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Neuropharmacology Jun 2019Opioid drugs are important tools to alleviate pain of different origins, but they have strong addictive potential and their abuse at higher doses often results in... (Review)
Review
Opioid drugs are important tools to alleviate pain of different origins, but they have strong addictive potential and their abuse at higher doses often results in serious health complications. Respiratory depression that leads to brain hypoxia is perhaps the most dangerous symptom of acute intoxication with opioids, and it could result in lethality. The development of substrate-specific sensors coupled with amperometry made it possible to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely-moving rats. The goal of this review paper is to consider changes in brain oxygen levels induced by several opioid drugs (heroin, fentanyl, oxycodone, morphine). While some of these drugs are widely used in clinical practice, they all are abused, often at doses exceeding the clinical range and often resulting in serious health complications. First, we consider some basic knowledge regarding brain oxygen, its physiological fluctuations, and mechanisms involved in regulating its entry into brain tissue. Then, we present and discuss data on brain oxygen changes induced by each opioid drug within a wide range of doses, from low, behaviorally relevant, to high, likely to be self-administered by drug users. These data allowed us to compare the effects of these drugs on brain oxygen in terms of their potency, time-course, and their potential danger when used at high doses via rapid-onset administration routes. While most data discussed in this work were obtained in rats, we believe that these data have clear human relevance in addressing the alarming rise in lethality associated with the opioid abuse.
Topics: Analgesics, Opioid; Animals; Brain; Fentanyl; Heroin; Humans; Hypoxia, Brain; Morphine; Oxycodone; Rats; Respiratory Insufficiency
PubMed: 30735692
DOI: 10.1016/j.neuropharm.2019.02.008 -
JAMA Psychiatry Jul 2021Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment.
IMPORTANCE
Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment.
OBJECTIVE
To assess the cost-effectiveness of OUD treatments and association of these treatments with outcomes in the US.
DESIGN AND SETTING
This model-based cost-effectiveness analysis included a US population with OUD.
INTERVENTIONS
Medication-assisted treatment (MAT) with buprenorphine, methadone, or injectable extended-release naltrexone; psychotherapy (beyond standard counseling); overdose education and naloxone distribution (OEND); and contingency management (CM).
MAIN OUTCOMES AND MEASURES
Fatal and nonfatal overdoses and deaths throughout 5 years, discounted lifetime quality-adjusted life-years (QALYs), and costs.
RESULTS
In the base case, in the absence of treatment, 42 717 overdoses (4132 fatal, 38 585 nonfatal) and 12 660 deaths were estimated to occur in a cohort of 100 000 patients over 5 years, and 11.58 discounted lifetime QALYs were estimated to be experienced per person. An estimated reduction in overdoses was associated with MAT with methadone (10.7%), MAT with buprenorphine or naltrexone (22.0%), and when combined with CM and psychotherapy (range, 21.0%-31.4%). Estimated deceased deaths were associated with MAT with methadone (6%), MAT with buprenorphine or naltrexone (13.9%), and when combined with CM, OEND, and psychotherapy (16.9%). MAT yielded discounted gains of 1.02 to 1.07 QALYs per person. Including only health care sector costs, methadone cost $16 000/QALY gained compared with no treatment, followed by methadone with OEND ($22 000/QALY gained), then by buprenorphine with OEND and CM ($42 000/QALY gained), and then by buprenorphine with OEND, CM, and psychotherapy ($250 000/QALY gained). MAT with naltrexone was dominated by other treatment alternatives. When criminal justice costs were included, all forms of MAT (with buprenorphine, methadone, and naltrexone) were associated with cost savings compared with no treatment, yielding savings of $25 000 to $105 000 in lifetime costs per person. The largest cost savings were associated with methadone plus CM. Results were qualitatively unchanged over a wide range of sensitivity analyses. An analysis using demographic and cost data for Veterans Health Administration patients yielded similar findings.
CONCLUSIONS AND RELEVANCE
In this cost-effectiveness analysis, expanded access to MAT, combined with OEND and CM, was associated with cost-saving reductions in morbidity and mortality from OUD. Lack of widespread MAT availability limits access to a cost-saving medical intervention that reduces morbidity and mortality from OUD. Opioid overdoses in the US likely reached a record high in 2020 because of COVID-19 increasing substance use, exacerbating stress and social isolation, and interfering with opioid treatment. It is essential to understand the cost-effectiveness of alternative forms of MAT to treat OUD.
Topics: Adult; Buprenorphine; Combined Modality Therapy; Cost-Benefit Analysis; Delayed-Action Preparations; Female; Humans; Male; Methadone; Middle Aged; Naloxone; Opiate Overdose; Opiate Substitution Treatment; Opioid-Related Disorders; Psychotherapy; Treatment Outcome
PubMed: 33787832
DOI: 10.1001/jamapsychiatry.2021.0247 -
Nature Communications Oct 2022The nucleus accumbens (NAc) is critical in mediating reward seeking and is also involved in negative emotion processing, but the cellular and circuitry mechanisms...
The nucleus accumbens (NAc) is critical in mediating reward seeking and is also involved in negative emotion processing, but the cellular and circuitry mechanisms underlying such opposing behaviors remain elusive. Here, using the recently developed AAV1-mediated anterograde transsynaptic tagging technique in mice, we show that NAc neurons receiving basolateral amygdala inputs (NAc) promote positive reinforcement via disinhibiting dopamine neurons in the ventral tegmental area (VTA). In contrast, NAc neurons receiving paraventricular thalamic inputs (NAc) innervate GABAergic neurons in the lateral hypothalamus (LH) and mediate aversion. Silencing the synaptic output of NAc neurons impairs reward seeking behavior, while silencing of NAc or NAc→LH pathway abolishes aversive symptoms of opiate withdrawal. Our results elucidate the afferent-specific circuit architecture of the NAc in controlling reward and aversion.
Topics: Mice; Animals; Nucleus Accumbens; Reward; Ventral Tegmental Area; Dopaminergic Neurons; Opiate Alkaloids
PubMed: 36271048
DOI: 10.1038/s41467-022-33843-3 -
Molecules (Basel, Switzerland) May 2022-dealkylation, the removal of an -alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of... (Review)
Review
-dealkylation, the removal of an -alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of pharmaceuticals, agrochemicals, bulk and fine chemicals. -dealkylation of amines is also an important in vivo metabolic pathway in the metabolism of xenobiotics. Identification and synthesis of drug metabolites such as -dealkylated metabolites are necessary throughout all phases of drug development studies. In this review, different approaches for the -dealkylation of amines including chemical, catalytic, electrochemical, photochemical and enzymatic methods will be discussed.
Topics: Amines; Dealkylation
PubMed: 35630770
DOI: 10.3390/molecules27103293 -
The Western Journal of Medicine May 1990Treating opiate-dependent patients can be difficult for many physicians because the patients' life-styles, values, and beliefs differ from those of the physicians.... (Review)
Review
Treating opiate-dependent patients can be difficult for many physicians because the patients' life-styles, values, and beliefs differ from those of the physicians. Primary care physicians, however, are often involved in the treatment of the medical complications of opiate abuse, and physicians must often manage a patient's opiate dependence until appropriate referral to a drug abuse treatment program can be arranged. Treatment is guided by an understanding of the patient's addictive disease, for which there are specific diagnostic criteria, and an understanding of the pharmacology of opiates of abuse and the medications used in treating opiate dependence. The opiate agonist, methadone, is useful for both detoxification and maintenance. The opiate antagonist, naloxone, is the treatment of choice for opiate overdose, and naltrexone, also an opiate antagonist, is a useful adjunct in subgroups of opiate-dependent patients for preventing relapse. New medications for the treatment of opiate dependence are being developed.
Topics: Central Nervous System; Humans; Inactivation, Metabolic; Methadone; Naloxone; Naltrexone; Narcotics; Opioid-Related Disorders; Primary Health Care; Receptors, Opioid
PubMed: 2161588
DOI: No ID Found -
Cellular and Molecular Life Sciences :... Jun 2008There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse. A number of... (Review)
Review
There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse. A number of peptides with effects on hypothalamic function also modulate the mesolimbic dopamine system (ventral tegmental area and nucleus accumbens). Similarly, common stress-related pathways can modulate food intake, drug reward and symptoms of drug withdrawal. Galanin promotes food intake and the analgesic properties of opiates; thus it initially seemed possible that galanin might potentiate opiate reinforcement. Instead, galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiate reward and withdrawal are increased in knock-out mice lacking galanin. This is consistent with studies showing that galanin decreases activity-evoked dopamine release in striatal slices and decreases the firing rate of noradrenergic neurons in locus coeruleus, areas involved in drug reward and withdrawal, respectively. These data suggest that polymorphisms in genes encoding galanin or galanin receptors might be associated with susceptibility to opiate abuse. Further, galanin receptors might be potential targets for development of novel treatments for addiction.
Topics: Acetylcholine; Alcohol Drinking; Animals; Dopamine; Galanin; Humans; Locomotion; Mice; Morphine; Reward; Signal Transduction; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 18500649
DOI: 10.1007/s00018-008-8151-x -
American Journal of Respiratory and... Aug 2020
Topics: Critical Care; Humans; Intensive Care Units; Opiate Alkaloids; Patient Discharge; Respiration, Artificial
PubMed: 32464072
DOI: 10.1164/rccm.202005-1815ED -
Cancer Epidemiology, Biomarkers &... Mar 2020There is little information on human exposure to carcinogens and other toxicants related to opiate use, alone or in combination with tobacco.
BACKGROUND
There is little information on human exposure to carcinogens and other toxicants related to opiate use, alone or in combination with tobacco.
METHODS
Among male participants of the Golestan Cohort Study in Northeast Iran, we studied 28 never users of either opiates or tobacco, 33 exclusive cigarette smokers, 23 exclusive users of smoked opiates, and 30 opiate users who also smoked cigarettes (dual users; 21 smoked opiates and 9 ingested them). We quantified urinary concentrations of 39 exposure biomarkers, including tobacco alkaloids, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC), and used decomposition to parse out the share of the biomarker concentrations explained by opiate use and nicotine dose.
RESULTS
Dual users had the highest concentrations of all biomarkers, but exclusive cigarette smokers and exclusive opiate users had substantially higher concentrations of PAH and VOC biomarkers than never users of either product. Decomposition analysis showed that opiate use contributed a larger part of the PAH concentrations than nicotine dose, and the sum of 2- and 3-hydroxyphenanthrene (∑-phe) resulted almost completely from opiate use. Concentrations of most VOC biomarkers were explained by both nicotine dose and opiate use. Two acrylamide metabolites, a 1,3-butadiene metabolite and a dimethylformamide metabolite, were more strongly explained by opiate use. Acrylamide metabolites and ∑-phe were significantly higher in opiate smokers than opiate eaters; other biomarkers did not vary by the route of opiate intake.
CONCLUSIONS
Both cigarette smokers and opiate users (by smoking or ingestion) were exposed to many toxicants and carcinogens.
IMPACT
This high exposure, particularly among dual opiate and cigarette users, can have a substantial global public health impact.
Topics: Administration, Oral; Adult; Biomarkers; Carcinogens; Cigarette Smoking; Cohort Studies; Humans; Iran; Male; Middle Aged; Opiate Alkaloids; Smoking, Non-Tobacco Products; Tobacco Products
PubMed: 31915141
DOI: 10.1158/1055-9965.EPI-19-1212 -
British Journal of Hospital Medicine... Sep 2022The forearm is the most common site of fracture in children. At the time of initial assessment, a thorough examination and neurovascular assessment of the limb is... (Review)
Review
The forearm is the most common site of fracture in children. At the time of initial assessment, a thorough examination and neurovascular assessment of the limb is necessary. X-rays allow evaluation of the fracture location and type, in addition to the degree of displacement. With the help of intranasal opiates, manipulation of fracture fragments can be performed in the emergency department. Immobilisation in plaster is the gold standard treatment for paediatric forearm fractures where the degree of displacement is within acceptable parameters. Manipulation and casting should be followed by orthogonal radiographs and a repeated neurovascular assessment of the limb. Oral analgesia and safety netting information should be provided on discharge and the child should be reviewed in fracture clinic within a week of the injury. This article reviews the British Orthopaedic Association Standards for Trauma and Orthopaedics for the early management of paediatric forearm fractures that do not require operative management.
Topics: Child; Forearm; Forearm Injuries; Humans; Opiate Alkaloids; Radiography; Radius Fractures
PubMed: 36193916
DOI: 10.12968/hmed.2021.0564 -
American Journal of Respiratory and... Sep 2021
Topics: Analgesia; Delirium; Humans; Opiate Alkaloids; Pain; Pain Management
PubMed: 33956575
DOI: 10.1164/rccm.202104-0968ED