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Frontiers in Pharmacology 2023Opioids are the leading cause of overdose death in the United States, accounting for almost 70,000 deaths in 2020. Deep brain stimulation (DBS) is a promising new...
Opioids are the leading cause of overdose death in the United States, accounting for almost 70,000 deaths in 2020. Deep brain stimulation (DBS) is a promising new treatment for substance use disorders. Here, we hypothesized that VTA DBS would modulate both the dopaminergic and respiratory effect of oxycodone. Multiple-cyclic square wave voltammetry (M-CSWV) was used to investigate how deep brain stimulation (130 Hz, 0.2 ms, and 0.2 mA) of the rodent ventral segmental area (VTA), which contains abundant dopaminergic neurons, modulates the acute effects of oxycodone administration (2.5 mg/kg, i.v.) on nucleus accumbens core (NAcc) tonic extracellular dopamine levels and respiratory rate in urethane-anesthetized rats (1.5 g/kg, i.p.). I.V. administration of oxycodone resulted in an increase in NAcc tonic dopamine levels (296.9 ± 37.0 nM) compared to baseline (150.7 ± 15.5 nM) and saline administration (152.0 ± 16.1 nM) (296.9 ± 37.0 vs. 150.7 ± 15.5 vs. 152.0 ± 16.1, respectively, = 0.022, = 5). This robust oxycodone-induced increase in NAcc dopamine concentration was associated with a sharp reduction in respiratory rate (111.7 ± 2.6 min vs. 67.9 ± 8.3 min; pre- vs. post-oxycodone; < 0.001). Continuous DBS targeted at the VTA ( = 5) reduced baseline dopamine levels, attenuated the oxycodone-induced increase in dopamine levels to (+39.0% vs. +95%), and respiratory depression (121.5 ± 6.7 min vs. 105.2 ± 4.1 min; pre- vs. post-oxycodone; = 0.072). Here we demonstrated VTA DBS alleviates oxycodone-induced increases in NAcc dopamine levels and reverses respiratory suppression. These results support the possibility of using neuromodulation technology for treatment of drug addiction.
PubMed: 37408764
DOI: 10.3389/fphar.2023.1199655 -
Behavioural Pharmacology Sep 2022The prescription opioid oxycodone is widely used for the treatment of pain in humans. Oxycodone misuse is more common among people with an anxiety disorder than those...
The prescription opioid oxycodone is widely used for the treatment of pain in humans. Oxycodone misuse is more common among people with an anxiety disorder than those without one. Therefore, oxycodone might be misused for its anxiolytic properties. We investigated if oxycodone affects anxiety-like behavior in adult male and female rats. The rats were treated with oxycodone (0.178, 0.32, 0.56, or 1 mg/kg), and anxiety-like behavior was investigated in the elevated plus-maze test. Immediately after the elevated plus-maze test, a small open field test was conducted to determine the effects of oxycodone on locomotor activity. In the elevated plus-maze test, oxycodone increased the percentage of time spent on the open arms, the percentage of open arm entries, time on the open arms, open arm entries, and the distance traveled. The males treated with vehicle had a lower percentage of open arm entries than the females treated with vehicle, and oxycodone treatment led to a greater increase in the percentage of open arm entries in the males than females. Furthermore, the females spent more time on the open arms, made more open arm entries, spent less time in the closed arms, and traveled a greater distance than the males. In the small open field test, treatment with oxycodone did not affect locomotor activity or rearing. Sex differences were observed; the females traveled a greater distance and displayed more rearing than the males. In conclusion, oxycodone decreases anxiety-like behavior in rats, and oxycodone has a greater anxiolytic-like effect in males than females.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Elevated Plus Maze Test; Female; Humans; Locomotion; Male; Maze Learning; Oxycodone; Rats
PubMed: 35947068
DOI: 10.1097/FBP.0000000000000690 -
British Journal of Clinical Pharmacology Apr 2023We describe the distribution of prescribers responsible for opioid initiation and maintenance (general practice, hospital prescribers and other prescribers) in Denmark.
AIMS
We describe the distribution of prescribers responsible for opioid initiation and maintenance (general practice, hospital prescribers and other prescribers) in Denmark.
METHODS
We leveraged data on opioid fills from a 20% sample of all Danes alive during 2000-2021.
RESULTS
Overall, general practitioners were responsible for most treatment initiation (74% during 2000-2021) and maintenance treatment (92%). However, while hospital prescribers initiated ≈20% of treatments during 2001-2012, this increased to 35% in 2021. Similarly, hospital prescriber's share of maintenance treatment increased from 5.9% during 2000-2012 to 13% in 2021. This change was particularly pronounced for morphine initiation (48% hospital prescribers in 2021 up from 38% during 2000-2010) and oxycodone initiation (78% up from 41%). Regarding choice of opioids, codeine use dropped markedly, in particular among hospital prescribers. Tramadol was consistently the most common first choice opioid in general practice (33% in 2021), whereas its use among hospital prescribers decreased (54% during 2000-2015 to 15% in 2021). Conversely, the proportion of treatment initiation by hospital prescribers composed of morphine and oxycodone increased to 38% and 42% in 2021, respectively.
CONCLUSIONS
General practice prescribes most opioids; however, hospital prescribers are increasingly responsible for opioid prescribing, in particular initiation of morphine and oxycodone.
Topics: Humans; Analgesics, Opioid; Oxycodone; Practice Patterns, Physicians'; Morphine; Drug Utilization; Drug Prescriptions
PubMed: 36366867
DOI: 10.1111/bcp.15595 -
Pain Reports Dec 2023Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and...
INTRODUCTION
Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and safety for ibuprofen and oxycodone were studied.
OBJECTIVE
Primary objectives were to AU2 evaluate if allelic variations would affect clinical effectiveness and adverse events (AEs) occurrence.
METHODS
This pragmatic prospective, observational cohort included children aged 4 to 16 years who were seen in a pediatric emergency department with an acute fracture and prescribed ibuprofen or oxycodone for at-home pain management. Saliva samples were obtained for genotyping of allelic variants, and daily telephone follow-up was conducted for 3 days. Pain was measured using the Faces Pain Scale-Revised.
RESULTS
We included 210 children (n = 140 ibuprofen and n = 70 oxycodone); mean age was 11.1 (±SD 3.5) years, 33.8% were female. Median pain reduction on day 1 was similar between groups [ibuprofen 4 (IQR 2,4) and oxycodone 4 (IQR 2,6), = 0.69]. Over the 3 days, the oxycodone group experienced more AE than the ibuprofen group (78.3% vs 53.2%, < 0.001). Those with a CYP2C9*2 reduced function allele experienced less adverse events with ibuprofen compared with those with a normal functioning allele CYP2C9*1 ( = 0.003). Neither CYP3A4 variants nor CYP2D6 phenotype classification affected clinical effect or AE.
CONCLUSION
Although pain relief was similar, children receiving oxycodone experienced more AE, overall, than those receiving ibuprofen. For children receiving ibuprofen or oxycodone, pain relief was not affected by genetic variations in CYP2C9 or CYP3A4/CYP2D6, respectively. For children receiving ibuprofen, the presence of CYP2C9*2 was associated with less adverse events.
PubMed: 38027465
DOI: 10.1097/PR9.0000000000001113 -
British Journal of Clinical Pharmacology Sep 2022Tapentadol, an opioid with mu-opioid receptor agonism and noradrenaline reuptake inhibition, has been increasingly used in Australia since 2011. However, data on...
AIMS
Tapentadol, an opioid with mu-opioid receptor agonism and noradrenaline reuptake inhibition, has been increasingly used in Australia since 2011. However, data on hospital prescribing trends and indications are scarce. This study aimed to investigate hospital prescribing trends of tapentadol, oxycodone and tramadol in a Sydney local health district (LHD) and the indications for tapentadol hospital prescriptions in an Australian tertiary hospital.
METHODS
We analysed 5-year patient dispensing for tapentadol, oxycodone and tramadol from four hospitals in a Sydney LHD with data expressed as oral morphine equivalents (OME). We also conducted a retrospective review of 140 and 54 patients prescribed tapentadol at a tertiary hospital's surgical and spinal units in 2020.
RESULTS
Over 5 years in the Sydney LHD, there was a 19.5% reduction in total dispensing of these opioids from 1 225 210 to 986 477.5 OME milligrams. Decreases were specifically for oxycodone (-37.8% immediate-release, -65.2% sustained-release) and tramadol (-74.6% immediate-release, -70.1% sustained-release). Contrastingly, hospital prescriptions of tapentadol immediate-release increased by 223.2% between 2018-19 and 2020-21 while sustained-release increased by 17.9% from 2016-17 to 2020-21. By 2020-21, tapentadol overtook oxycodone to become the most prescribed opioid in the Sydney LHD (51.4%). At the hospital's surgical units, 137 (97.9%) patients were prescribed tapentadol for acute post-operative pain with the majority (54.0%) prescribed both immediate-release and sustained-release tapentadol, while 71.1% were prescribed for neuropathic pain in the spinal units.
CONCLUSION
In a Sydney LHD, tapentadol prescriptions increased significantly to become the preferred opioid analgesic. At the hospital's surgical units, off-label prescriptions of tapentadol sustained-release for acute post-operative pain were observed.
Topics: Analgesics, Opioid; Australia; Delayed-Action Preparations; Humans; Morphine; Oxycodone; Pain, Postoperative; Phenols; Tapentadol; Tramadol
PubMed: 35763675
DOI: 10.1111/bcp.15448 -
PloS One 2021To compare the effectiveness and safety of prescribing ibuprofen and oxycodone for at-home management of children's fracture pain. (Observational Study)
Observational Study
OBJECTIVE
To compare the effectiveness and safety of prescribing ibuprofen and oxycodone for at-home management of children's fracture pain.
METHODS
A prospective observational cohort was conducted at the Stollery Children's Hospital pediatric emergency department (June 2010-July 2014). Children aged 4-16 years with an isolated fracture discharged home with advice to use either ibuprofen or oxycodone were recruited.
RESULTS
A cohort of 329 children (n = 217 ibuprofen, n = 112 oxycodone) were included. Mean age was 11.1 years (SD 3.5); 68% (223/329) were male. Fracture distribution included 80.5% (264/329) upper limb with 34.3% (113/329) requiring fracture reduction. The mean reduction in Faces Pain Score-Revised score (maximum pain-post-treatment pain) for Day 1 was 3.6 (SD 1.9) (ibuprofen) and 3.8 (SD 2.1) (oxycodone) (p = 0.50); Day 2 was 3.6 (SD 1.8) (ibuprofen) and 3.7 (SD 1.6) (oxycodone) (p = 0.56); Day 3 was 3.7 (SD 1.7) (ibuprofen) and 3.3 (SD 1.7) (oxycodone) (p = 0.24). Children prescribed ibuprofen (51.2%, 109/213) experienced less adverse events compared to those prescribed oxycodone (70.5% 79/112) on Day 1 (p = 0.001). Children prescribed ibuprofen (71.8%, 150/209) had their function (eat, play, school, sleep) affected less than those prescribed oxycodone (83.0%, 93/112) (p = 0.03) on Day 1.
CONCLUSION
Children prescribed ibuprofen or oxycodone experienced similar analgesic effectiveness for at-home fracture pain. Oxycodone prescribing was associated with more adverse events and negatively impacted function. Oxycodone use does not appear to confer any benefit over ibuprofen for pain relief and has a negative adverse effect profile. Ibuprofen appears to be a safe option for fracture-related pain.
Topics: Acetaminophen; Adolescent; Analgesics, Non-Narcotic; Analgesics, Opioid; Child; Child, Preschool; Cohort Studies; Double-Blind Method; Emergency Service, Hospital; Female; Fractures, Bone; Humans; Ibuprofen; Male; Oxycodone; Pain Management; Pain Measurement; Pain, Postoperative
PubMed: 34499688
DOI: 10.1371/journal.pone.0257021 -
Neuropharmacology May 2020The increasing abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by chronic,...
The increasing abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by chronic, voluntary, oral intake and sex differences. To develop interventions, the field would benefit from a preclinical paradigm that similarly provides rodents with chronic, continuous, oral, voluntary and free-choice access to oxycodone. Here we show female and male rats voluntarily ingest and choose oxycodone over water and show both dependence and motivation to take oxycodone during a chronic oral voluntary, two-bottle choice, continuous access paradigm. Adult female and male Long-Evans rats were given unlimited, continuous homecage access to two bottles containing water (Control) or one bottle of water and one bottle of oxycodone dissolved in water (Experimental). Virtually all experimental rats voluntarily drank oxycodone (~10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone by body weight (leading to higher blood levels of oxycodone) and engaged in more gnawing behavior of wooden blocks relative to males. Precipitated withdrawal revealed high levels of dependence in both sexes. Reflecting motivation to drink oxycodone, ascending concentrations of citric acid suppressed the intake of oxycodone (Experimental) and the intake of water (Control); however, Experimental rats returned to pre-citric acid preference levels whereas Controls rats did not. Pre-screening behaviors of rats on open field exploration predicted oxycodone intake. Thus, rats consumed and preferred oxycodone over time in this chronic two-bottle oral choice paradigm and both sexes displayed many features of human oxycodone abuse.
Topics: Administration, Oral; Analgesics, Opioid; Animals; Choice Behavior; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Male; Opioid-Related Disorders; Oxycodone; Rats; Rats, Long-Evans; Self Administration; Sex Characteristics; Substance Withdrawal Syndrome; Water
PubMed: 32001238
DOI: 10.1016/j.neuropharm.2020.107978 -
Bioengineered Apr 2022Endothelial dysfunction is an important mechanism involved in myocardial ischemia-reperfusion (I/R) injury. We aimed to explore the effects of Oxycodone on myocardial...
Endothelial dysfunction is an important mechanism involved in myocardial ischemia-reperfusion (I/R) injury. We aimed to explore the effects of Oxycodone on myocardial I/R injury in vivo and in vitro to reveal its mechanisms related to Sigma-1 Receptor (SIGMAR1). A rat model of I/R-induced myocardial injury was developed. The ischemic area and myocardial histopathological changes after oxycodone addition were evaluated by TTC staining and H&E staining. LDH, CK-MB and cTnI levels were used to assess myocardial function. Then, the endothelial integrity was reflected by the expressions of ZO-1, Claudin-1 and Occludin. Afterward, ELISA, RT-qPCR, western blot and immunofluorescence assays were adopted for the detection of inflammation-related genes. SIGMAR1 expression in myocardial tissues induced by I/R and cardiac microvascular endothelial cells (CMECs) under hypoxic/reoxygenation (H/R) was determined using RT-qPCR and western blotting. Subsequently, after SIGMAR1 silencing or BD1047 addition (a SIGMAR1 antagonist), cell apoptosis and endothelial integrity were analyzed in the presence of Oxycodone in H/R-stimulated CMECs. Results indicated that Oxycodone decreased the ischemic area and improved myocardial function in myocardial I/R injury rat. Oxycodone improved myocardial histopathological injury and elevated endothelial integrity, evidenced by upregulated ZO-1, Claudin-1 and Occludin expressions. Moreover, inflammatory response was alleviated after Oxycodone administration. Molecular docking suggested that SIGMAR1 could directly bind to Oxycodone. Oxycodone elevated SIGMAR1 expression and SIGMAR1 deletion or BD1047 addition attenuated the impacts of Oxycodone on apoptosis and endothelial integrity of CMECs induced by H/R. Collectively, Oxycodone alleviates myocardial I/R injury in vivo and in vitro by binding to SIGMAR1.
Topics: Animals; Apoptosis; Claudin-1; Endothelial Cells; Molecular Docking Simulation; Myocardial Reperfusion Injury; Myocytes, Cardiac; Occludin; Oxycodone; Rats; Receptors, sigma; Sigma-1 Receptor
PubMed: 35412431
DOI: 10.1080/21655979.2022.2057632 -
BioRxiv : the Preprint Server For... Jun 2023The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely...
The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-hr sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.
PubMed: 37333293
DOI: 10.1101/2023.06.02.543393 -
Neuropharmacology Mar 2021Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic...
BACKGROUND
Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice.
METHODS
Combinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry.
RESULTS
MNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier.
CONCLUSIONS
These results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted.
Topics: Analgesics, Opioid; Animals; Blood-Brain Barrier; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Morphine; Naltrexone; Narcotic Antagonists; Oxycodone; Pain Measurement; Quaternary Ammonium Compounds
PubMed: 33316279
DOI: 10.1016/j.neuropharm.2020.108437