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Cold Spring Harbor Perspectives in... Nov 2021There are currently effective Food and Drug Administration (FDA)-approved therapies for alcohol, nicotine, and opioid use disorders. This article will review the...
There are currently effective Food and Drug Administration (FDA)-approved therapies for alcohol, nicotine, and opioid use disorders. This article will review the development of eight compounds used in the treatment of drug addiction with an emphasis on pharmacological mechanisms and the utility of preclinical animal models of addiction in therapeutic development. In contrast to these successes, animal research has identified a number of promising medications for the treatment of psychostimulant use disorder, none of which have proven to be clinically effective. A specific example of an apparently promising pharmacotherapeutic for cocaine that failed clinically will be examined to determine whether this truly represents a challenge to the predictive validity of current models of cocaine addiction. In addition, the development of promising cocaine use disorder therapeutics derived from animal research will be reviewed, with some discussion regarding how preclinical studies might be modified to better inform clinical outcomes.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Bupropion; Central Nervous System Stimulants; Cocaine-Related Disorders; Drug Therapy; Humans; Naltrexone; Narcotic Antagonists; Nicotinic Agonists; Smoking Cessation Agents; Substance-Related Disorders; Varenicline
PubMed: 32601131
DOI: 10.1101/cshperspect.a040311 -
The Australian and New Zealand Journal... Feb 2024Alcohol use disorders confer a significant burden of disease and economic cost worldwide. However, the utilisation of pharmacotherapies to manage alcohol use disorder is... (Review)
Review
OBJECTIVE
Alcohol use disorders confer a significant burden of disease and economic cost worldwide. However, the utilisation of pharmacotherapies to manage alcohol use disorder is poor. We aimed to conduct a systematic review of economic evaluation studies of alcohol use disorder pharmacotherapies.
METHODS
A search was conducted in Embase, Medline, CINAHL, PsychINFO and EconLit (August 2019, updated September 2022). Full economic evaluations using pharmacotherapy to treat alcohol use disorders were included. Included studies were stratified by medication and summarised descriptively. The Consensus on Health Economic Criteria list was used to assess the methodological quality.
RESULTS
A total of 1139 studies were retrieved, of which 15 met the inclusion criteria. All studies were conducted in high-income countries. Four studies analysed nalmefene, four studies assessed acamprosate, three for naltrexone and four for stand-alone and/or combinations of naltrexone and acamprosate. There were 21 interventions synthesised from 15 studies as some studies evaluated multiple interventions and comparators. More than half of the included studies (73%) reported pharmacotherapy as dominant (less costly and more effective than comparators). From healthcare payer perspectives, five studies found that pharmacotherapy added to psychosocial support was dominant or cost-effective, accruing additional benefits at a higher cost but under accepted willingness to pay thresholds. Three analyses from a societal perspective found pharmacotherapy added to psychosocial support was a dominant or cost-effective strategy. Quality scores ranged from 63% to 95%.
CONCLUSION
Pharmacotherapy added to psychosocial support was cost-effective from both healthcare and societal perspectives, emphasising an increased role for pharmacotherapy to reduce the burden of alcohol use disorders.
Topics: Humans; Alcoholism; Acamprosate; Cost-Benefit Analysis; Naltrexone; Alcohol Drinking; Ethanol
PubMed: 37822267
DOI: 10.1177/00048674231201541 -
Molecular Psychiatry Jul 2021We previously reported that SNPs near TSPAN5 were associated with plasma serotonin (5-HT) concentrations which were themselves associated with selective serotonin...
We previously reported that SNPs near TSPAN5 were associated with plasma serotonin (5-HT) concentrations which were themselves associated with selective serotonin reuptake inhibitor treatment outcomes in patients with major depressive disorder (MDD). TSPAN5 SNPs were also associated with alcohol consumption and alcohol use disorder (AUD) risk. The present study was designed to explore the biological function of TSPAN5 with a focus on 5-HT and kynurenine concentrations in the tryptophan pathway. Ethanol treatment resulted in decreased 5-HT concentrations in human induced pluripotent stem cell (iPSC)-derived neuron culture media, and the downregulation of gene expression of TSPAN5, DDC, MAOA, MAOB, TPH1, and TPH2 in those cells. Strikingly, similar observations were made when the cells were treated with acamprosate-an FDA approved drug for AUD therapy. These results were replicated in iPSC-derived astrocytes. Furthermore, TSPAN5 interacted physically with proteins related to clathrin and other vesicle-related proteins, raising the possibility that TSPAN5 might play a role in vesicular function in addition to regulating expression of genes associated with 5-HT biosynthesis and metabolism. Downregulation of TSPAN5 expression by ethanol or acamprosate treatment was also associated with decreased concentrations of kynurenine, a major metabolite of tryptophan that plays a role in neuroinflammation. Knockdown of TSPAN5 also influenced the expression of genes associated with interferon signaling pathways. Finally, we determined that TSPAN5 SNPs were associated with acamprosate treatment outcomes in AUD patients. In conclusion, TSPAN5 can modulate the concentrations of 5-HT and kynurenine. Our data also highlight a potentially novel pharmacogenomic mechanism related to response to acamprosate.
Topics: Acamprosate; Alcohol Drinking; Alcoholism; Depressive Disorder, Major; Humans; Induced Pluripotent Stem Cells; Kynurenine; Neuroinflammatory Diseases; Pharmacogenetics; Serotonin; Tetraspanins; Tryptophan Hydroxylase
PubMed: 32753686
DOI: 10.1038/s41380-020-0855-9 -
Addiction (Abingdon, England) Sep 2020To examine whether World Health Organization (WHO) risk-level reductions in drinking were achievable, associated with improved functioning and maintained over time among... (Randomized Controlled Trial)
Randomized Controlled Trial
World Health Organization risk drinking level reductions are associated with improved functioning and are sustained among patients with mild, moderate and severe alcohol dependence in clinical trials in the United States and United Kingdom.
AIMS
To examine whether World Health Organization (WHO) risk-level reductions in drinking were achievable, associated with improved functioning and maintained over time among patients at varying initial alcohol dependence severity levels. Design and setting Secondary data analysis of multi-site randomized clinical trials: the US Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study and the UK Alcohol Treatment Trial (UKATT).
PARTICIPANTS
Individuals with alcohol dependence enrolled in COMBINE (n = 1383; 68.8% male) and seeking treatment for alcohol problems in UKATT (n = 742; 74.1% male). Interventions Naltrexone, acamprosate or placebo, and combined behavioral intervention or medication management in COMBINE. Social behavior network therapy or motivational enhancement therapy in UKATT.
MEASUREMENTS
WHO risk-level reductions were assessed via the calendar method. Alcohol dependence was measured by the Alcohol Dependence Scale, the Leeds Dependence Questionnaire and the Diagnostic and Statistical Manual of Mental Disorders. Measures of functioning included alcohol-related consequences (Drinker Inventory of Consequences and Alcohol Problems Questionnaire), mental health (Short Form Health Survey) and liver enzyme tests.
FINDINGS
One- and two-level reductions in WHO risk levels in the last month of treatment were maintained at the 1-year follow-up [adjusted odds ratio (OR), 95% confidence interval (CI) = one-level reduction in COMBINE: 3.51 (2.73, 4.29) and UKATT: 2.65 (2.32, 2.98)] and associated with fewer alcohol-related consequences [e.g. B, 95% CI = one-level reduction COMBINE: -26.22 (-30.62, -21.82)], better mental health [e.g. B, 95% CI = one-level reduction UKATT: 9.53 (7.36, 11.73)] and improvements in γ-glutamyltransferase [e.g. B, 95% CI = one-level reduction UKATT: -89.77 (-122.50, -57.04)] at the end of treatment, even among patients with severe alcohol dependence. Results were similar when abstainers were excluded. Conclusions Reductions in World Health Organization risk levels for alcohol consumption appear to be achievable, associated with better functioning and maintained over time in both the United States and the United Kingdom.
Topics: Acamprosate; Adult; Alcohol Deterrents; Alcohol Drinking; Alcohol-Related Disorders; Alcoholism; Behavior Therapy; Female; Health Surveys; Humans; Male; Mental Health; Middle Aged; Motivational Interviewing; Naltrexone; Risk; Treatment Outcome; United Kingdom; United States; World Health Organization
PubMed: 32056311
DOI: 10.1111/add.15011 -
Journal of General Internal Medicine Apr 2022Hospitalizations related to the consequences of substance use are rising yet most hospitalized patients with substance use disorder do not receive evidence-based...
INTRODUCTION
Hospitalizations related to the consequences of substance use are rising yet most hospitalized patients with substance use disorder do not receive evidence-based addiction treatment. Opportunities to leverage the hospitalist workforce could close this treatment gap.
AIM
To describe the development, implementation, and evaluation of a hospitalist-directed addiction consultation service (ACS) to provide in-hospital addiction treatment.
SETTING
Six hundred fifty-bed university hospital in Aurora, Colorado.
PROGRAM DESCRIPTION
Hospitalists completed buprenorphine waiver training, participated in a 13-part addiction lecture series, and completed a minimum of 40 hours of online addiction training. Hospitalists participated in shadow shifts with an addiction-trained physician. Dedicated addiction social workers developed relationships with local addiction treatment services.
PROGRAM EVALUATION METRICS
Physician-related metrics included education, training, and clinical time spent in addiction practice. Patient and encounter-related metrics included a description of ACS care provision.
RESULTS
Eleven hospitalists completed an average of 95 hours of addiction-related didactics. Once addiction training was complete, hospitalists spent an average of 30 days over 12 months staffing a weekday ACS. Between October 2019 and November 2020, the ACS completed 1620 consultations on 1350 unique patients. Alcohol was the most common substance (n = 1279; 79%), followed by tobacco (979; 60.4%), methamphetamines/amphetamines (n = 494; 30.5%), and opioids (n = 400; 24.7%). Naltrexone was the most frequently prescribed medication (n = 350; 21.6%), followed by acamprosate (n = 93; 5.7%), and buprenorphine (n = 77, 4.8%). Trauma was a frequent discharge diagnoses (n = 1564; 96.5%). Leaving prior to treatment completion was commonly noted (n = 120, 7.4%). The ACS completed 47 in-hospital methadone enrollments.
DISCUSSION
The hospitalist-directed ACS is a promising clinical initiative that could be implemented to expand hospital-based addiction treatment. Future research is needed to understand challenges to disseminating this model into other hospital settings, and to evaluate intended and unintended effects of broad implementation.
Topics: Addiction Medicine; Hospitalists; Hospitalization; Humans; Medicine; Referral and Consultation
PubMed: 34013473
DOI: 10.1007/s11606-021-06849-8 -
Alcoholism, Clinical and Experimental... Jun 2022Investigations show that medications for alcohol use disorders (MAUD) reduce heavy drinking and relapses. However, only 1.6% of individuals with alcohol use disorders...
RATIONALE
Investigations show that medications for alcohol use disorders (MAUD) reduce heavy drinking and relapses. However, only 1.6% of individuals with alcohol use disorders (AUD) receive MAUD across care settings. The epidemiology of MAUD prescribing in the acute care setting is incompletely described. We hypothesized that MAUD would be under prescribed in inpatient acute care hospital settings compared to the outpatient, emergency department (ED), and inpatient substance use treatment settings.
METHODS
We evaluated electronic health record (EHR) data from adult patients with an International Classification of Diseases, 10th revision (ICD-10) alcohol-related diagnosis in the University of Colorado Health (UCHealth) system between January 1, 2016 and 31 December, 2019. Data from patients with an ICD-10 diagnosis code for opioid use disorder and those receiving MAUD prior to their first alcohol-related episode were excluded. The primary outcome was prescribing of MAUD, defined by prescription of naltrexone, acamprosate, and/or disulfiram. We performed bivariate and multivariate analyses to identify independent predictors of MAUD prescribing at UCHealth.
RESULTS
We identified 48,421 unique patients with 136,205 alcohol-related encounters at UCHealth. Encounters occurred in the ED (42%), inpatient acute care (17%), inpatient substance use treatment (18%), or outpatient primary care (12%) settings. Only 2270 (5%) patients received MAUD across all settings. Female sex and addiction medicine consults positively predicted MAUD prescribing. In contrast, encounters outside inpatient substance use treatment, Hispanic ethnicity, and black or non-white race were negative predictors of MAUD prescribing. Compared to inpatient substance use treatment, inpatient acute care hospitalizations for AUD was associated with a 93% reduced odds of receiving MAUD.
CONCLUSIONS
AUD-related ED and inpatient acute care hospital encounters in our healthcare system were common. Nevertheless, prescriptions for MAUD were infrequent in this population, particularly in inpatient settings. Our findings suggest that the initiation of MAUD for patients with alcohol-related diagnoses in acute care settings deserves additional evaluation.
Topics: Adult; Alcoholism; Colorado; Delivery of Health Care; Ethanol; Female; Humans; Naltrexone; Opioid-Related Disorders
PubMed: 35723682
DOI: 10.1111/acer.14837 -
WMJ : Official Publication of the State... Apr 2022Phenibut is a psychoactive drug with GABA agonism. It remains unregulated and easily attainable in the United States, where it has become a novel drug of abuse.
INTRODUCTION
Phenibut is a psychoactive drug with GABA agonism. It remains unregulated and easily attainable in the United States, where it has become a novel drug of abuse.
CASE PRESENTATION
We present the case of a 34-year-old man who used phenibut consistently for 3 years. After 6 months of use, he developed signs of dependence and failed outpatient detoxification. While taking high doses, he experienced parasomnia-like symptoms and periods of dysexecutive function. After abrupt cessation, he developed severe withdrawal symptoms, was hospitalized, and required intubation. His condition improved after 1 week of treatment. After recovery and discharge, he remains stable utilizing an extended taper of acamprosate and baclofen.
DISCUSSION
Phenibut is not detected on urine drug screen and withdrawal symptoms are nonspecific. Optimal treatment of withdrawal remains unknown. Baclofen and phenobarbital have been successful for treatment of dependence.
CONCLUSION
Clinicians should be aware of phenibut abuse and the potential for dependence and withdrawal.
Topics: Adult; Baclofen; Humans; Male; Substance Withdrawal Syndrome; gamma-Aminobutyric Acid
PubMed: 35442585
DOI: No ID Found -
Hepatology Communications Apr 2023Medications for alcohol use disorder (MAUD) are highly effective in achieving and maintaining abstinence in patients with alcohol use disorder (AUD). Our aim was to...
BACKGROUND
Medications for alcohol use disorder (MAUD) are highly effective in achieving and maintaining abstinence in patients with alcohol use disorder (AUD). Our aim was to evaluate the effect of MAUD on all-cause mortality in patients with alcohol-associated cirrhosis and active alcohol use.
METHODS
This was a retrospective cohort study of patients with alcohol-associated cirrhosis and high-risk alcohol use disorder in the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) database. Propensity score matching for exposure to MAUD (acamprosate or naltrexone) within a year after cirrhosis diagnosis was performed to account for potential confounders, and the association between MAUD and all-cause mortality was subsequently evaluated using Cox regression analysis.
RESULTS
A total of 9131 patients were included, of whom 886 (9.7%) were exposed to MAUD (naltrexone: 520, acamprosate: 307, both medications: 59). The duration of MAUD exposure was >3 months in 345 patients (39%). The strongest positive predictor of MAUD prescription was an inpatient diagnosis code for AUD, followed by a concurrent diagnosis of depression; the strongest negative predictor was a history of cirrhosis decompensation. After propensity score matching (866 patients in each group) with excellent covariate balance (absolute standardized mean differences <0.1), MAUD exposure was associated with improved survival, with an HR of 0.80 relative to no MAUD exposure (95% CI: 0.67-0.97, p = 0.024).
CONCLUSION
MAUD are underutilized in patients with alcohol-associated cirrhosis with high-risk alcohol use behavior but are associated with improved survival after adjustment for confounders such as the severity of liver disease, age, and engagement in the healthcare system.
Topics: Humans; Alcoholism; Acamprosate; Naltrexone; Alcohol Deterrents; Retrospective Studies; Liver Cirrhosis, Alcoholic; Liver Cirrhosis
PubMed: 36972386
DOI: 10.1097/HC9.0000000000000093 -
Canadian Geriatrics Journal : CGJ Mar 2020Alcohol use disorder (AUD) is an increasingly common, under-recognized, and under-treated health concern in older adults. Its prevalence is expected to reach...
BACKGROUND
Alcohol use disorder (AUD) is an increasingly common, under-recognized, and under-treated health concern in older adults. Its prevalence is expected to reach unprecedented levels as the Canadian population ages. In response, Health Canada commissioned the Canadian Coalition of Seniors' Mental Health to create guidelines for the prevention, screening, assessment, and treatment of AUD in older adults.
METHODS
A systematic review of English language literature from 2008-2018 regarding AUD in adults was conducted. Previously published guidelines were evaluated using AGREE II, and key guidelines updated using ADAPTE method by drawing on current literature. Recommendations were created and assessed using the GRADE method.
RESULTS
Twenty-two recommendations were created. Prevention recommendations: Best advice for older adults who choose to drink is to limit intake to well below the national Low-Risk Alcohol Drinking Guidelines. Screening recommendations: Alcohol consumption should be reviewed and discussed on an annual basis by primary care providers. This type of discussion needs to be normalized and approached in a simple, neutral, straight-forward manner. Assessment recommendations: Positive screens for AUD should be followed by a comprehensive assessment. Once more details are obtained an individualized treatment plan can be recommended, negotiated, and implemented. Treatment recommendations: AUD falls on a spectrum of mild, moderate, and severe. It can also be complicated by concurrent mental health, physical, or social issues, especially in older adults. Naltrexone and Acamprosate pharmacotherapies can be used for the treatment of AUD in older adults, as individually indicated. Psychosocial treatment and support should be offered as part of a comprehensive treatment plan.
CONCLUSION
These guidelines provide practical and timely clinical recommendations on the prevention, assessment, and treatment of AUD in older adults within the Canadian context.
PubMed: 32226573
DOI: 10.5770/cgj.23.425 -
Cells Mar 2020Peripheral nerve injury (PNI) leads to the loss of motor, sensory, and autonomic functions, and often triggers neuropathic pain. During the last years, many efforts have...
Peripheral nerve injury (PNI) leads to the loss of motor, sensory, and autonomic functions, and often triggers neuropathic pain. During the last years, many efforts have focused on finding new therapies to increase axonal regeneration or to alleviate painful conditions. Still only a few of them have targeted both phenomena. Incipient or aberrant sensory axon regeneration is related to abnormal unpleasant sensations, such as hyperalgesia or allodynia. We recently have discovered NeuroHeal, a combination of two repurposed drugs; Acamprosate and Ribavirin. NeuroHeal is a neuroprotective agent that also enhances motor axon regeneration after PNI. In this work, we investigated its effect on sensory fiber regeneration and PNI-induced painful sensations in a rat model of spare nerve injury and nerve crush. The follow up of the animals showed that NeuroHeal treatment reduced the signs of neuropathic pain in both models. Besides, the treatment favored sensory axon regeneration, as observed in dorsal root ganglion explants. Mechanistically, the effects observed in vivo may improve the resolution of cell-protective autophagy. Additionally, NeuroHeal treatment modulated the P2X4-BDNF-KCC2 axis, which is an essential driver of neuropathic pain. These data open a new therapeutic avenue based on autophagic modulation to foster endogenous regenerative mechanisms and reduce the appearance of neuropathic pain in PNI.
Topics: Acamprosate; Animals; Autophagy; Axons; Brain-Derived Neurotrophic Factor; Calcium-Binding Proteins; Drug Combinations; Female; Hyperalgesia; Male; Microfilament Proteins; Motor Neurons; Nerve Regeneration; Neuralgia; Neurites; Neurogenesis; Peripheral Nerves; Rats, Sprague-Dawley; Receptors, Purinergic P2X4; Ribavirin; Sensory Thresholds; Spinal Cord Dorsal Horn; Symporters; K Cl- Cotransporters
PubMed: 32230770
DOI: 10.3390/cells9040808