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JAMA Nov 2023Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality. (Comparative Study)
Comparative Study Meta-Analysis
IMPORTANCE
Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality.
OBJECTIVE
To compare efficacy and comparative efficacy of therapies for alcohol use disorder.
DATA SOURCES
PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO, CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature was subsequently systematically monitored to identify relevant articles up to August 14, 2023, and the PubMed search was updated on August 14, 2023.
STUDY SELECTION
For efficacy outcomes, randomized clinical trials of at least 12 weeks' duration were included. For adverse effects, randomized clinical trials and prospective cohort studies that compared drug therapies and reported health outcomes or harms were included.
DATA EXTRACTION AND SYNTHESIS
Two reviewers evaluated each study, assessed risk of bias, and graded strength of evidence. Meta-analyses used random-effects models. Numbers needed to treat were calculated for medications with at least moderate strength of evidence for benefit.
MAIN OUTCOMES AND MEASURES
The primary outcome was alcohol consumption. Secondary outcomes were motor vehicle crashes, injuries, quality of life, function, mortality, and harms.
RESULTS
Data from 118 clinical trials and 20 976 participants were included. The numbers needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32) for acamprosate and 18 (95% CI, 4-32) for oral naltrexone at a dose of 50 mg/d. Compared with placebo, oral naltrexone (50 mg/d) was associated with lower rates of return to heavy drinking, with a number needed to treat of 11 (95% CI, 5-41). Injectable naltrexone was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, -4.99 days; 95% CI, -9.49 to -0.49 days) Adverse effects included higher gastrointestinal distress for acamprosate (diarrhea: risk ratio, 1.58; 95% CI, 1.27-1.97) and naltrexone (nausea: risk ratio, 1.73; 95% CI, 1.51-1.98; vomiting: risk ratio, 1.53; 95% CI, 1.23-1.91) compared with placebo.
CONCLUSIONS AND RELEVANCE
In conjunction with psychosocial interventions, these findings support the use of oral naltrexone at 50 mg/d and acamprosate as first-line pharmacotherapies for alcohol use disorder.
Topics: Humans; Acamprosate; Alcohol Drinking; Alcoholism; Drug-Related Side Effects and Adverse Reactions; Naltrexone; Prospective Studies; Quality of Life; United States; Alcohol Deterrents; Psychosocial Intervention
PubMed: 37934220
DOI: 10.1001/jama.2023.19761 -
Gut Microbes Dec 2023Opioid crisis is an ongoing epidemic since the past several decades in the United States. Opioid use-associated microbial dysbiosis is emerging as a key regulator of...
Opioid crisis is an ongoing epidemic since the past several decades in the United States. Opioid use-associated microbial dysbiosis is emerging as a key regulator of intestinal homeostasis and behavioral responses to opioid. However, the mechanistic insight into the role of microbial community in modulating host response is unavailable. To uncover the role of opioid-induced dysbiosis in disrupting intestinal homeostasis we utilized whole genome sequencing, untargeted metabolomics, and mRNA sequencing to identify changes in microbiome, metabolome, and host transcriptome respectively. Morphine treatment resulted in significant expansion of , , and depletion of . These changes correlated with alterations in lipid metabolites and flavonoids. Significant alteration in microbial metabolism (metabolism of lipids, amino acids, vitamins and cofactors) and increased expression of virulence factors and biosynthesis of lipopolysaccharides (LPS) and lipoteichoic acid (LTA) were observed in microbiome of morphine-treated animals. In concurrence with changes in microbiome and metabolome extensive changes in innate and adaptive immune response, lipid metabolism, and gut barrier dysfunction were observed in the host transcriptome. Microbiome depleted mice displayed lower levels of inflammation, immune response and tissue destruction compared to mice harboring a dysbiotic microbiome in response to morphine treatment, thus establishing dysbiotic microbiome as mediator of morphine gut pathophysiology. Integrative analysis of multi-omics data highlighted the associations between , , and altered levels of riboflavin, flavonoids, and lipid metabolites including phosphocholines, carnitines, bile acids, and ethanolamines with host gene expression changes involved in inflammation and barrier integrity of intestine. Omic analysis also highlighted the role of probiotic bacteria , metabolites flavonoids and riboflavin that were depleted with morphine as important factors for intestinal homeostasis. This study presents for the first time ever an interactive view of morphine-induced changes in microbial metabolism, strain level gut microbiome analysis and comprehensive view of changes in gut transcriptome. We also identified areas of potential therapeutic interventions to limit microbial dysbiosis and present a unique resource to the opioid research community.
Topics: Animals; Mice; Gastrointestinal Microbiome; Analgesics, Opioid; Dysbiosis; Multiomics; Opioid-Related Disorders; Riboflavin; Morphine Derivatives; Lipids
PubMed: 37610102
DOI: 10.1080/19490976.2023.2246184 -
Forensic Science International Aug 2023New synthetic opioids (NSO) constitute one of the fastest-growing group of New Psychoactive Substances, which emerged on the illicit drug marker in the second half of... (Review)
Review
BACKGROUND
New synthetic opioids (NSO) constitute one of the fastest-growing group of New Psychoactive Substances, which emerged on the illicit drug marker in the second half of 2000's. The most popular and the largest NSO subgroup are high potency fentanyl and its analogs. Subsequent to core-structure scheduling of fentanyl-related substances many opioids with different chemical structures are now emerging on the illicit drug market, rendering the landscape highly complex and dynamic.
METHODS
PubMed, Scopus and Google Scholar were searched for appropriate articles up to December 2022. Moreover, a search for reports was conducted on Institutional websites to identify documentation published by World Health Organization, United Nations Office on Drugs and Crime, United States Drug Enforcement Administration, and European Monitoring Centre for Drugs and Drug Addiction. Only articles or reports written in English were selected.
RESULTS
Non-fentanyl derived synthetic opioids, i.e., 2-benzylbenzimidazoles (nitazenes), brorphine, U-compounds, AH-7921, MT-45 and related compounds are characterized, describing them in terms of available forms, pharmacology, metabolism as well as their toxic effects. Sample procedures and analytical techniques available for detection and quantification of these compounds in biological matrices are also presented. Finally, as overdoses involving highly potent NSO may be difficult to reverse, the effectiveness of naloxone as a rescue agent in NSO overdose is discussed.
CONCLUSIONS
Current review presents key information on non-fentanyl derived NSO. Access to upto-date data on substances of abuse is of great importance for clinicians, public health authorities and professionals performing analyses of biological samples.
Topics: Humans; Analgesics, Opioid; Fentanyl; Opioid-Related Disorders; Naloxone; Illicit Drugs; Drug Overdose
PubMed: 37423031
DOI: 10.1016/j.forsciint.2023.111775 -
Scientific Reports Nov 2023Opiate alkaloids and their synthetic derivatives are still widely used in pain management, drug addiction, and abuse. To avoid serious side effects, compounds with...
Opiate alkaloids and their synthetic derivatives are still widely used in pain management, drug addiction, and abuse. To avoid serious side effects, compounds with properly designed pharmacological profiles at the opioid receptor subtypes are long needed. Here a series of 17-N-substituted derivatives of normorphine and noroxymorphone analogues with five- and six-membered ring substituents have been synthesized for structure-activity study. Some compounds showed nanomolar affinity to MOR, DOR and KOR in in vitro competition binding experiments with selective agonists [H]DAMGO, [H]Ile-deltorphin II and [H]HS665, respectively. Pharmacological characterization of the compounds in G-protein signaling was determined by [S]GTPγS binding assays. The normorphine analogues showed higher affinity to KOR compared to MOR and DOR, while most of the noroxymorphone derivatives did not bind to KOR. The presence of 14-OH substituent resulted in a shift in the pharmacological profiles in the agonist > partial agonist > antagonist direction compared to the parent compounds. A molecular docking-based in silico method was also applied to estimate the pharmacological profile of the compounds. Docking energies and the patterns of the interacting receptor atoms, obtained with experimentally determined active and inactive states of MOR, were used to explain the observed pharmacological features of the compounds.
Topics: Receptors, Opioid, mu; Molecular Docking Simulation; Receptors, Opioid; Binding, Competitive; Structure-Activity Relationship; Receptors, Opioid, kappa
PubMed: 37985681
DOI: 10.1038/s41598-023-46317-3 -
Drug and Alcohol Dependence Aug 2023The emergence of novel synthetic opioids (NSOs) is contributing to the opioid overdose crisis. While fentanyl analogs have historically dominated the NSO market, a shift...
BACKGROUND
The emergence of novel synthetic opioids (NSOs) is contributing to the opioid overdose crisis. While fentanyl analogs have historically dominated the NSO market, a shift towards non-fentanyl compounds is now occurring.
METHODS
Here, we examined the neuropharmacology of structurally distinct non-fentanyl NSOs, including U-47700, isotonitazene, brorphine, and N-desethyl isotonitazene, as compared to morphine and fentanyl. Compounds were tested in vitro using opioid receptor binding assays in rat brain tissue and by monitoring forskolin-stimulated cAMP accumulation in cells expressing the human mu-opioid receptor (MOR). Compounds were administered subcutaneously to male Sprague-Dawley rats, and hot plate antinociception, catalepsy score, and body temperature changes were measured.
RESULTS
Receptor binding results revealed high MOR selectivity for all compounds, with MOR affinities comparable to those of morphine and fentanyl (i.e., nM). All drugs acted as full-efficacy MOR agonists in the cyclic AMP assay, but nitazene analogs had greater functional potencies (i.e., pM) compared to the other drugs (i.e., nM). When administered to rats, all compounds induced opioid-like antinociception, catalepsy, and body temperature changes, but nitazenes were the most potent. Similar to fentanyl, the nitazenes had faster onset and decline of in vivo effects when compared to morphine. In vivo potencies to induce antinociception and catalepsy (i.e., EDs) correlated with in vitro functional potencies (i.e., ECs) but not binding affinities (i.e., Ks) at MOR.
CONCLUSIONS
Collectively, our findings indicate that non-fentanyl NSOs pose grave danger to those individuals who use opioids. Continued vigilance is needed to identify and characterize synthetic opioids as they emerge in clandestine drug markets.
Topics: Rats; Male; Humans; Animals; Analgesics, Opioid; Fentanyl; Illicit Drugs; Catalepsy; Neuropharmacology; Rats, Sprague-Dawley; Morphine; Receptors, Opioid, mu
PubMed: 37276825
DOI: 10.1016/j.drugalcdep.2023.109939 -
Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.British Journal of Pharmacology Dec 2023Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The...
BACKGROUND AND PURPOSE
Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy.
EXPERIMENTAL APPROACH
Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays.
KEY RESULTS
Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds.
CONCLUSION AND IMPLICATIONS
In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.
Topics: Male; Humans; Animals; Mice; Analgesics, Opioid; Oxycodone; HEK293 Cells; Morphine; Respiratory Insufficiency; Methadone
PubMed: 37489013
DOI: 10.1111/bph.16199 -
Phytomedicine : International Journal... Dec 2023Sinomenine (SIN) is the main pharmacologically active component of Sinomenii Caulis and protects against rheumatoid arthritis (RA). In recent years, many studies have... (Review)
Review
BACKGROUND
Sinomenine (SIN) is the main pharmacologically active component of Sinomenii Caulis and protects against rheumatoid arthritis (RA). In recent years, many studies have been conducted to elucidate the pharmacological mechanisms of SIN in the treatment of RA. However, the molecular mechanism of SIN in RA has not been fully elucidated.
PURPOSE
To summarize the pharmacological effects and molecular mechanisms of SIN in RA and clarify the most valuable regulatory mechanisms of SIN to provide clues and a basis for basic research and clinical applications.
METHODS
We systematically searched SciFinder, Web of Science, PubMed, China National Knowledge Internet (CNKI), the Wanfang Databases, and the Chinese Scientific Journal Database (VIP). We organized our work based on the PRISMA statement and selected studies for review based on predefined selection criteria.
OUTCOME
After screening, we identified 201 relevant studies, including 88 clinical trials and 113 in vivo and in vitro studies on molecular mechanisms. Among these studies, we selected key results for reporting and analysis.
CONCLUSIONS
We found that most of the known pharmacological mechanisms of SIN are indirect effects on certain signaling pathways or proteins. SIN was manifested to reduce the release of inflammatory cytokines such as Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1β, thereby reducing the inflammatory response, and apparently blocking the destruction of bone and cartilage. The regulatory effects on inflammation and bone destruction make SIN a promising drug to treat RA. More notably, we believe that the modulation of α7nAChR and the regulation of methylation levels at specific GCG sites in the mPGES-1 promoter by SIN, and its mechanism of directly targeting GBP5, certainly enriches the possibilities and the underlying rationale for SIN in the treatment of inflammatory immune-related diseases.
Topics: Humans; Arthritis, Rheumatoid; Anti-Inflammatory Agents; Morphinans; Signal Transduction
PubMed: 37816287
DOI: 10.1016/j.phymed.2023.155114 -
Molecular Metabolism Sep 2023Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and...
OBJECTIVE
Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the μ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties.
METHODS
Receptor and channel binding assays were conducted to evaluate the drug safety of our DXM derivative. Pancreatic islets were used to investigate the effect of the compound on insulin secretion and islet cell survival. Via liquor collection from the brain and a behavioral assay, we analyzed the BBB permeability. By performing intraperitoneal and oral glucose tolerance tests as well as pharmacokinetic analyses, the antidiabetic potential and elimination half-life were investigated, respectively. To analyze the islet cell-protective effect, we used fluorescence microscopy as well as flow cytometric analyses.
RESULTS
Here, we report the design and synthesis of an optimized, orally available BBB-impermeable DXM derivative with lesser binding to hERG and MOR than previous ones. We also show that the new compound substantially enhances glucose-stimulated insulin secretion (GSIS) from mouse and human islets and glucose tolerance in mice as well as protects pancreatic islets from cell death induced by reactive oxygen species and that it amplifies the effects of tirzepatide on GSIS and islet cell viability.
CONCLUSIONS
We succeeded to design and synthesize a novel morphinan derivative that is BBB-impermeable, glucose-lowering and islet cell-protective and has good drug safety despite its morphinan and imidazole structures.
Topics: Mice; Humans; Animals; Diabetes Mellitus, Type 2; Insulin; Morphinans; Islets of Langerhans; Glucose; Hypoglycemic Agents; Oxidative Stress
PubMed: 37451343
DOI: 10.1016/j.molmet.2023.101775 -
Sleep Sep 2023Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found...
Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXB's mechanism of action on narcolepsy.
Topics: Humans; Mice; Animals; Dogs; Orexins; Sodium Oxybate; Cataplexy; Locus Coeruleus; Narcolepsy; Neurons; Opiate Alkaloids
PubMed: 37155728
DOI: 10.1093/sleep/zsad135 -
JAMA Psychiatry Dec 2023Gabapentin prescriptions have drastically increased in the US due to off-label prescribing in settings such as opioid use disorder (OUD) treatment to manage a range of...
IMPORTANCE
Gabapentin prescriptions have drastically increased in the US due to off-label prescribing in settings such as opioid use disorder (OUD) treatment to manage a range of comorbid conditions and withdrawal symptoms, despite a lack of evidence.
OBJECTIVE
To assess the purpose and associated risks of off-label gabapentin use in OUD treatment.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective recurrent-event case-control study with a crossover design used administrative claims data from MarketScan Commercial and Multi-State Medicaid databases from January 1, 2006, to December 31, 2016. Individuals aged 12 to 64 years with an OUD diagnosis and filling buprenorphine prescriptions were included in the primary analysis conducted from July 1, 2022, through June 1, 2023. Unit of observation was the person-day.
EXPOSURES
Days covered by filled gabapentin prescriptions.
MAIN OUTCOMES AND MEASURES
Primary outcomes were receipt of gabapentin in the 90 days after initiation of buprenorphine treatment and drug-related poisoning. Drug-related poisonings were defined using codes from International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.
RESULTS
A total of 109 407 patients were included in the analysis (mean [SD] age, 34.0 [11.2] years; 60 112 [54.9%] male). Among the 29 967 patients with Medicaid coverage, 299 (1.0%) were Hispanic, 1330 (4.4%) were non-Hispanic Black, 23 112 (77.1%) were non-Hispanic White, and 3399 (11.3%) were other. Gabapentin was significantly less likely to be prescribed to Black or Hispanic patients, and more likely to be prescribed to female patients, those with co-occurring substance use or mood disorders, and those with comorbid physical conditions such as neuropathic pain. Nearly one-third of persons who received gabapentin (4336 [31.1%]) had at least 1 drug-related poisoning after initiating buprenorphine treatment, compared with 13 856 (14.5%) among persons who did not receive gabapentin. Adjusted analyses showed that days of gabapentin use were not associated with hospitalization for drug-related poisoning (odds ratio, 0.98 [95% CI, 0.85-1.13]). Drug-related poisoning risks did not vary based on dosage.
CONCLUSIONS AND RELEVANCE
Gabapentin is prescribed in the context of a myriad of comorbid conditions. Even though persons receiving gabapentin are more likely to have admissions for drug-related poisoning, these data suggest that gabapentin is not associated with an increased risk of drug-related poisoning alongside buprenorphine in adjusted analyses. More data on the safety profile of gabapentin in OUD settings are needed.
Topics: Adult; Female; Humans; Male; Analgesics, Opioid; Buprenorphine; Case-Control Studies; Drug-Related Side Effects and Adverse Reactions; Gabapentin; Opiate Substitution Treatment; Opioid-Related Disorders; Retrospective Studies; United States; Cross-Over Studies
PubMed: 37672238
DOI: 10.1001/jamapsychiatry.2023.3145