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Journal of Neurochemistry Mar 1998The effects of opiate drugs (heroin, morphine, and methadone) on the levels of G protein-coupled receptor kinase 2 (GRK2) were studied in rat and human brain frontal...
The effects of opiate drugs (heroin, morphine, and methadone) on the levels of G protein-coupled receptor kinase 2 (GRK2) were studied in rat and human brain frontal cortices. The density of brain GRK2 was measured by immunoblot assays in acute and chronic opiate-treated rats as well as in opiate-dependent rats after spontaneous or naloxone-precipitated withdrawal and in human opiate addicts who had died of an opiate overdose. In postmortem brains from human addicts, total GRK2 immunoreactivity was not changed significantly, but the level of the membrane-associated kinase was modestly but significantly increased (12%) compared with matched controls. In rats treated chronically with morphine or methadone modest increases of the enzyme levels (only significant after methadone) were observed. Acute treatments with morphine and methadone induced dose- and time-dependent increases (8-22%) in total GRK2 concentrations [higher increases were observed for the membrane-associated enzyme (46%)]. Spontaneous and naloxone-precipitated withdrawal after chronic morphine or methadone induced a marked up-regulation in the levels of total GRK2 in the rat frontal cortex (18-25%). These results suggest that GRK2 is involved in the short-term regulation of mu-opioid receptors in vivo and that the activity of this regulatory kinase in brain could have a relevant role in opiate tolerance, dependence, and withdrawal.
Topics: Adolescent; Adult; Animals; Brain; Cyclic AMP-Dependent Protein Kinases; Female; G-Protein-Coupled Receptor Kinase 2; Humans; Male; Methadone; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors; beta-Adrenergic Receptor Kinases
PubMed: 9489748
DOI: 10.1046/j.1471-4159.1998.70031249.x -
Molecules (Basel, Switzerland) Jun 2023All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space...
All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, , , and , were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, (3-((1,5,9)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (E = 85%) and subnanomolar potency (EC = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1,5,9 stereochemistry () was more potent than the comparable C9-hydroxymethyl compound (EC = 0.65 nM for vs. 2.05 nM for ). Both and were fully efficacious.
Topics: Receptors, Opioid, mu; Morphinans; Morphine; Analgesics, Opioid
PubMed: 37375350
DOI: 10.3390/molecules28124795 -
The American Journal of Managed Care Mar 2019This study sought to formulate a consolidation of guidelines representing best practices related to office-based opioid treatment (OBOT) of opioid use disorder (OUD)...
OBJECTIVES
This study sought to formulate a consolidation of guidelines representing best practices related to office-based opioid treatment (OBOT) of opioid use disorder (OUD) using buprenorphine. It also demonstrates how a set of evidence-based guidelines may be linked with claims data to leverage analytic techniques that drive cost-effective, positive health outcomes.
STUDY DESIGN
Literature review of US and international guidelines for OBOT using buprenorphine for OUD.
METHODS
The study conducted a review of currently available US and several international guidelines from 2009 to 2018 published on OUD and the use of buprenorphine in OBOT. Guidelines were consolidated based on common elements. The process of correlating common elements with available commercial and state Medicaid claims data is described, including which elements are amenable to analysis along with relative complexity.
RESULTS
Seven guidelines met inclusion criteria and are presented as 3 tables, organized by clinical themes and phase of care related to OBOT use of buprenorphine for OUD. Themes included establishing care, monitoring treatment stability and engagement, and nonpharmacologic treatment to improve outcomes. Areas of agreement and divergence between guidelines are highlighted. Specific components are identified as they relate to metrics of interest to public and private payers.
CONCLUSIONS
Among US and international guidelines for treatment of OUD, common themes are readily identified and may indicate agreement in regard to interventions. Linking pharmacy and medical billing claims data to evidence-supported best practices provides public and private payers the ability to track individual patients, facilitate high-quality care, and monitor outcomes.
Topics: Analgesics, Opioid; Buprenorphine; Drug Monitoring; Global Health; Humans; Insurance Claim Review; Opiate Substitution Treatment; Opioid-Related Disorders; Practice Guidelines as Topic; Quality of Health Care; United States
PubMed: 30875177
DOI: No ID Found -
British Journal of Clinical Pharmacology Sep 2018Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is...
AIMS
Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for nonpregnant adults. However, physiological changes during pregnancy may alter BUP exposure and efficacy. The objectives of this study were to develop a physiologically-based pharmacokinetic (PBPK) model for BUP in pregnant women, to predict changes in BUP exposure at different stages of pregnancy, and to demonstrate the utility of PBPK modelling in optimizing BUP pharmacotherapy during pregnancy.
METHODS
A full PBPK model for BUP was initially built and validated in healthy subjects. A fetoplacental compartment was included as a combined compartment in this model to simulate pregnancy induced anatomical and physiological changes. Further, gestational changes in physiological parameters were incorporated in this model. The PBPK model predictions of BUP exposure in pregnancy and during the postpartum period were compared to published data from a prospective clinical study.
RESULTS
The predicted BUP plasma concentration-time profiles in the virtual pregnant populations are consistent with the observed data in the 2 and 3 trimesters, and the postpartum period. The differences in the predicted means of dose normalized area under the plasma drug concentration-time curve up to 12 h, average concentration and maximum concentration were within ±25% of the corresponding observed means with the exception of average concentration in the 3 trimester (-26.3%).
CONCLUSION
PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.
Topics: Administration, Sublingual; Adult; Area Under Curve; Buprenorphine; Computer Simulation; Female; Humans; Maternal-Fetal Exchange; Models, Biological; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Placenta; Pregnancy; Pregnancy Complications; Prospective Studies; Tissue Distribution
PubMed: 29873094
DOI: 10.1111/bcp.13642 -
Molecules (Basel, Switzerland) Nov 2023(-)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a -OH or -F substituent in the aromatic ring of the -phenethyl moiety were synthesized and found to...
Potent MOR Agonists from 2'-Hydroxy-5,9-dimethyl--phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of -Phenethylnormetazocine.
(-)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a -OH or -F substituent in the aromatic ring of the -phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1,5,9)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1,5,9)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound -phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the , , or position in the aromatic ring of the -phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The -phenethyl moiety was also modified by increasing chain length to form a -phenylpropyl side chain with and without a -nitro moiety, and by an -cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the -phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the -nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC = 12 nM), and was fully efficacious (%E = 102%) in the cAMP assay. Retention of the -phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (-)--phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.
Topics: Benzomorphans; Morphine; Ethylamines; Indoles; Structure-Activity Relationship
PubMed: 38067439
DOI: 10.3390/molecules28237709 -
Journal of Applied Behavior Analysis Jul 2020Polydrug use is a common problem among patients in opioid-substitution treatment. Polydrug use has been reduced by administering abstinence-reinforcement contingencies...
Polydrug use is a common problem among patients in opioid-substitution treatment. Polydrug use has been reduced by administering abstinence-reinforcement contingencies in a sequence, such that a single drug is targeted until abstinence is achieved, and then an additional drug is targeted. The present study examined effects of administering abstinence-reinforcement contingencies sequentially based on time rather than on achieved abstinence. Participants accessed paid work (about $10/hr maximum) in the Therapeutic Workplace by providing urine samples 3 times per week. The urine samples were tested for opiates and cocaine. During an induction period, participants earned maximum pay independent of drug abstinence. Then, maximum pay depended upon urine samples that were negative for opiates. Two weeks later, maximum pay depended upon urine samples that were negative for both opiates and cocaine. Opiate and cocaine abstinence increased following administration of the respective contingencies. The time-based administration of abstinence reinforcement increased opiate and cocaine abstinence.
Topics: Cocaine; Cocaine-Related Disorders; Female; Humans; Male; Opiate Alkaloids; Opioid-Related Disorders; Reinforcement, Psychology; Time Factors
PubMed: 32249414
DOI: 10.1002/jaba.702 -
The International Journal of... May 2017Previous studies suggested that opiate withdrawal may increase anxiety and disrupt brain-derived neurotrophic factor function, but the effects of i.v. morphine...
BACKGROUND
Previous studies suggested that opiate withdrawal may increase anxiety and disrupt brain-derived neurotrophic factor function, but the effects of i.v. morphine self-administration on these measures remain unclear.
METHODS
Adult male Sprague-Dawley rats were implanted with a catheter in the jugular vein. After 1 week of recovery, the animals were allowed to self-administer either i.v. morphine (0.5 mg/kg per infusion, 4 h/d) or saline in the operant conditioning chambers. The acoustic startle reflex and prepulse inhibition were measured at a baseline and on self-administration days 1, 3, 5, and 7 (1- and 3-hour withdrawal). Blood samples were collected on self-administration days 3, 5, and 7 from separate cohorts of animals, and the levels of brain-derived neurotrophic factor and corticosterone were assayed using the enzyme-linked immunosorbent assay method.
RESULTS
Compared with the saline group, the morphine self-administration group showed hyper-locomotor activity and reduced defecation during the self-administration. The morphine self-administration increased acoustic startle reflex at 1-hour but not 3-hour withdrawal from morphine and disrupted prepulse inhibition at 3-hour but not 1-hour withdrawal. The blood brain-derived neurotrophic factor levels were decreased in the morphine self-administration group at self-administration days 3 and 5, while the corticosterone levels remained unchanged throughout the study.
CONCLUSIONS
The current findings suggest that spontaneous withdrawal from i.v. morphine self-administration may have transient effects on acoustic startle, sensorimotor gating, and peripheral brain-derived neurotrophic factor levels, and these changes may contribute to the adverse effects of opiate withdrawal.
Topics: Acoustic Stimulation; Analgesics, Opioid; Analysis of Variance; Animals; Brain-Derived Neurotrophic Factor; Conditioning, Operant; Enzyme-Linked Immunosorbent Assay; Hydrocortisone; Male; Morphine; Prepulse Inhibition; Rats; Rats, Sprague-Dawley; Reflex, Startle; Self Administration; Time Factors
PubMed: 27927738
DOI: 10.1093/ijnp/pyw107 -
Health Services Research Oct 2021To compare measures of spatial access to care commonly used by policy makers and researchers with the more comprehensive enhanced two-step floating catchment area...
OBJECTIVE
To compare measures of spatial access to care commonly used by policy makers and researchers with the more comprehensive enhanced two-step floating catchment area (E2SFCA) method.
STUDY SETTING
Fourteen southwestern Pennsylvania counties.
STUDY DESIGN
We estimated spatial access to buprenorphine-waivered prescribers using three commonly used measures-Euclidean travel distance to the closest prescriber, travel time to the closest provider, and provider-to-population ratios-and the E2SFCA. Unlike other measures, the E2SFCA captures provider capacity, potential patient volume, and travel time to prescribers.
DATA COLLECTION/EXTRACTION METHODS
We measured provider capacity as the number of buprenorphine prescribers listed at a given address in the Drug Enforcement Agency's 2020 Controlled Substances Act Registrants Database, and we measured potential patient volume as the number of nonelderly adults in a given census tract as reported by the 2018 American Community Survey. We estimated travel times between potential patients and prescribers with Bing Maps and Mapbox application programming interfaces. We then calculated each spatial access measure using the R programming language. We used each measure of spatial access to identify census tracts in the lowest quintile of spatial access to prescribers.
PRINCIPAL FINDINGS
The Euclidean distance, travel time, and provider-to-population ratio measures identified 48.3%, 47.2%, and 69.9% of the census tracts that the E2SFCA measure identified as being in the lowest quintile of spatial access to care, meaning that these measures misclassify 30%-52% of study area census tracts as having sufficient spatial access to buprenorphine prescribers.
CONCLUSIONS
Measures of spatial access commonly used by policy makers do not sufficiently accurately identify geographic areas with relatively low access to prescribers of buprenorphine. Using the E2SFCA in addition to the commonly used measures would allow policy makers to precisely target interventions to increase spatial access to opioid use disorder treatment and other types of health care services.
Topics: Buprenorphine; Catchment Area, Health; Health Services Accessibility; Health Workforce; Humans; Opiate Substitution Treatment; Pennsylvania; Spatial Analysis; Travel
PubMed: 34250592
DOI: 10.1111/1475-6773.13700 -
Drug and Alcohol Dependence Apr 2019To determine whether extended-release injectable naltrexone (XR-NTX), incentives for opiate abstinence, and their combination reduce opiate use compared to a usual care... (Randomized Controlled Trial)
Randomized Controlled Trial
The effects of extended-release injectable naltrexone and incentives for opiate abstinence in heroin-dependent adults in a model therapeutic workplace: A randomized trial.
AIM
To determine whether extended-release injectable naltrexone (XR-NTX), incentives for opiate abstinence, and their combination reduce opiate use compared to a usual care control and whether the combination reduces opiate use compared to either treatment alone.
DESIGN
Randomized 2 × 2 single-site controlled trial conducted from November 2012 through May 2016. After a detoxification and oral naltrexone induction, participants were assigned to a Usual Care, Abstinence Incentives, XR-NTX, or XR-NTX plus Abstinence Incentives group for a six-month intervention period.
SETTING
A model therapeutic workplace where participants could work on automated computer programs that targeted job-skills training for 4 h every weekday for 24 weeks and earn about $10 per hour.
PARTICIPANTS
84 heroin-dependent adults who were unemployed and medically approved for naltrexone. Most participants were male (71.4%), African American (80.1%), and cocaine dependent (71.4%).
MEASUREMENTS
The primary outcome measure was the percentage of urine samples negative for opiates that were collected at once weekly assessments (24 per participant) that were not part of the intervention and for which participants were paid $10 for completing.
INTERVENTION
Participants who attended the workplace provided thrice-weekly urine samples. Abstinence Incentives participants had to provide opiate-free urine samples to maintain maximum pay. XR-NTX participants received one injection every 4 weeks and were required to take injections in order to work and to maintain maximum pay. Usual Care participants were not offered XR-NTX and opiate urinalysis results did not affect pay.
FINDINGS
A large percentage (65 of 149; 43.6%) of individuals failed the induction protocol required for randomization and to be eligible to receive XR-NTX. When missing urine samples were considered positive, there was no significant interaction between XR-NTX and Abstinence Incentives. XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (81.3%, SD 39.0%) than XR-NTX participants (64.5%, SD 47.9%; aOR 10.4, 95% CI 1.3-85.5; P = .030). When urine samples were not replaced, there was a significant interaction between XR-NTX and Abstinence Incentives (aOR 77.0, 95% CI 1.3-4432;P = 0.036); XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (99.6%, SD 0.1%) than XR-NTX participants (85.0%, SD 35.7%; aOR 147.6, 95% CI 6.3-3472; P = 0.002), Abstinence Incentives participants (91.9%, SD 27.3%; aOR 121.7, 95% CI 4.8-3067; P =0.004), and Usual Care participants (78.7%, SD 41.0%; aOR 233.4, 95% CI 9.4-5814; P <.001). No other group differences were significant.
CONCLUSION
XR-NTX plus incentives for opiate abstinence increased opiate abstinence, but XR-NTX alone did not. XR-NTX can promote opiate abstinence when it is combined with incentives for opiate abstinence in a model therapeutic workplace.
Topics: Adult; Black or African American; Cocaine; Delayed-Action Preparations; Female; Heroin; Humans; Injections; Male; Middle Aged; Motivation; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Substance Abuse Detection; Workplace
PubMed: 30852374
DOI: 10.1016/j.drugalcdep.2018.12.026 -
Journal of the American Chemical Society Oct 2017The present study highlights a sensing approach for opiates using acyclic cucurbituril (aCBs) sensors comprising four glycouril units terminated on both ends with...
The present study highlights a sensing approach for opiates using acyclic cucurbituril (aCBs) sensors comprising four glycouril units terminated on both ends with naphthalene fluorophore walls. The connectivity between the glycourils and naphthalene rings largely defines the opening size of the cucurbituril cavity and its diameter. The large hydrophobic binding cavity is flexible and is able to adapt to guests of various size and topology. The recognition event between the aCBs and guests results in modification of the fluorescence of the terminal walls, a fluorescence response that can be used to sense the drugs of abuse morphine, heroin, and oxycodone as well as their metabolites. Molecular dynamics is employed to understand the nature of the binding interactions. A simple three sensor cross-reactive array enables the determination of drugs and their metabolites in water with high fidelity and low error. Quantitative experiments performed in urine using a new three-way calibration model allows for determination of drugs and their metabolites using one sensor from a single fluorescence reading.
Topics: Calibration; Chemistry Techniques, Analytical; Fluorescence; Heroin; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Morphine; Opiate Alkaloids; Oxycodone
PubMed: 28820934
DOI: 10.1021/jacs.7b06371