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ACS Chemical Neuroscience May 2021Opioids 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...
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 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.
Topics: Computer Simulation; Diazepam; Drug Interactions; Humans; Models, Biological; Molecular Docking Simulation; Oxycodone; Pharmaceutical Preparations
PubMed: 33950681
DOI: 10.1021/acschemneuro.0c00810 -
JMIR Public Health and Surveillance Dec 2021Opioid use disorder and its consequences are a persistent public health concern for Australians. Web activity has been used to understand the perception of drug safety...
BACKGROUND
Opioid use disorder and its consequences are a persistent public health concern for Australians. Web activity has been used to understand the perception of drug safety and diversion of drugs in contexts outside of Australia. The anonymity of the internet offers several advantages for surveilling and inquiring about specific covert behaviors, such as diversion or discussion of sensitive subjects where traditional surveillance approaches might be limited.
OBJECTIVE
This study aims to characterize the content of web posts and compare reports of illicit sales of tapentadol and oxycodone from sources originating in Australia. First, post content is evaluated to determine whether internet discussion encourages or discourages proper therapeutic use of the drugs. Second, we hypothesize that tapentadol would have lower street price and fewer illicit sales than oxycodone.
METHODS
Web posts originating in Australia between 2017 and 2019 were collected using the Researched Abuse, Diversion, and Addiction-Related Surveillance System Web Monitoring Program. Using a manual coding process, unstructured post content from social media, blogs, and forums was categorized into topics of discussion related to the harms and behaviors that could lead to harm. Illicit sales data in a structured format were collected through a crowdsourcing website between 2016 and 2019 using the Researched Abuse, Diversion, and Addiction-Related Surveillance System StreetRx Program. In total, 2 multivariable regression models assessed the differences in illicit price and number of sales.
RESULTS
A total of 4.7% (28/600) of tapentadol posts discussed an adverse event, whereas 10.27% (95% CI 9.32-11.21) of oxycodone posts discussed this topic. A total of 10% (60/600) of tapentadol posts discussed unsafe use or side effects, whereas 20.17% (95% CI 18.92-21.41) of oxycodone posts discussed unsafe use or side effects. There were 31 illicit sales reports for tapentadol (geometric mean price per milligram: Aus $0.12 [US $0.09]) and 756 illicit sales reports for oxycodone (Aus $1.28 [US $0.91]). Models detected no differences in the street price or number of sales between the drugs when covariates were included, although the potency of the pill significantly predicted the street price (P<.001) and availability predicted the number of sales (P=.03).
CONCLUSIONS
Australians searching the web for opinions could judge tapentadol as safer than oxycodone because of the web post content. The illicit sales market for tapentadol was smaller than that of oxycodone, and drug potency and licit availability are likely important factors influencing the illicit market.
Topics: Analgesics, Opioid; Australia; Humans; Internet; Oxycodone; Tapentadol
PubMed: 34932012
DOI: 10.2196/29187 -
Scandinavian Journal of Pain Apr 2021Opioids are often used in treatment of severe pain, although many patients experience gastrointestinal side-effects like constipation. The aim of the current study was... (Randomized Controlled Trial)
Randomized Controlled Trial
Although tapentadol and oxycodone both increase colonic volume, tapentadol treatment resulted in softer stools and less constipation: a mechanistic study in healthy volunteers.
OBJECTIVES
Opioids are often used in treatment of severe pain, although many patients experience gastrointestinal side-effects like constipation. The aim of the current study was to investigate changes in colonic volume, as the result of both colonic motility and fluid transport, in healthy volunteers during opioid treatment with tapentadol as compared with oxycodone and placebo.
METHODS
In a randomized, double-blind, cross-over study, 21 healthy male volunteers were administered equianalgesic dosages of oral tapentadol (50 mg bid), oxycodone (10 mg bid) or corresponding placebo for 14 days. Segmental colonic volumes were quantified using T2-weighted magnetic resonance images, and gastrointestinal side-effects were assessed with questionnaires.
RESULTS
Total colonic volume increase during treatment was higher during tapentadol and oxycodone treatment (median 48 and 58 mL) compared to placebo (median -14 mL, both p≤0.003). Tapentadol (and placebo) treatment resulted in more bowel movements (both p<0.05) and softer stool consistency as compared with oxycodone (both p<0.01). Only oxycodone treatment was associated with increased constipation, straining during defecation, and tiredness (all p≤0.01). The colonic volume increase during treatment was directly associated with softer stools during tapentadol treatment (p=0.019).
CONCLUSIONS
Tapentadol treatment increased colonic volume without leading to harder stools, likely as the opioid sparing effects result in less water absorption from the gut lumen. Oxycodone treatment also increased colonic volume, but with a simultaneous increase in stool dryness and gastrointestinal and central nervous system side-effects. The results confirm that tapentadol treatment may be advantageous to oxycodone regarding tolerability to pain treatment.
Topics: Colon; Constipation; Cross-Over Studies; Healthy Volunteers; Humans; Male; Oxycodone; Tapentadol
PubMed: 33606931
DOI: 10.1515/sjpain-2020-0151 -
Drug and Alcohol Dependence Feb 2020Prescription opioid abuse continues to be a public health concern of epidemic proportions. Notwithstanding the extensive literature regarding opioid action, there has...
BACKGROUND
Prescription opioid abuse continues to be a public health concern of epidemic proportions. Notwithstanding the extensive literature regarding opioid action, there has been little systematic research regarding the effects of opioid dependence and withdrawal on aspects of cognition-related behavior in laboratory animals. The present studies examined the effects of the prescription opioid oxycodone on learning processes in nonhuman primates.
METHODS
The ability of subjects to repeatedly learn novel touchscreen-based visual discriminations was examined during three conditions of opioid exposure. Discrimination learning was examined, first, during oxycodone self-administration (3-hr sessions, 0.1 mg/kg/injection) and, next, during non-contingent chronic treatment with oxycodone (10 mg/kg/day). Finally, discrimination learning was re-examined during antagonist-precipitated opioid withdrawal (0.001-0.1 mg/kg naltrexone) and, subsequently, following abrupt discontinuation of oxycodone treatment.
RESULTS
Although motoric behavior was disrupted by oxycodone, neither the development of discrimination learning nor steady-state performance were impaired following oxycodone self-administration or during non-contingent chronic oxycodone treatment. However, discrimination learning was substantially impaired during oxycodone withdrawal, whether elicited by naltrexone or by abrupt oxycodone discontinuation. Moreover, these learning impairments were concordant with autonomic signs of opioid withdrawal.
CONCLUSIONS
Taken together, the present studies indicate that impairment of learning processes can accompany the unconditioned signs of opioid withdrawal.
Topics: Analgesics, Opioid; Animals; Discrimination Learning; Dose-Response Relationship, Drug; Male; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Oxycodone; Primates; Saimiri; Self Administration; Substance Withdrawal Syndrome
PubMed: 31816487
DOI: 10.1016/j.drugalcdep.2019.107778 -
Journal of Analytical Toxicology Jul 2022Peripheral blood (PB) concentrations are generally preferred for postmortem toxicological interpretation, but some autopsy cases may lack blood for sampling due to...
Peripheral blood (PB) concentrations are generally preferred for postmortem toxicological interpretation, but some autopsy cases may lack blood for sampling due to decomposition or large traumas, etc. In such cases, other tissues or bodily fluids must be sampled; however, limited information exists on postmortem concentrations in matrices other than blood. Pericardial fluid (PF), muscle and vitreous humor (VH) have been suggested as alternatives to blood, but only a few studies have investigated the detection of opioids in these matrices. In this study, we aimed to investigate the detection of methadone, buprenorphine, oxycodone, fentanyl and tramadol in postmortem samples of PF, skeletal muscle and VH, in addition to PB and cardiac blood and if drug concentrations in these alternative matrices were comparable to those in PB and thereby useful for interpretation. In most of the 54 included cases, only one opioid was detected. Methadone, oxycodone, fentanyl and tramadol were detected in all of the alternative matrices in almost all cases, while buprenorphine was detected less often. For methadone, the concentrations in the alternative matrices, except in VH, were relatively similar to those in PB. Larger variations in concentrations were found for buprenorphine, oxycodone and tramadol. Quantitative analyses appeared useful for fentanyl, in all of the alternative matrices, but only four cases were included. Toxicological analyses of opioids in these alternative postmortem matrices can be useful for detection, but quantitative results must be interpreted with caution.
Topics: Analgesics, Opioid; Autopsy; Buprenorphine; Fentanyl; Methadone; Oxycodone; Tramadol
PubMed: 34115841
DOI: 10.1093/jat/bkab071 -
Medical Science Monitor : International... Mar 2021BACKGROUND The aim of the present study was to evaluate the effects of different doses of oxycodone during endoscopic injection sclerotherapy (EIS) for esophageal...
BACKGROUND The aim of the present study was to evaluate the effects of different doses of oxycodone during endoscopic injection sclerotherapy (EIS) for esophageal varices with painless sclerosing agents. MATERIAL AND METHODS A total of 119 patients were randomly divided into 3 groups: Group A, midazolam and 0.075 mg/kg oxycodone (n=40); Group B, midazolam and 0.1 mg/kg oxycodone (n=40); and Group C, midazolam and 0.125 mg/kg oxycodone (n=39). The main observation index was the incidence of body movement during the perioperative period. The secondary indices were additional propofol usage; postoperative analgesic usage; other adverse effects, such as hypoxia, myoclonus, and cough; and satisfaction scores for surgeons and patients. RESULTS The incidence rates for body movement during the perioperative period in groups A, B, and C were 33%, 13%, and 0, respectively (P<0.001). The satisfaction scores for surgeons and patients were highest in Group C (0.125 mg/kg oxycodone). The incidence rates for hypoxia before EIS were 15%, 8%, and 33% (P=0.026) and during EIS were 23%, 3%, and 0% (P<0.001), respectively. There were no significant between-group differences with respect to other adverse effects. CONCLUSIONS The ideal dose of oxycodone for perioperative analgesia during EIS for esophageal varices is 0.125 mg/kg.
Topics: Adult; China; Dose-Response Relationship, Drug; Endoscopy; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Incidence; Injections; Liver Cirrhosis; Male; Midazolam; Middle Aged; Oxycodone; Perioperative Period; Prospective Studies; Sclerosing Solutions; Sclerotherapy
PubMed: 33727522
DOI: 10.12659/MSM.929111 -
The Journal of Pharmacology and... May 2018Heroin and oxycodone abuse occurs over a wide range of drug doses and by various routes of administration characterized by differing rates of drug absorption. The...
Heroin and oxycodone abuse occurs over a wide range of drug doses and by various routes of administration characterized by differing rates of drug absorption. The current study addressed the efficacy of a heroin vaccine [morphine hapten conjugated to keyhole limpet hemocyanin (M-KLH)] or oxycodone vaccine [oxycodone hapten conjugated to keyhole limpet hemocyanin (OXY-KLH)] for reducing drug distribution to brain after intravenous heroin or oxycodone, or subcutaneous oxycodone. Rats immunized with M-KLH or keyhole limpet hemocyanin (KLH) control received an intravenous bolus dose of 0.26 or 2.6 mg/kg heroin. Vaccination with M-KLH increased retention of heroin and its active metabolites 6-acetylmorphine (6-AM) and morphine in plasma compared with KLH controls, and reduced total opioid (heroin + 6-AM + morphine) distribution to brain but only at the lower heroin dose. Immunization also protected against respiratory depression at the lower heroin dose. Rats immunized with OXY-KLH or KLH control received 0.22 or 2.2 mg/kg oxycodone intravenously, the molar equivalent of the heroin doses. Immunization with OXY-KLH significantly reduced oxycodone distribution to brain after either oxycodone dose, although the magnitude of effect of immunization at the higher oxycodone dose was small (12%). By contrast, vaccination with OXY-KLH was more effective when oxycodone was administered subcutaneously rather than intravenously, reducing oxycodone distribution to brain by 44% after an oxycodone dose of 2.3 mg/kg. Vaccination also reduced oxycodone-induced antinociception. These data suggest that the efficacy of OXY-KLH and M-KLH opioid vaccines is highly dependent upon opioid dose and route of administration.
Topics: Animals; Brain; Dose-Response Relationship, Drug; Drug Administration Routes; Heroin; Male; Opioid-Related Disorders; Oxycodone; Rats; Vaccines
PubMed: 29535156
DOI: 10.1124/jpet.117.247049 -
Scientific Reports Aug 2023Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact...
Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.
Topics: Adult; Humans; Rats; Female; Male; Animals; Rats, Sprague-Dawley; Oxycodone; Analgesics, Opioid; Estrous Cycle; Reward
PubMed: 37626154
DOI: 10.1038/s41598-023-40971-3 -
Pharmacology, Biochemistry, and Behavior Oct 2021Recent data suggest that glial cells may be involved in the analgesic effects and abuse liability of opioids. Preclinical studies have demonstrated that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recent data suggest that glial cells may be involved in the analgesic effects and abuse liability of opioids. Preclinical studies have demonstrated that mu-opioid-receptor-selective agonists, such as oxycodone, activate glia and increase the release of cytokines, causing a suppression of opioid-induced analgesic effects. Preclinical studies also show that certain medications, such as the broad-spectrum tetracycline antibiotic minocycline, inhibit opioid-induced glial activation and thereby enhance the analgesic effects of opioids. Importantly, minocycline reduces the rewarding effects of opioids at the same doses that it enhances opioid-induced analgesia.
AIMS
The purpose of the present study was to assess the effects of acute administration of minocycline on the subjective, physiological, and analgesic effects of oxycodone in human research volunteers.
DESIGN
This study was a within-subject, randomized, double-blind outpatient study. Participants completed five separate sessions in which they received 0, 100, or 200 mg minocycline (MINO) simultaneously with either 0 or 40 mg oxycodone (OXY). The subjective, physiological, and analgesic effects of OXY were measured before and repeatedly after drug administration.
SETTINGS AND PARTICIPANTS
Participants were between 21 and 45 years of age, non-treatment seeking, non-dependent recreational opioid users (N = 12). This study was conducted between 2013 and 2014 at the New York State Psychiatric Institute in New York, NY.
FINDINGS
MINO 100 and 200 mg were safe and well-tolerated in combination with OXY 40 mg. MINO 200 mg administered with OXY 40 mg attenuated OXY-induced positive subjective effects such as "Good Effect" and "Liking" compared to OXY alone. MINO did not alter the physiological or analgesic effects of OXY.
CONCLUSIONS
MINO may attenuate the abuse liability of mu-opioid-receptor-selective agonists.
Topics: Adult; Analgesia; Analgesics, Opioid; Anti-Bacterial Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Microglia; Middle Aged; Minocycline; New York; Opioid-Related Disorders; Oxycodone; Reward; Young Adult
PubMed: 34298029
DOI: 10.1016/j.pbb.2021.173241 -
BMC Anesthesiology Jul 2021The objective of this study was to compare the analgesic potency of oxycodone versus morphine after laparoscopic deep infiltrating endometriosis resection. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The objective of this study was to compare the analgesic potency of oxycodone versus morphine after laparoscopic deep infiltrating endometriosis resection.
METHODS
Fifty patients undergoing laparoscopic deep infiltrating endometriosis resection were randomized to receive oxycodone or morphine intravenous-PCA after surgery. The primary outcome was opioid consumption during the 24 h after surgery. Secondary outcomes included time to first request for analgesia, the number of bolus, pain, sedation, nausea, vomiting, respiratory depression, and bradycardia. The prominent pain that caused patients to press the analgesic device was also recorded.
RESULTS
Oxycodone consumption (14.42 ± 2.83) was less than morphine consumption (20.14 ± 3.83). Compared with the morphine group, the total number of bolus (78 vs 123) was less and the average time to first request for analgesia (97.27 ± 59.79 vs 142.17 ± 51) was longer in the oxycodone group. The incidence of nausea was higher in the morphine group than in the oxycodone group at 0-2 h (45.45% vs 17.19%), 2-4 h (50% vs 17.19%),12-24 h (40.91% vs 13.04%) and 0-24 h (39.17% vs 19.13%). The overall incidence of vomiting was higher in the morphine group (27.27% vs 13.92%). There was no difference in visual analogue scale score, the incidence of respiratory depression, and bradycardia between groups. Of the three types of pain that prompted patients to request analgesia, the incidence of visceral pain was highest (59.9%, P < 0.01).
CONCLUSION
Oxycodone was more potent than morphine for analgesia after laparoscopic endometriosis resection, and oxycodone has fewer side effects than morphine. Name of the registry: Chinese Clinical Trial Registry Trial registration number: ChiCTR1900021870 URL of trial registry record: http://www.chictr.org.cn/edit.aspx?pid=35799&htm=4 Date of registration: 2019/3/13 0:00:00.
Topics: Adult; Analgesia, Patient-Controlled; Analgesics, Opioid; Double-Blind Method; Endometriosis; Female; Humans; Laparoscopy; Morphine; Oxycodone; Pain, Postoperative; Prospective Studies; Time Factors
PubMed: 34289814
DOI: 10.1186/s12871-021-01417-3