, but not acute, abstinence from oxycodone self-administration, with females exhibiting higher relapse rates. Notably, prolonged abstinence led to similar increases in synaptic strength at PVT-NAcSh inputs compared to saline controls in both sexes, which was not observed after acute abstinence. Thus, prolonged abstinence results in a time-dependent increase in PVT-NAcSh synaptic strength and sex-specific effects on cue-induced relapse rates. These findings suggest that prolonged abstinence leads to significant synaptic changes, contributing to heightened relapse vulnerability, highlighting the need for targeted therapeutic strategies in opioid use disorder.
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Intravenous injection of pulverized tablet formulations intended for oral use may lead to pulmonary foreign body granulomatosis, a rare and serious condition. This case report details an unusual case of pulmonary micronodular disease resulting from the injection of crushed hydrocodone bitartrate and acetaminophen tablets via a peripherally inserted central catheter (PICC). A 62-year-old female on total parenteral nutrition presented with progressive dyspnea on exertion. A high-resolution CT scan revealed bilateral diffuse pulmonary nodules. Bronchoscopy and lung biopsy confirmed the presence of granulomatous inflammation with foreign-body giant cells, consistent with a foreign-body reaction. A detailed history uncovered that the patient had been administering crushed oral medication through her PICC line for better pain control. This case report adds to the literature by documenting the severe consequences of PICC line misuse and enhancing the understanding of lung granulomatous reactions from foreign materials.
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Oxycodone, often used as an analgesic, is a potent opioid. While its effectiveness has been proven in the control of moderate to acute pain, excessive use of oxycodone imposes heart failure, heart palpitations, reduction of red blood cells, bone pain, and even death. Therefore, monitoring the oxycodone concentration in blood is vital for emergency care. For this purpose, a novel electrochemical sensor was designed based on a glassy carbon electrode modified with mesoporous g-C3N4 (M-C3N4), carbon nano-onions doped with nitrogen (N-CNO), and gold nanoparticles. At first, the SEM and XRD techniques were employed to characterize prepared M-C3N4 and N-CNO samples. The electro-oxidation behavior of the oxycodone was evaluated by cyclic and differential pulse voltammetric methods. Based on the influence of the potential scanning rate and solution pH on the voltammetric response of oxycodone oxidation, a redox mechanism was proposed. A 16 nM detection limit was acquired for the oxycodone analysis with a linear response in the 0.05-150 µM range. This sensor showed a remarkable ability for oxycodone detection in plasma samples. The long-term stability, superior selectivity, and reproducibility of this sensor prove its ability to measure oxycodone accurately and precisely in authentic spices.
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Técnicas Electroquímicas , Oro , Nanopartículas del Metal , Oxicodona , Oxicodona/sangre , Oxicodona/química , Nanopartículas del Metal/química , Técnicas Electroquímicas/métodos , Oro/química , Humanos , Oxidación-Reducción , Límite de Detección , Porosidad , Electrodos , Analgésicos Opioides/sangre , Analgésicos Opioides/análisis , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The influences of Oxycodone (OXY) combined with Paclitaxel (PTX) on breast cancer cells are unclear. The present study aimed to examine the effects of OXY combined with PTX on the proliferation, apoptosis, and migration of human breast cancer SKBR3 cells and the underlying mechanism. METHODS: The proliferation, apoptosis and invasion of SKBR3 cells were assessed by CCK-8, colony formation assay, flowcytometric, Transwell assay and scratch assays, respectively. In addition, Western blotting was used to detect the expression of related proteins in these cells. The autophagic bodies were observed under a transmission electron microscope. RESULTS: OXY (0.25, 0.5 and 1 mM) significantly inhibited the viability, colony-forming, migration, and invasion of SKBR3 cells as compared to the control group. Furthermore, OXY (0.25, 0.5 and 1 mM) markedly induced the apoptosis of SKBR3 cells and the levels of apoptosis-related proteins. In addition, OXY (0.25, 0.5 and 1 mM) and PTX inhibited the proliferation of SKBR3 cells synergistically as compared to PTX group in vitro. Moreover, OXY (0.25, 0.5 and 1 mM) significantly elevated the PTX-induced apoptosis in SKBR3 cells via downregulating the expression of N-cadherin, Becline-1 LC3-â ¡, p-Akt and p-mTOR and upregulating E-cadherin expression. Compared with the control group, OXY (1 mM) treatment induced autophagy in SKBR3 cells. CONCLUSIONS: The present study indicates that OXY can enhance the antitumor effect of PTX on breast cancer in vitro. Hence, the combination of OXY with PTX may serve as a potential strategy for the treatment of breast cancer.
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Apoptosis , Neoplasias de la Mama , Movimiento Celular , Proliferación Celular , Oxicodona , Paclitaxel , Humanos , Paclitaxel/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Línea Celular Tumoral , Oxicodona/farmacología , Movimiento Celular/efectos de los fármacos , Sinergismo Farmacológico , Supervivencia Celular/efectos de los fármacos , Autofagia/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Reproducibilidad de los Resultados , Western BlottingRESUMEN
N6-methyladenosine (m6A) methylation is a vital epigenetic mechanism associated with drug addiction. However, the relationship between m6A modification and oxycodone rewarding is less well explored. Based on an open field test, the present study evaluated oxycodone rewarding using chromatin immunoprecipitation PCR, immunofluorescence, and RNA sequencing. A marked increase in METTL14 protein and a decrease in PP1α protein due to oxycodone abundance in the striatal neurons were observed in a dose- and time-dependent manner. Oxycodone markedly increased LSD1 expression, and decreased H3K4me1 expression in the striatum. In the open field test, intra-striatal injection of METTL14 siRNA, HOTAIR siRNA, or LSD1 shRNA blocked oxycodone-induced increase in locomotor activity. The downregulation of PP1α was also inhibited after treatment with METTL14/HOTAIR siRNA and LSD1 shRNA. Enhanced binding of LSD1 with CoRest and of CoRest with the PP1α gene induced by oxycodone was also reversed by LSD1 shRNA. In addition, H3K4me1 demethylation was also blocked by the treatment. In summary, the investigation confirmed that METTL14-mediated upregulation of HOTAIR resulted in the repression of PP1α, which in turn facilitated the recruitment of LSD1, thus catalyzing H3K4me1 demethylation and promoting oxycodone addiction.
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Metiltransferasas , Oxicodona , ARN Largo no Codificante , Animales , Masculino , Ratones , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Desmetilación , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Histonas/metabolismo , Lisina/análogos & derivados , Metiltransferasas/metabolismo , Metiltransferasas/genética , Ratones Endogámicos C57BL , Oxicodona/farmacología , Proteína Fosfatasa 1/metabolismo , Proteína Fosfatasa 1/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/genética , Regulación hacia ArribaRESUMEN
Over the past decades, extensive preclinical research has been conducted to develop vaccinations to protect against substance use disorder caused by opioids, nicotine, cocaine, and designer drugs. Morphine or fentanyl derivatives are small molecules, and these compounds are not immunogenic, but when conjugated as haptens to a carrier protein will elicit the production of antibodies capable of reacting specifically with the unconjugated hapten or its parent compound. The position of the attachment in opioid haptens to the carrier protein will influence the specificity of the antiserum produced in immunized animals with the hapten-carrier conjugate. Immunoassays for the determination of opioid drugs are based on the ability of drugs to inhibit the reaction between drug-specific antibodies and the corresponding drug-carrier conjugate or the corresponding labelled hapten. Pharmacological studies of the hapten-carrier conjugates resulted in the development of vaccines for treating opioid use disorders (OUDs). Immunotherapy for opioid addiction includes the induction of anti-drug vaccines which are composed of a hapten, a carrier protein, and adjuvants. In this review we survey the design of opioid haptens, the development of the opioid radioimmunoassay, and the results of immunotherapy for OUDs.
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Analgésicos Opioides , Haptenos , Inmunoterapia , Trastornos Relacionados con Opioides , Haptenos/inmunología , Humanos , Animales , Inmunoterapia/métodos , Trastornos Relacionados con Opioides/inmunología , Analgésicos Opioides/uso terapéutico , Vacunas/inmunología , RadioinmunoensayoRESUMEN
OBJECTIVES: A substantial proportion of patients with chronic noncancer pain (CNCP) are treated with tapentadol (TAP) or oxycodone/naloxone (OXN) to improve their perceived physical and mental health over time. METHODS: A cross-sectional study was conducted in 135 CNCP outpatients with usual prescribing (TAP: n = 58, OXN: n = 77) at a tertiary-care Spanish Hospital to compare health-related quality-of-life (HRQoL) records. Health utility was derived from the EQ-5D-3L. Regression models were performed to search for other HRQoL determinants. Pain intensity, relief, analgesic prescription, adverse events, inpatient stays, emergency department visits, and change to painkiller prescriptions were registered from electronic records. RESULTS: Health utility (0.43 ± 0.24 scores, from -0.654 to 1) was similar for both opioids, although TAP showed a significantly low daily opioid dose requirement, neuromodulators use, and constipation side effect compared with OXN. After multivariable adjustment, the significant predictors of impaired HRQoL were pain intensity (ß = -0.227, 95% CI -0-035 to -0.005), number of adverse events (ß = -0.201, 95% CI -0.024 to -0.004), and opioid daily dose (ß = -0.175, 95% CI -0.097 to -0.012). Male sex (ß = -0.044) and pain relief (ß = 0.158) should be taken into account for future studies. CONCLUSIONS: HRQoL was similar for TAP and OXN in real-world patients with CNCP, albeit with a TAP opioid-sparing effect. More work is needed to explore HRQoL determinants in relation to long-term opioid use in CNCP.
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Background: Postoperative pain (POP) is one of the most common and most important types of pain. Objectives: The aim of this study was to compare the effects of pre-emptive oxycodone, diclofenac, and gabapentin on postoperative pain (POP) among patients with tibia fracture surgery. Materials and Methods: This double-blind three-group randomised controlled trial was conducted in 2023. Participants were 111 candidates for tibia fracture surgery under general anaesthesia. They were randomly allocated to oxycodone, gabapentin, and diclofenac groups through block randomisation. Baseline arterial oxygen saturation, heart rate, and blood pressure were documented before surgery and POP and sedation status were measured during postoperative recovery and 2, 4, 6, 12, and 24 h after surgery. Postoperative opioid analgesic use was also documented. The data were analysed using the SPSS software (v. 20.0) at a significance level of less than 0.05. Results: Groups did not significantly differ from each other respecting participants' baseline age, gender, body mass index, arterial oxygen saturation, heart rate, blood pressure, and surgery duration (P > 0.05). Moreover, there were no significant differences among the groups respecting POP and sedation status at different measurement time points (P > 0.05), except for six hours after surgery at which the POP mean score in the gabapentin group was significantly less than the other two groups (P = 0.001). Among-group differences respecting postoperative use of opioid analgesics and medication side effects were also insignificant (P > 0.05). Conclusion: Pre-emptive oxycodone, diclofenac, and gabapentin significantly reduce POP among patients with tibia fracture surgery, though gabapentin may produce more significant analgesic effects. All these three medications can be used for pre-emptive analgesia. Of course, the best pre-emptive analgesic agent is determined based on the opinion of the treating physician.
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Myocardial injury and cardiovascular dysfunction are the most common complications of sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in myocardial injury of lipopolysaccharide-induced sepsis and its related signalling pathways. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout mice, as well as H9c2 cardiomyocytes cultures treated with lipopolysaccharide (LPS) were used as models of septic myocardial injury. H9c2 cardiomyocytes culture showed that oxycodone protected cells from pyroptosis induced by LPS. Mice model confirmed that oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function demonstrated by increased ejection fraction (EF) and fractional shortening (FS), as well as decreased cardiac troponin I (cTnI) and creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including: Nod-like receptor protein 3 (NLRP3), Caspase 1, Apoptosis-associated speck-like protein contain a CARD (ASC), and Gasdermin D (GSDMD). These changes were mediated by Nrf2 and heme oxygenase-1 (HO-1) because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings yielded that oxycodone therapy reduces LPS-induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signalling pathway in vivo and in vitro.
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Hemo-Oxigenasa 1 , Inflamación , Lipopolisacáridos , Miocitos Cardíacos , Factor 2 Relacionado con NF-E2 , Oxicodona , Piroptosis , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Piroptosis/efectos de los fármacos , Lipopolisacáridos/toxicidad , Transducción de Señal/efectos de los fármacos , Ratones , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Hemo-Oxigenasa 1/metabolismo , Oxicodona/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Línea Celular , Ratas , Oxidación-Reducción/efectos de los fármacos , Ratones Noqueados , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacosRESUMEN
Background: The effect of oxycodone as an opioid receptor agonist on immune function is still controversial. In this study, we investigated the possible effects of oxycodone on immune function in mice and its possible mechanisms of action. Methods: By repeated intraperitoneal injections of 25 mg/kg morphine and 5 mg/kg, 20 mg/kg, and 60 mg/kg oxycodone, we assessed possible changes in the number of splenic lymphocytes and inflammatory cytokines in the serum of mice. CD4+ T cells and CD8+ T cells were sorted from the spleen to observe whether the expression levels of opioid receptors and downstream signals were altered. Results: Repeated administration of oxycodone at a dose above 20 mg/kg resulted in significant weight loss. Repeated administration of oxycodone exhibits significant dose-dependent reduction in CD4+ T cells, with little effect on CD8+ T cells and little effect on inflammatory cytokine levels. Low- and intermediate-dose oxycodone increased the mRNA expression level of MOR, KOR, and DOR to varying degrees. Moreover, oxycodone increases the mRNA expression levels of the TLR4 signaling pathway to varying degrees. Conclusion: Repeated intraperitoneal injection of oxycodone induces immunosuppression in mice.
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Opioid use disorder (OUD) is a serious health problem that may lead to physical dependence, in addition to affective disorders. Preclinical models are essential for studying the neurobiology of and developing pharmacotherapies to treat these problems. Historically, chronic morphine injections have most often been used to produce opioid-dependent animals, and withdrawal signs indicative of dependence were precipitated by administering an opioid antagonist. In the present studies, we have developed and validated a model of dependence on oxycodone (a widely prescribed opioid) during spontaneous withdrawal in male and female C57BL/6J mice. Dependence was induced by chronically administering oxycodone through osmotic minipumps at different doses for 7 days. Somatic withdrawal signs were measured after 3, 6, 24, and 48 h following minipump removal. Additionally, sensitivity to mechanical, thermal, and cold stimuli, along with anxiety-like behavior, were also measured. Our results indicated that spontaneous withdrawal following discontinuation of oxycodone produced an increase in total withdrawal signs after 60 and 120 mg/kg/day regimens of oxycodone administration. These signs were reversed by the administration of clinically approved medications for OUD. In general, both female and male mice showed similar profiles of somatic signs of spontaneous withdrawal. Spontaneous withdrawal also resulted in mechanical and cold hypersensitivity lasting for 24 and 14 days, respectively, and produced anxiety-like behaviors after 2 and 3 weeks following oxycodone removal. These results help validate a new model of oxycodone dependence, including the temporally distinct emergence of somatic, hyperalgesic, and anxiety-like behaviors, potentially useful for mechanistic and translational studies of opioid dependence.
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Analgésicos Opioides , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Oxicodona , Síndrome de Abstinencia a Sustancias , Animales , Oxicodona/administración & dosificación , Oxicodona/farmacología , Femenino , Masculino , Ratones , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Analgésicos Opioides/efectos adversos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológicoRESUMEN
Purpose: Oxycodone is a potent µ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery. Methods: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1. Results: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups. Conclusion: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2100052085).
Asunto(s)
Analgésicos Opioides , Laparoscopía , Oxicodona , Dolor Postoperatorio , Dolor Visceral , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Analgesia Controlada por el Paciente , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacología , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Método Doble Ciego , Flurbiprofeno/análogos & derivados , Laparoscopía/efectos adversos , Oxicodona/administración & dosificación , Oxicodona/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Sufentanilo/administración & dosificación , Dolor Visceral/tratamiento farmacológicoRESUMEN
Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.
Asunto(s)
Adenina , Analgésicos Opioides , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Osteoclastos , Insuficiencia Renal Crónica , Animales , Adenina/farmacología , Adenina/efectos adversos , Masculino , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Analgésicos Opioides/efectos adversos , Ratones , Inflamación , Remodelación Ósea/efectos de los fármacos , Oxicodona/farmacología , Huesos/metabolismo , Huesos/efectos de los fármacosRESUMEN
OBJECTIVES: Addressing the challenges of ambulatory surgery involves balancing effective pain relief with minimizing the side effects of pain medication. Due to the heightened risk of opioid abuse, Helsinki University Hospital (Finland) has had a stringent oxycodone prescription policy. This policy prompts an exploration into whether ambulatory surgery patients experience severe post-surgical pain and whether an increase in prescribed opioids would cause elevation in adverse effects. METHODS: This prospective cohort study, with a 1-week follow-up, included 111 adult ambulatory surgery patients (orthopaedics, urology). The patients documented their pain levels within the first postoperative week (using a numerical rating scale [NRS] of 0-10) and pain medication intake up to two days postoperatively. Furthermore, they completed a questionnaire assessing their satisfaction with pain relief, medication-related adverse effects, and adherence to instructions. Medication intake was cross-referenced with the provided instructions and prescriptions. RESULTS: A notable 56% of patients reported experiencing intense pain (NRS ≥5) within a week following surgery. Of these, 52% received a single dose of slow-release oxycodone (5-20 mg) at discharge for use on the night of surgery. Predominantly prescribed pain medications included a combination of paracetamol and codeine (64%) or ibuprofen (62%). Satisfaction rates were high, with 87% expressing satisfaction with pain medication given at hospital discharge and 90% expressing contentment with the prescribed medication. The most common adverse effects were tiredness/grogginess (45%), sleep disturbances (38%), nausea (37%), and constipation (27%). Also, 24% of patients self-reported deviations from medication instructions. A comparison of self-reported and instructed medications revealed that 14% exceeded prescribed dosages, and 28% opted for preparations different from those prescribed. Notably, patients who self-reported deviations from instructions differed from those objectively deviating from instructions. CONCLUSIONS: Although 56% of patients had intense pain, the majority expressed satisfaction with the provided pain relief. Instances of non-adherence to medication instructions were prevalent, often going unnoticed by the patients themselves.