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Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial (vol 293, pg 1617, 2005)
... Participants were randomized to a group treated with naltrexone (either oral once daily or targeted (drinking days only) 50 to 150 mg or injectable naltrexone 380 or 190 mg, with or without a behavioral intervention or to a group receiving placebo with or without a behavioral intervention. Six studies enrolled participants with alcohol dependence, diagnosed by the American Psychiatric Association's Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) (Garbutt et al., 2005; Greenfield et al., 2010; Kiefer et al., 2005; Kranzler et al., 2009; O'Malley et al., 2007; Pettinati et al., 2008). All of the studies except Pettinati and colleagues (2008) excluded persons who were dependent on substances other than alcohol or nicotine. ...
... In the 4 studies that reported race/ethnicity, the majority of women were Caucasian (n = 576), followed by Hispanic (n = 38), and then African American (n = 37). Five studies reported the proportion of women who received naltrexone (daily or targeted) (n = 271) or placebo (n = 202) (Garbutt et al., 2005; Greenfield et al., 2010; Kiefer et al., 2005; O'Malley et al., 2007; Pettinati et al., 2008). All of the studies reported the timing of intervention application, ranging from 8 to 16 weeks. ...
... All of the studies reported the timing of intervention application, ranging from 8 to 16 weeks. Furthermore , the 7 studies utilized variable participant recruitment methods: advertisements (Greenfield et al., 2010; Hernandez-Avila et al., 2006; O'Malley et al., 2007 ), clinicians referrals (Hernandez-Avila et al., 2006; Kranzler et al., 2009), alcohol treatment study sites (Greenfield et al., 2010; Kiefer et al., 2005; O'Malley et al., 2007; Pettinati et al., 2008), public hospitals, private and Veteran Administration clinics, or tertiary care settings (Garbutt et al., 2005). ...
Several clinical trials have evaluated naltrexone as a treatment for alcohol use disorders (AUDs), but few have focused on women. The aim of this review was to systematically review and summarize the evidence regarding the impact of naltrexone compared to placebo for attenuating alcohol consumption in women with an AUD. A systematic review was conducted using PubMed, Cochrane, Web of Science, CINAHL, and Alcohol Studies Database to identify relevant peer-reviewed randomized controlled trials (RCTs) published between January 1990 and August 2016. Seven published trials have evaluated the impact of naltrexone on drinking outcomes in women distinct from men; 903 alcohol-dependent or heavy drinking women were randomized to receive once daily oral or depot (injectable) naltrexone or placebo with/without behavioral intervention. Two studies examining the quantity of drinks per day observed trends toward reduction in drinking quantity among women who received naltrexone versus placebo. The 4 studies examining the frequency of drinking had mixed results, with 1 study showing a trend that favored naltrexone, 2 showing a trend that favored placebo, and 1 that showed no difference. Two of the 3 studies examining time to relapse observed trends that tended to favor naltrexone for time to any drinking and time to heavy drinking among women who received naltrexone versus placebo. While the growing body of evidence suggests a variety of approaches to treat AUD, the impact of naltrexone to combat AUD in women is understudied. Taken together, the results suggest that naltrexone may lead to modest reductions in quantity of drinking and time to relapse, but not on the frequency of drinking in women. Future research should incorporate sophisticated study designs that examine gender differences and treatment effectiveness among those diagnosed with an AUD and present data separately for men and women.
... The efficacy of XR-NTX was demonstrated in a multicenter randomized controlled trial including 624 participants, receiving a monthly injection with XR-NTX 380mg, XR-NTX 190mg or placebo, combined with a 12 sessions of low-intensity psychosocial intervention. Compared with placebo XR-NTX 380mg decreased in 25% the rate of heavy drinking days [142]. A secondary analysis of outcomes determine that XR-NTX 380mg was more effective in reducing drinking days and heavy drinking days in patient with at least 4 days of abstinence, while XR-NTX show intermediate results indicating a dose-effect response [143] . ...
... A Cochrane review indicate that XR- NTX reduced the risk of any drinking after detoxification to 92% of the placebo [129]. XR-NTX have a safety profile similar to oral Naltrexone excepted for injection site reactions, and theoretically lower risk of liver toxicity because of its lack of first-pass hepatic metabolism, and reduced doses [129,142]. Copyright Fonte A.This book chapter is open access distributed under the Creative Commons Attribution 4.0 International License, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited. ...
... Numerous potentials factors associated with a better response to Naltrexone in alcohol dependence have been suggested like: family history of alcoholism [144][145][146][147]; history of abuse of other substances [144]; onset of alcohol abuse before age 25 [144,148]; higher levels of craving [145,149]; antisocial traits [146]; high baseline depressive symptomatology [148]; type III and IV of Lesch's typology [148]; poor cognitive functioning [149]; Asn40Asp polymorphism of the μ-opioid receptor [150,151]; male gender [142,152]; type A of Babor's typology [153]. Of this, only Family History of Alcoholism and Asn40Asp polymorphism of the μ-opioid receptor has a consistent evidence of improving the effect of Naltrexone in patient with alcohol dependence [154]. ...
... This was a post hoc analysis of a 24-week, multicenter, randomized placebo-controlled study. The study design, methodology, and primary results have been described previously (Garbutt et al., 2005). Eligible patients were adult men and women aged 18 years who had a diagnosis of alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. ...
... The intent-to-treat sample included 624 patients: 205 in the XR-NTX 380-mg group, 210 in the XR-NTX 190-mg group, and 209 in the placebo group. Patient demographic and baseline characteristics have been reported previously (Garbutt et al., 2005). At baseline, the majority of patients did not have a goal of abstinence (57%) and had not established 4 days of abstinence (87%). ...
... A nonparametric analysis of variance revealed that significantly better drinking outcomes were found in association both with membership in the XR-NTX 380 mg treatment group (P 0.03, as reported in theGarbutt et al. (2005)article) and greater attendance at self-help groups (P 0.04). There was no significant interaction (P 0.44) between treatment group and attendance at self-help meetings in relation to heavy drinking outcomes. ...
: The impact of intramuscular, injectable, extended-release naltrexone (XR-NTX; Vivitrol) on counseling and support group participation was examined in a post hoc analysis of a 24-week, randomized, double-blind study in 624 alcohol-dependent adults, most of whom were nonabstinent at baseline.
: Patients were offered 6 monthly injections of XR-NTX 380 mg, XR-NTX 190 mg, or placebo (n = 205, 210, and 209, respectively) and 12 sessions of manualized brief counseling. Voluntary participation in extramural counseling (eg, couples or family therapy) and self-help support groups (eg, Alcoholics Anonymous) was permitted and assessed.
: The proportion of patients attending all 12 Biopsychosocial, Report, Empathy, Needs, Direct advice, and Assessment sessions was nonsignificantly greater for XR-NTX 380 mg (45%) than for placebo (39%), as was the proportion attending extramural counseling (10% vs 7%) and support groups (13% vs 10%). Attendance rates were intermediate with XR-NTX 190-mg. Attending self-help groups was significantly (P = 0.04) related to reduced heavy drinking across all treatment groups.
: XR-NTX is compatible with counseling and support group participation in the treatment of alcohol dependence.
... Naltrexone, an opioid antagonist, is used to treat alcoholism and opioid dependence (1). A diffuse pneumonia has been rarely reported secondary to naltrexone (1). A markedly elevated lactate is usually an ominous finding (2). ...
... We identified 2 other case reports of acute eosinophilic pneumonia following naltrexone injection (1,6). We speculate that the dose of methylprednisolone given in the emergency department lowered the eosinophil percentage in her BAL to slightly below what is usually seen in acute eosinophilic pneumonia. ...
No abstract available. Article truncated after 150 words. History of Present Illness: A 61-year-old woman presented to the emergency department for 3 days of fevers up to 102º F, malaise, and progressive shortness of breath. Her symptoms started immediately after he last naltrexone injection for alcohol use disorder. Past Medical History, Social History and Family History: Alcohol use disorder; Treated with monthly naltrexone injections, received 3 doses total, and gabapentin; No other previous medical issues; Nonsmoker. Physical Examination; Vital signs: Pulse 100, BP 108/90, respiratory rate 34, SpO2 93% 10L non-rebreathing mask; Cyanotic on room air; Lungs clear. Radiography: A portable chest x-ray was performed in the emergency department (Figure 1). A thoracic CT scan was performed (Figure 2). Laboratory: CBC showed a white blood cell count of 12,000 cells/mcL; The differential shows a left shift; Lactate was 5.2 mmol/L. Which of the following is (are) true? 1. A lactate level of 5.2 can be a normal finding …
... A recent development designed to deal with the advice, or even a legal dictate, to take Ntx tablets daily is to prescribe an injection providing 28 days of circulating Ntx. The prescription to take injections providing extended release of Ntx (XR-Ntx) increases indices of success [55, 56]. The study of Garbutt et al. [55] was done with some patients who were not abstinent at the time of their first injections. ...
... The prescription to take injections providing extended release of Ntx (XR-Ntx) increases indices of success [55, 56]. The study of Garbutt et al. [55] was done with some patients who were not abstinent at the time of their first injections. ...
The idea is developed that computer-assisted game-like programs are a reasonable next step toward improving the treatment of alcoholism. Such programs are apt to be useful in rehabilitating the cognitive processes reduced by sustained intake of toxic amounts of ethanol and in counterconditioning the unconscious cues sustaining the habit of drinking alcoholic beverages. The evidence indicates that it is likely that prescribing naltrexone will facilitate psychotherapy for alcoholism, including practices useful in rehabilitating diminished cognitive ability.
... We hypothesized that the organizational readiness intervention would increase provider and staff acceptance and perceptions of appropriateness and feasibility of three evidence based SUD treatments-extended-release injectable naltrexone (XR-NTX) for alcohol use disorders, buprenorphine/naloxone (BUP/NX) for opioid use disorders, and a 6-session motivational interviewing/ cognitive behavioral therapy (MI/CBT)-based psychotherapy for both disorders-and greater intention to adopt these treatments among the providers (i.e., physicians for the medications and therapists for the psychotherapy). XR-NTX is effective for people with alcohol or opioid disorders and also is feasible for delivery in primary care [52][53][54][55][56]; BUP/NX has been proven effective for patients with opioid use disorders and is feasible for delivery in office-based settings [1][2][3][4][5][6][7]; and MI/CBT-based therapies have shown efficacy in reducing substance use across settings [57][58][59][60]. For this study, prescribing medical providers were trained to deliver XR-NTX for alcohol use disorders only. ...
Background
Millions of people with substance use disorders (SUDs) need, but do not receive, treatment. Delivering SUD treatment in primary care settings could increase access to treatment because most people visit their primary care doctors at least once a year, but evidence-based SUD treatments are underutilized in primary care settings. We used an organizational readiness intervention comprised of a cluster of implementation strategies to prepare a federally qualified health center to deliver SUD screening and evidence-based treatments (extended-release injectable naltrexone (XR-NTX) for alcohol use disorders, buprenorphine/naloxone (BUP/NX) for opioid use disorders and a brief motivational interviewing/cognitive behavioral –based psychotherapy for both disorders). This article reports the effects of the intervention on key implementation outcomes. Methods
To assess changes in organizational readiness we conducted pre- and post-intervention surveys with prescribing medical providers, behavioral health providers and general clinic staff (N = 69). We report on changes in implementation outcomes: acceptability, perceptions of appropriateness and feasibility, and intention to adopt the evidence-based treatments. We used Wilcoxon signed rank tests to analyze pre- to post-intervention changes. ResultsAfter 18 months, prescribing medical providers agreed more that XR-NTX was easier to use for patients with alcohol use disorders than before the intervention, but their opinions about the effectiveness and ease of use of BUP/NX for patients with opioid use disorders did not improve. Prescribing medical providers also felt more strongly after the intervention that XR-NTX for alcohol use disorders was compatible with current practices. Opinions of general clinic staff about the appropriateness of SUD treatment in primary care improved significantly. Conclusions
Consistent with implementation theory, we found that an organizational readiness implementation intervention enhanced perceptions in some domains of practice acceptability and appropriateness. Further research will assess whether these factors, which focus on individual staff readiness, change over time and ultimately predict adoption of SUD treatments in primary care.
... This agent is administered in a 360mg monthly gluteal injection. It alleviates the problem of non-adherence, has been shown to be effective compared to placebo in reducing heavy drinking [72] and has also recently been FDA approved for treatment of opiate dependence. Additional advantages of long-acting intramuscular naltrexone include less risk of hepatotoxicity and less nausea. ...
... Patients treated with naltrexone had significantly fewer drinking days, fewer heavy drinking days, and reported less craving than did those treated with placebo, with no worsening psychosis. A long-acting, injectable form of naltrexone is available [66], but to our knowledge it has not been studied in patients with schizophrenia and alcohol disorders. Acamprosate Acamprosate is thought to restore the balance between inhibitory and excitatory systems [67] involved in the negative reinforcing effects of alcohol and the response to alcohol cues [68]. ...
Substance use disorders, common in patients with schizophrenia, can lead to poor outcomes. Here we review the literature on the use of antipsychotics in patients with co-occurring schizophrenia and substance use disorder as well as evidence for the use of adjunctive pharmacological treatments targeting substance use in these patients. We also discuss a neurobiological formulation suggesting that the co-occurrence of these disorders may be related to a dysfunction in the dopamine mediated brain reward circuitry. Typical antipsychotics do not appear to decrease substance use in this population. Randomized, controlled trials provide some support for use of the atypical antipsychotic clozapine for co-occurring cannabis use disorder, naltrexone and disulfiram for alcohol use disorder, and also nicotine replacement therapy, sustained-release bupropion and varenicline for tobacco use disorder. Nonetheless, data regarding treatment in patients with these co-occurring disorders are still limited, and many studies reported to date have been either underpowered or did not include a control condition. Further research is needed to evaluate optimal pharmacotherapeutic strategies for this population.
... All patients demonstrated a sharp reduction in the percentage of heavy drinking days during the treatment period—from ∼75% to ∼20%, regardless of their SL/SDL status. The robust effect of this treatment is consistent with results reported in other published clinical trials, e.g. Garbutt et al., (2005). However, SL and SDL individuals differed significantly in their ability to abstain from alcohol (seeFig. ...
... Oral naltrexone is known for its hepatotoxicity but may merit further assessment as to its role in the treatment of subjects with pre-existent and ongoing liver damage. The same can be said about extendedrelease naltrexone, especially since there is no clear evidence for its hepatoxicity [45,46]. The present systematic review has some significant limitations, including the lack of mechanism to exclude publication bias, as no search for unpublished studies was undertaken other than on clinicaltrials.gov. ...
Treating alcohol use disorders (AUD) is critical in individuals suffering from hepatitis C infection (HCV). Aside from psychosocial interventions, pharmacological treatment is effective for decreasing alcohol consumption and promoting abstinence. However, unique factors belonging to HCV-infected individuals, such as baseline hepatic vulnerability and possible ongoing hepatitis C treatment, complicate AUD drug therapy. The goal of this review is to systematically identify, summarize, and evaluate the existing evidence on the pharmacological management of AUD in HCV-infected individuals. MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were searched for English- and French-language articles published from 1993 to December 2013. The search criteria focused on clinical trials and observational studies assessing the efficacy and/or safety of pharmacological management of AUD in patients infected with HCV. Of 421 identified studies, three were included for analysis. Two were observational studies assessing the safety of disulfiram. One was a randomized controlled trial assessing the efficacy and safety of baclofen. There is paucity of data regarding the efficacy and safety of pharmacological treatment of AUD in HCV-infected individuals, with studies being small series and showing significant heterogeneity. No strong recommendations can be made based on the current studies as to which pharmacological option should be preferred in this sub-population.
... A Treatment Improvement Protocol (TIPS) published by the Substance Abuse Mental Health Services Administration (SAMHSA) provides comprehensive information and treatment guidelines for naltrexone [34]. To address poor medication adherence with oral naltrexone, a sustained-release, intramuscular naltrexone preparation is FDA approved for the treatment of alcohol dependence via a once monthly injection [35]. Nalmefene is an opioid antagonist initially approved for the reversal of opioid intoxication. ...
Advances in neurobiology have increased our understanding of the underlying mechanisms of drug and alcohol dependence and led to the development of medications to treat addictive disorders (Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35(1):217-38). Addictive disorders are increasingly recognized as medical conditions, influenced by genetic, biological and psychosocial factors, for which the optimal treatment combines both pharmacological and psychosocial therapies (McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284(13):1689-95). This review discusses the neurobiology and physiology of addiction, the putative mechanisms of action of pharmacotherapies in the treatment of addictive disorders and the evidence for their efficacy.
... The results obtained with these formulations are inconsistent. In a large, placebo-controlled, double-blind, randomized, multi-site, 24-week clinical trial, Garbutt et al. [135] found that high-dose Vivitrex ® (380 mg) recipients had a significantly lower percentage of heavy drinking days than the subjects who received placebo. Recipients of low-dose Vivitrex ® (190 mg) had outcomes similar to those who received placebo. ...
The development of alcohol dependence is the result of a combination of various factors. Psychosocial and psychiatric conditions, together with functional alterations of the brain or genetic traits, contribute to the development of problems related to alcohol use or alcohol dependence. Clinical studies using neuroimaging techniques (PET, fMRI) and preclinical studies using different animal models of problems related to ethanol consumption have improved our knowledge of the neurochemical mechanisms involved in alcohol dependence. These studies have served to identify peptides or receptors modified by ethanol consumption, which are functionally altered in strains of rats or mice highly vulnerable to ethanol consumption. Such peptides or receptors may be interesting targets for the treatment of alcoholism. Among the different targets studied in recent years, the opioid and cannabinoid systems meet a number of conditions for eligibility as candidates for the treatment of alcohol dependence. The -opioid receptor and cannabinoid CB1 receptor, in particular, are affected by ethanol consumption. In clinical studies, genetic polymorphisms of the -opioid and CB1 receptors have been associated with increased vulnerability to alcohol consumption. Similarly, functional alterations in -opioid and cannabinoid receptors have been identified in specific strains of rats or mice with high preference to ethanol consumption. Furthermore, several studies have shown that the manipulation of these receptors using agonists or antagonists may increase or decrease ethanol consumption, which confirms the validity of these receptors as targets for the treatment of alcohol dependence. In this review, we analyzed the genetic traits and psychiatric and/or psychosocial conditions that affect vulnerability to and the pharmacologic treatment of alcohol dependence, with special emphasis on the role of opioid and cannabinoid receptors. The use of animal models as important tools for identifying neurochemical mechanisms relevant to understanding and treating alcohol use problems was evaluated.
The eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! Using Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. The new edition includes over 500 new or refreshed figures, an intuitive color scheme, 14 new uses for older drugs and 18 brand new drugs, coverage of Parkinson's Disease Psychosis, behavioural symptoms of dementia, and mixed features in major depressive episodes, and expanded information on the medical uses of cannabis and hallucinogen assisted psychotherapy. This product combines the fifth edition of the textbook with a one-year subscription to www.stahlonline.org, providing access to the full range of Dr Stahl's content. The one-year subscription is activated via a code provided with the printed book.
Zusammenfassung
Bislang sind nur wenige Medikamente zur pharmakologischen Rückfallprophylaxe der Alkoholabhängigkeit zugelassen. Neben dem in Deutschland nicht mehr vertriebenen Disulfiram sind es die Opioidantagonisten Naltrexon und Nalmefen sowie das vermutlich über glutamaterge Neurone wirkende Acamprosat. Baclofen und γ‑Hydroxybutyrat (GHB) sind in einzelnen Ländern zugelassen. Wirkstoffe wie z. B. Vareniclin, Gabapentin und Topiramat können für die Rückfallprophylaxe der Alkoholabhängigkeit von Interesse sein, jedoch ist bislang keine Zulassung erfolgt. Vor dem Hintergrund der zur Revision anstehenden S3-Leitlinie zur Diagnose und Behandlung alkoholbezogener Störungen wird der heutige Kenntnisstand zur Pharmakotherapie der Alkoholabhängigkeit dargestellt.
Robust semiparametric models for recurrent events have received increasing attention in the analysis of clinical trials in a variety of diseases including chronic heart failure. In comparison to parametric recurrent event models, robust semiparametric models are more flexible in that neither the baseline event rate nor the process inducing between-patient heterogeneity needs to be specified in terms of a specific parametric statistical model. However, implementing group sequential designs in the robust semiparametric model is complicated by the fact that the sequence of Wald statistics does not follow asymptotically the canonical joint distribution. In this manuscript, we propose two types of group sequential procedures for a robust semiparametric analysis of recurrent events. The first group sequential procedure is based on the asymptotic covariance of the sequence of Wald statistics and it guarantees asymptotic control of the type I error rate. The second procedure is based on the canonical joint distribution and does not guarantee asymptotic type I error rate control but is easy to implement and corresponds to the well-known standard approach for group sequential designs. Moreover, we describe how to determine the maximum information when planning a clinical trial with a group sequential design and a robust semiparametric analysis of recurrent events. We contrast the operating characteristics of the proposed group sequential procedures in a simulation study motivated by the ongoing phase 3 PARAGON-HF trial (ClinicalTrials.gov identifier: NCT01920711) in more than 4600 patients with chronic heart failure and a preserved ejection fraction. We found that both group sequential procedures have similar operating characteristics and that for some practically relevant scenarios, the group sequential procedure based on the canonical joint distribution has advantages with respect to the control of the type I error rate. The proposed method for calculating the maximum information results in appropriately powered trials for both procedures.
Background:
Psychotic illnesses, such as schizophrenia, are typically enduring and disabling conditions, impacting individual, family, and societal outcomes. Individuals with these face greater vulnerabilities in developing alcohol-use disorder (AUD). Furthermore, the nature of psychoses, often manifesting with paranoia, cognitive impairment, a lack of insight, sub-optimal treatment adherence, and stigma from others, means that they can pose unique treatment challenges when these two conditions comorbidly occur. These challenges mean that the standard literature on the effectiveness of the opioid antagonist naltrexone in AUD does not necessarily translate to this vulnerable population.
Methods:
Following PRISMA guidelines, we herein systematically reviewed the evidence for naltrexone in individuals with both psychosis and AUD. Overall, there is a paucity of research in this important area, with only nine reports meeting search criteria, only four of which were randomized control trials. Studies compared naltrexone with: placebo, another pharmaceutical agent, or upon changes to baseline drinking behaviour. One study evaluated the long-acting injectable formulation of this drug.
Results:
Most studies, including the methodologically more robust ones, supported naltrexone's effectiveness over placebo in terms of reduction in drinking days and numbers of drinks consumed on such days in this cohort. Work comparing naltrexone to other pharmaceutical interventions showed approximate equivalence with disulfiram, and modest superiority over acamprosate.
Conclusions:
On this limited evidence base, this review endorses the use of naltrexone as both safe and effective in those with both psychotic illnesses and AUD. Several key issues remain to be elucidated. Critically, study designs meant that they were limited to individuals with good engagement with services, and levels of adherence were attained that are unlikely to be replicated in this cohort in real-world settings. Finally, effects of specific psychosis symptomatology, not least paranoia and insight, upon naltrexone use, and the reverse directional potential of 'double dysphoria' from an opioid antagonist remain largely unexplored.
Introduction:
Approximately 17 million Americans and 300 000 veterans have an alcohol use disorder (AUD). Both oral naltrexone (NTX) and long-acting, injectable naltrexone (LAI NTX) are FDA-approved to treat AUD. LAI NTX is often reserved for patients with adherence concerns due to considerable differences in drug cost and administration requirements. To date, there are no randomized trials comparing efficacy of LAI NTX to oral NTX. This retrospective cohort study compared clinical outcomes in veterans treated with LAI NTX or oral NTX.
Methods:
Health care utilization in veterans at 1 Veterans Affairs facility treated for AUD with oral NTX and LAI NTX was compared. The primary outcome was 90-day alcohol-related hospital admissions per patient (ARA90). Secondary outcomes included 90-day outpatient clinic and emergency department visits and 30-day alcohol-related admissions (ARA30). Inclusion criteria included first-time prescription of NTX for AUD from January 1, 2015, through December 1, 2015. Veterans receiving concurrent acamprosate or disulfiram were excluded.
Results:
Seventy-nine patients were included with 65 in the oral NTX group and 14 in the LAI NTX group. The ARA90 was 0.17 for the oral NTX group and 0.64 for the LAI NTX group (P = .06). The oral NTX group had significantly fewer ARA30 than the LAI NTX group (P < .01). Oral NTX also had significantly lower health care utilization for all other parameters.
Discussion:
Oral NTX was associated with lower health care utilization compared to LAI NTX in this veteran population. This indicates that LAI NTX may not provide additional benefit justifying the cost. This study had several limitations. Randomized trials comparing efficacy between oral NTX and LAI NTX are needed.
Alcohol misuse among individuals receiving agonist treatment for an opioid use disorder is common and is associated with significant morbidity and mortality. At present, though substantial research highlights effective strategies for the screening, diagnosis and management of an alcohol or opioid use disorder individually, less is known about how best to care for those with a dual diagnosis especially since common treatments for opioid addiction may be contraindicated in a setting of alcohol use. This review summarizes existing research and characterizes the prevalence, clinical implications and management of alcohol misuse among individuals with opioid addiction. Furthermore, it highlights clinically relevant management strategies in need of future research to advance care for this unique, but important, patient population.
Maternal separation alters the activity of the opioid system, which modulates ethanol-induced stimulation and behavioral sensitization. This study examined the effects of an opioid antagonist, naltrexone (NTX), on the expression of behavioral sensitization to ethanol in adult male and female mice submitted to maternal separation from postnatal days (PNDs) 2 to 14. Whole litters of Swiss mice were either not separated [animal facility rearing (AFR)] or separated from their mothers for 3 h [long maternal separation (LMS)]. Starting on PND 90, male and female AFR and LMS mice received daily i.p. injections of saline (SAL) or ethanol (EtOH, 2.2 g/kg) for 21 days. Locomotor activity was assessed in cages containing photoelectric beams, once a week, to examine the development of behavioral sensitization. Five days after the end of the chronic treatment, animals were submitted to four locomotor activity tests spaced by 48 h, to assess the expression of behavioral sensitization. In all tests, animals received two i.p. injections with a 30-min interval and were then assessed for locomotor response to different treatment challenges, which were: SAL/SAL, SAL/EtOH (2.2 g/kg), NTX 2.0 mg/kg (NTX2)/EtOH, and NTX 4.0 mg/kg (NTX4)/EtOH. Regardless of maternal separation, EtOH-treated male and female mice displayed increased locomotor responses to EtOH during the 21-day treatment, indicating the development of behavioral sensitization. In the SAL/EtOH challenge, EtOH-treated LMS and AFR male and female mice exhibited higher locomotor activity than their SAL-treated counterparts, indicating the expression of sensitization. The coadministration of either dose of NTX blocked the expression of locomotor sensitization in both AFR and LMS male mice with a history of EtOH sensitization. In females, a significant attenuation of EtOH sensitization was promoted by both NTX doses, while still maintaining an augmented stimulant response to EtOH. Importantly, maternal separation did not interfere in this phenomenon. These results indicate that expression of behavioral sensitization was importantly modulated by opioidergic mechanisms both in male and female mice and that maternal separation did not play a major role in either development or expression of this EtOH sensitization.
LEARNING OBJECTIVES: This lesson will enable clinicians to (1) understand the criteria for substance dependence, (2) become familiar with approved medications used for treating alcohol dependence, and (3) recognize the approved medications for opioid dependence. LESSON ABSTRACT: Substance use disorders are among the costliest and deadliest diseases; however, very few medications are approved for their treatment. Disulfiram, naltrexone, extendedrelease naltrexone, and acamprosate are all approved for the maintenance treatment of alcohol dependence. These medications have unique properties and different mechanisms of action and should be offered to patients as a tool for recovery. Buprenorphine and methadone are both approved for maintenance therapy for opioid dependence and each is subject to a different set of regulations. Both are effective in reducing illicit opioid use and, in turn, decreasing the many psychosocial and medical complications. Naltrexone is also approved for treatment for opioid dependence as an opioid receptor blocker. While the selection is limited, effective medications are available for the very common and costly diseases of alcohol and opioid dependence. They should be considered as part of treatment and the larger recovery program. COMPETENCY AREAS: This lesson addresses the gap in learning such as medical knowledge, patient care, and employing evidencebased practice. Should clinicians encounter patients dependent upon opioid medications or alcohol, there are approved medications to aid in their recovery. This lesson reviews opioid dependence and provides clinicians with guidelines for administering approved medications aiding in patients' recovery. 15 Volume 33
The burden of alcoholic liver disease continues to be a major public health problem worldwide. The spectrum of disease ranges from fatty liver to cirrhosis and hepatocellular carcinoma. Alcoholic hepatitis (AH) is a type of acute-on-chronic liver failure and the most severe form of alcoholic liver disease. Severe AH carries a poor short-term prognosis and its management is still challenging, with scarce advances in the last decades. Corticosteroids are still the first line of therapy in severe cases. Unfortunately, many patients do not respond and novel targeted therapies are urgently needed. Liver transplantation has shown extraordinary results in non-responders to corticosteroids however; its applicability is very low. This review summarizes the epidemiology, natural history, risk factors and pathogenesis of alcoholic liver disease with special focus on the latest advances in prognostic stratification and therapy of patients with alcoholic hepatitis.
Alcohol use disorders (AUD) cause significant morbidity and mortality worldwide, but pharmacological treatments for them are underused, despite evidence of efficacy. Acamprosate, naltrexone, nalmefene and disulfiram are all approved in one or more region for the treatment of alcohol use disorders. Baclofen currently has a temporary indication in France. Safety considerations for using psychopharmacological treatments in this patient group include the impact
of concurrent alcohol consumption at high levels, multiple physical comorbidities which may interfere with pharmacological effects, distribution and metabolism, and concomitant medication for the treatment of comorbid physical and psychiatric conditions. The five drugs, including an extended-release injectable suspension of naltrexone, have different safety profiles which need to
be balanced with the objective of treatment (initiation or continuation of abstinence, or reduction of drinking), individual patient preferences and comorbid conditions. Appropriate treatment will be based on the unique risk- benefit profile in each case.<br/
It is well accepted that drinking alcohol regularly for years is toxic to every tissue of our body. After consumption alcohol is metabolized by various enzymes such as alcohol dehyrogenase, catalase and cytochrome P450 into acetaldehyde in the body which leads to intoxication. Metabolic products of alcohol are responsible for the development of various diseases such as liver cirrhosis, trauma, depression etc. An alcohol addict not only keeps his health and day to day life on the linebut also the family welfare's. Considering the wide nature of damage by chronic alcoholism its treatment includes psychological and chemotherapy both. There are several drugs that decreases the alcohol craving it includes acamprosate calcium, fluoxetine, disulfiram, ondansetron and naltrexone hydrochloride. The presented work summaries the details of these drugs including various methods for quantitative estimation of these drugs in the formulations, bulk drugs and biological fluids.
Aims:
Alcohol is the most commonly used addictive substance and alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide, responsible for 47.9% of all liver chronic deaths. Despite ALD has a significant burden on the health, few therapeutic advances have been made in the last 40 years, particularly in the long-term management of these patients.
Methods:
we searched in PubMed, Scopus, Google Scholar, and MEDLINE databases to identify relevant English language publications focused on long-term therapy of ALD.
Results:
From the huge literature on this topic, including about 755 studies, 75 were selected as eligible including clinical trials and meta-analysis.
Conclusions:
Abstinence remains the cornerstone of ALD therapy but it is also the most difficult therapeutic target to achieve and the risk of recidivism is very high at any time. Several drugs (disulfiram, naltrexone, acamprosate, sodium oxybate) have proven to be effective to prevent alcohol relapse and increase the abstinence, although the psychotherapeutic support remains crucial. Baclofen seems to be effective to improve abstinence, showing an excellent safety and tolerability. ALD is often complicated by a state of malnutrition, which is related to a worst mortality. A nutritional therapy may improve survival in cirrhotic patients, reversing muscle wasting, weight loss and specific nutritional deficiencies. While in aggressive forms of alcoholic hepatitis are recommended specific drug treatments, including glucocorticoids or pentoxifylline, for the long-term treatment of ALD, specific treatments aimed at stopping the progression of fibrosis are not yet approved, but there are some future perspective in this field, including probiotics and antibiotics, caspase inhibitors, osteopontin and endocannabinoids.
We describe primary care practice and how the care of people with drug and alcohol use fits into it. The detection, evaluation, and short or long-term management of chronic behavioral problems are core functions of primary care that may be profoundly enhanced by the therapeutic relationship of primary care provider with patient. We describe screening for risky, unhealthy or problematic use of substances. The evaluation of patients who have positive screens dictates the next steps for provider and patient: this may include a brief intervention, the prescription of medications or referral for other specialty care. The management of concomitant or secondary psychiatric and medical illness is discussed. Finally, we provide guidance on the chronic management of routine medical conditions for patients in recovery.
Naltrexone is a semi-synthetic opioid with competitive antagonist activity at mu opioid receptors. Its efficacy has been demonstrated in the treatment of alcohol and opioid dependence, but adherence to daily dosing has been recognized as a factor limiting long-term effectiveness. Recently, a long-acting injectable formulation of naltrexone has received FDA-approval for treating alcohol and opioid dependence. This article reviews the pharmacology of naltrexone, the current evidence supporting the use of extended-release naltrexone, and the clinical challenges in the induction of patients to this medication.
Alcohol use is highly prevalent globally with numerous negative consequences to human health, including HIV progression, in people living with HIV (PLH). The HIV continuum of care, or treatment cascade, represents a sequence of targets for intervention that can result in viral suppression, which ultimately benefits individuals and society. The extent to which alcohol impacts each step in the cascade, however, has not been systematically examined. International targets for HIV treatment as prevention aim for 90 % of PLH to be diagnosed, 90 % of them to be prescribed with antiretroviral therapy (ART), and 90 % to achieve viral suppression; currently, only 20 % of PLH are virally suppressed. This systematic review, from 2010 through May 2015, found 53 clinical research papers examining the impact of alcohol use on each step of the HIV treatment cascade. These studies were mostly cross-sectional or cohort studies and from all income settings. Most (77 %) found a negative association between alcohol consumption on one or more stages of the treatment cascade. Lack of consistency in measurement, however, reduced the ability to draw consistent conclusions. Nonetheless, the strong negative correlations suggest that problematic alcohol consumption should be targeted, preferably using evidence-based behavioral and pharmacological interventions, to indirectly increase the proportion of PLH achieving viral suppression, to achieve treatment as prevention mandates, and to reduce HIV transmission.
Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder that is associated with long-term microvascular (retinopathy, neuropathy and nephropathy) and macrovascular (myocardial infarction, stroke, peripheral arterial disease) complications. Both the prevalence of T2DM and the cost of its long-term complications have driven the focus and emphasis on treatments aimed at reducing hyperglycemia and controlling hypertension and dyslipidemia while minimizing hypoglycemia and weight gain. Exenatide twice daily, the first GLP-1R agonist approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA), has been shown to reduce hemoglobin A1C, lower fasting and postprandial plasma blood glucose concentrations as well as reduce body weight without causing significant hypoglycemia. However, its current formulation requires twice daily subcutaneous injections and does not provide continuous GLP-1R activation. Therefore, a long-acting release form of exenatide has been developed for use as a once-weekly injection, providing for convenient administration and continuous GLP-1R activation. This review covers the currently published data on this new formulation including mechanism of action, pharmacokinetics, efficacy and comparison trials to other commonly used anti-diabetic agents. © the author(s), publisher and licensee Libertas Academica Ltd.
Alain Braillon,1,* Bernard Granger,2,*1Alcohol Treatment Unit, University Hospital, Amiens, France; 2Psychiatry, Tarnier Hospital (AP-HP), Paris, France*Both authors contributed equally to this work“A great deal of intelligence can be invested in ignorance when the need for illusion is deep”. Saul BellowPaille and Martini’s review on nalmefene for alcohol dependence deserves some comment.1 Read the original article
Millions of people who need treatment for substance use disorders (SUD) do not receive it. Evidence-based practices for treating SUD exist, and some are appropriate for delivery outside of specialty care settings. Primary care is an opportune setting in which to deliver SUD treatment because many individuals see their primary care providers at least once a year. Further, the Patient Protection and Affordable Care Act (PPACA) increases coverage for SUD treatment and is increasing the number of individuals seeking primary care services. In this article, we present the protocol for a study testing the effects of an organizational readiness and service delivery intervention on increasing the uptake of SUD treatment in primary care and on patient outcomes.
In a randomized controlled trial, we test the combined effects of an organizational readiness intervention consisting of implementation tools and activities and an integrated collaborative care service delivery intervention based on the Chronic Care Model on service system (patient-centered care, utilization of substance use disorder treatment, utilization of health care services and adoption and sustainability of evidence-based practices) and patient (substance use, consequences of use, health and mental health, and satisfaction with care) outcomes. We also use a repeated measures design to test organizational changes throughout the study, such as acceptability, appropriateness and feasibility of the practices to providers, and provider intention to adopt the practices. We use provider focus groups, provider and patient surveys, and administrative data to measure outcomes.
The present study responds to critical gaps in health care services for people with substance use disorders, including the need for greater access to SUD treatment and greater uptake of evidence-based practices in primary care. We designed a multi-level study that combines implementation tools to increase organizational readiness to adopt and sustain evidence-based practices (EBPs) and tests the effectiveness of a service delivery intervention on service system and patient outcomes related to SUD services.
Current controlled trials: NCT01810159.
This study analyzed the cost-effectiveness of delivering alcohol screening, brief intervention, and referral to treatment (SBIRT) in emergency departments (ED) when compared to outpatient medical settings.
A probabilistic decision analytic tree categorized patients into health states. Utility weights and social costs were assigned to each health state. Health outcome measures were the proportion of patients not drinking above threshold levels at follow-up, the proportion of patients transitioning from above threshold levels at baseline to abstinent or below threshold levels at follow-up, and the quality-adjusted life years (QALYs) gained. Expected costs under a provider perspective were the marginal costs of SBIRT, and under a societal perspective were the sum of SBIRT cost per patient and the change in social costs. Incremental cost-effectiveness ratios were computed.
When considering provider costs only, compared to outpatient, SBIRT in ED cost 1500 per QALY gained.
Alcohol SBIRT generates costs savings and improves health in both ED and outpatient settings. EDs provide better effectiveness at a lower cost and greater social cost reductions than outpatient.
Copyright © 2015 Elsevier Inc. All rights reserved.
Background
Utilization of extended release naltrexone (XRN) for alcohol use disorders (AUDs) in the U.S. Veterans Health Administration (VHA) has been limited, perhaps due to high cost, lack of established superiority over less expensive alternatives including oral naltrexone, and related formulary restrictions. Despite these barriers, pockets of higher utilization exist in VHA, allowing for the quasi-experimental examination of the effects of XRN on 1-year mortality and number of subsequent detoxification episodes among patients with high rates of psychiatric comorbidities and previous psychosocial and pharmacological addiction treatment.Methods
Using propensity score-weighted mixed-effects logistic regression, 1-year mortality was compared between patients with AUDs who received XRN in fiscal year 2010 (n = 387) and a random sample of patients with AUDs who did not receive XRN (n = 3,759). Among the subgroup of patients who had at least 1 detoxification episode in the previous year, 1-year mortality and number of subsequent detoxification episodes were compared between those who did and did not receive XRN.ResultsOverall, 1-year mortality for the patients receiving XRN was significantly lower than for the comparison group who did not receive XRN (odds ratio [OR] = 0.30; p < 0.001). Among patients with a detoxification episode in the previous year, those receiving XRN had, on average, 0.80 fewer subsequent detoxification episodes (p < 0.001) and significantly lower mortality (OR = 0.78, p < 0.001) in the postindex year.Conclusions
Among patients with AUDs, those receiving XRN had lower 1-year mortality and fewer detoxifications compared to similar patients not receiving XRN. These results, although observational, support the use of XRN, especially among patients with high rates of psychiatric comorbidities and previous addiction treatment who are still struggling with AUDs and/or facing a period of vulnerability to relapse.
Background
There is a high co-occurrence of cocaine and alcohol use disorders, and patients with both of these problems are difficult to treat. There is a reasonable rationale and some empirical data to justify a pilot trial of an injectable, extended-release formulation of naltrexone for treating co-occurring cocaine and alcohol addiction.Methods
Eighty cocaine (n = 80) and alcohol dependent, treatment-seeking subjects were randomly assigned to receive either two monthly extended-release injections of naltrexone or two matching placebo injections in an 8-week clinical trial, with weekly medical management plus cognitive behavioral therapy visits.ResultsNo differences in reduction in cocaine or alcohol use were observed between the injectable naltrexone and placebo groups during the 8-week trial.Conclusions
Injectable extended-release naltrexone, while an ideal method for ensuring medication adherence in these traditionally hard-to-treat patients, did not result in any measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment. (Am J Addict 2014:XX: XX–XX)
Background:
Non-opioid psychotherapeutic medications significantly increase the risk of opioid overdose-related deaths. We prospectively followed HIV-infected indigent adults sampled from the community to examine rates of and factors associated with non-medical use of benzodiazepines, muscle relaxants, and prescription stimulants.
Methods:
We interviewed participants quarterly for 2 years about alcohol and illicit substance use; depression; use of prescribed opioid analgesics, benzodiazepines and muscle relaxants; opioid analgesic misuse; and non-medical use (i.e., use without a prescription) of benzodiazepines, muscle relaxants, and prescription stimulants. Using mixed-effects multivariate logistic regression, we determined factors associated with non-medical use of benzodiazepines, muscle relaxants, and prescription stimulants.
Results:
Among the 296 participants at enrollment, 52.0% reported taking opioid analgesics that had been prescribed, 17.9% took benzodiazepines that had been prescribed, and 8.1% took muscle relaxants that had been prescribed. Over the 2-year study interval, 53.4% reported prescription opioid misuse, 25.3% reported non-medical use of benzodiazepines, 11.5% reported non-medical use of muscle relaxants, and 6.1% reported non-medical use of prescription stimulants. In multivariable analysis, opioid analgesic misuse in the past 90 days was associated with non-medical use of benzodiazepines, muscle relaxants, and prescription stimulants during the same time interval. Illicit substance use and depression were not associated with non-medical use of these medications.
Conclusions:
Prescription opioid analgesic misuse is associated with non-medical use of other psychotherapeutic medications. Health care providers should monitor for non-medical use of a broad array of psychoactive medications among high-risk populations to minimize harm.
graphic
Alcohol use is a leading cause of preventable morbidity and mortality worldwide, with much of its negative impact as the result of alcoholic liver disease ( ALD ). ALD is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanisms underlying the development of these different disease stages are incompletely understood. Standard treatment of ALD , which includes abstinence, nutritional support, and corticosteroids, has not changed in the last 40 years despite continued poor outcomes. Novel therapies are therefore urgently needed. The development of such therapies has been hindered by inadequate resources for research and unsuitable animal models. However, recent developments in translational research have allowed for identification of new potential targets for therapy. These targets include: (i) CXC chemokines, (ii) IL ‐22/ STAT 3, (iii) TNF receptor superfamily, (iv) osteopontin, (v) gut microbiota and lipopolysaccharide ( LPS ), (vi) endocannabinoids, and (vii) inflammasomes. We review the natural history, risk factors, pathogenesis, and current treatments for ALD . We further discuss the findings of recent translational studies and potential therapeutic targets.
Although posttraumatic stress disorder (PTSD) and alcohol use disorders (AUD) frequently co-occur there are no specific treatments for individuals diagnosed with these comorbid conditions. The main objectives of this paper are to review the literature on pharmacological options for PTSD and comorbid AUD, and to summarize promising behavioral and alternative interventions for those with these dual diagnoses.
We conducted a comprehensive search on PsycINFO and MEDLINE/PubMed databases using Medical Subject Headings terms in various combinations to identify articles that used pharmacotherapy for individuals with dual diagnoses of PTSD and AUD. Similar strategies were used to identify articles on behavioral and alternative treatments for AUD and PTSD. We identified and reviewed six studies that tested pharmacological treatments for patients with PTSD and comorbid AUD.
The literature on treatment with US Food and Drug Administration approved medications for patients with dual diagnosis of PTSD and AUD is very limited and inconclusive. Promising evidence indicates that topiramate and prazosin may be effective in reducing PTSD and AUD symptoms in individuals with comorbidity. Seeking safety has had mixed efficacy in clinical trials. The efficacy of other behavioral and alternative treatments (mindfulness-based, yoga, and acupuncture) is more difficult to evaluate since the evidence comes from small, single studies without comparison groups.
There is a clear need for more systematic and rigorous study of pharmacological, behavioral, and alternative treatments for patients with dual diagnoses of PTSD and AUD.
Alcohol use disorder is one of the leading causes of disability worldwide. Despite the availability of efficacious treatments, few individuals with an alcohol use disorder are actively engaged in treatment. Available evidence suggests that primary care may play a crucial role in the identification of patients with an alcohol use disorder, delivery of interventions, and the success of treatment.
The principal aims of this study were to test the effectiveness of a primary care-based Alcohol Care Management (ACM) program for alcohol use disorder and treatment engagement in veterans.
The design of the study was a 26-week single-blind randomized clinical trial. The study was conducted in the primary care practices at three VA medical centers. Participants were randomly assigned to treatment in ACM or standard treatment in a specialty outpatient addiction treatment program.
One hundred and sixty-three alcohol-dependent veterans were randomized.
ACM focused on the use of pharmacotherapy and psychosocial support. ACM was delivered in-person or by telephone within the primary care clinic.
Engagement in treatment and heavy alcohol consumption.
The ACM condition had a significantly higher proportion of participants engaged in treatment over the 26 weeks [OR = 5.36, 95 % CI = (2.99, 9.59)]. The percentage of heavy drinking days were significantly lower in the ACM condition [OR = 2.16, 95 % CI = (1.27, 3.66)], while overall abstinence did not differ between groups.
Results demonstrate that treatment for an alcohol use disorder can be delivered effectively within primary care, leading to greater rates of engagement in treatment and greater reductions in heavy drinking.
The opioid system modulator nalmefene (Selincro(®)) is approved in the EU for as-needed use to reduce alcohol consumption in alcohol-dependent adults with a high drinking risk level. This article reviews the efficacy and tolerability of as-needed oral nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. In two randomized, double-blind, multinational trials (ESENSE 1 and ESENSE 2), as-needed nalmefene significantly reduced the number of heavy drinking days (in both trials) and total alcohol consumption (in ESENSE 1) at month 6. In the randomized, double-blind, multinational SENSE trial, as-needed nalmefene significantly improved both of these endpoints at month 13, but not at month 6. As-needed nalmefene had a greater beneficial effect in the target population (i.e. alcohol-dependent patients with at least a high drinking risk level at screening and randomization), with post hoc analyses revealing significant reductions in both the number of heavy drinking days and total alcohol consumption at month 6 (in ESENSE 1 and ESENSE 2) and at month 13 (in SENSE). Oral nalmefene was generally well tolerated in patients with alcohol dependence, with the most commonly occurring adverse events including nausea, insomnia and dizziness. In conclusion, as-needed nalmefene provides an important new option for use in the treatment of alcohol dependence.
Drug and alcohol dependence continue to be significant public health problems in the United States. The high rates of relapse associated with the psychosocial treatment of addiction have encouraged the development of medications to augment counseling for the prevention of relapse. Current medications have been developed to help prevent relapse by numerous different mechanisms, including making drug use aversive, reducing the euphoric effects of abused drugs, and reducing drug craving. Medications that can reduce drug craving have been the most effective. Effective medications for the treatment of alcohol dependence include disulfiram, naltrexone, and acamprosate. For opioid dependence, methadone, buprenorphine, and acamprosate have been shown to be effective. For nicotine dependence, nicotine replacement therapy is available as well as bupropion and varenicline. No medications have thus far been proven to be effective for stimulant dependence, but several promising leads have emerged.
The majority of drug addicts are polydrug dependent, and no effective pharmacological treatment is currently available for them. The authors studied the overall real-world effectiveness of naltrexone implant in this patient population.
The authors assessed the effectiveness of a naltrexone implant in the treatment of coexisting heroin and amphetamine polydrug dependence in 100 heroin- and amphetamine-dependent outpatients in a 10-week randomized, double-blind, placebo-controlled trial. The main outcome measures were retention in the study, proportion of drug-free urine samples, and improvement score on the Clinical Global Impressions Scale (CGI). Analyses were conducted in an intent-to-treat model.
At week 10, the retention rate was 52% for patients who received a naltrexone implant and 28% for those who received a placebo implant; the proportions of drug-free urine samples were 38% and 16%, respectively, for the two groups. On the CGI improvement item, 56% of the patients in the naltrexone group showed much or very much improvement, compared with 14% of those in the placebo group (number needed to treat=3).
Naltrexone implants resulted in higher retention in the study, decreased heroin and amphetamine use, and improved clinical condition for patients, thus providing the first evidence of an effective pharmacological treatment for this type of polydrug dependence.
Opioid dependence is a significant public health problem associated with high risk for relapse if treatment is not ongoing. While maintenance on opioid agonists (i.e., methadone, buprenorphine) often produces favorable outcomes, detoxification followed by treatment with the μ-opioid receptor antagonist naltrexone may offer a potentially useful alternative to agonist maintenance for some patients.
Treatment approaches for making this transition are described here based on a literature review and solicitation of opinions from several expert clinicians and scientists regarding patient selection, level of care, and detoxification strategies.
Among the current detoxification regimens, the available clinical and scientific data suggest that the best approach may be using an initial 2-4 mg dose of buprenorphine combined with clonidine, other ancillary medications, and progressively increasing doses of oral naltrexone over 3-5 days up to the target dose of naltrexone. However, more research is needed to empirically validate the best approach for making this transition.
Clinical trials testing the effectiveness of interventions for addictions, HIV transmission risk, and other behavioral health problems are important to advancing evidence-based treatment. Such trials are expensive and time-consuming to conduct, but the underlying effect sizes tend to be modest, and often findings are disappointing, failing to show evidence of treatment effects.
To demonstrate how appropriate covariation for baseline severity can enhance detection of treatment effects.
Explication and case example.
Baseline severity (the score of the outcome measure at baseline, prior to randomization) is often strongly associated with outcome in such studies. Covariation for baseline score may enhance detection of treatment effects, because the variance explained by the baseline score is removed from the error variance in the estimate of the difference in outcome between treatments. Alternatively, the effect of treatment may manifest in the form of a baseline-by-treatment interaction. Common interaction patterns include that treatment may be more effective among patients with higher levels of baseline severity, or treatment may be more effective among patients with low severity at baseline ('relapse prevention' effect). Such effects may be important to developing treatment guidelines and offer clues toward understanding the mechanisms of action of treatments and of the disorders.
This article illustrates principles of covariation for baseline and the baseline-by-treatment interaction in nontechnical graphical terms, and discusses examples from clinical trials. Implications for the design and analysis of clinical trials are discussed, and it is argued that covariation for baseline severity of the outcome measure and testing of the baseline-by-treatment interaction should be considered for inclusion in the primary outcome analyses of treatment effectiveness trials of substantial size.
Introduction:
Studies have shown that opioid antagonists like naltrexone are efficient in reducing heavy drinking. The neurobiological mechanism by which opioid modulators affect drinking behavior is based on the strong connection between the endogenous opioid system, the dopamine system and the influence of the CNS stress response.
Areas covered:
This review provides an overview of the pathophysiological role of the opioid system in alcohol dependence and the neurobiological mechanisms of possible pharmacological interventions. An extensive Medline and Internet research was performed to retrieve information on existing and currently investigated opioid modulators. The findings were assessed critically and interpreted with regard to an individualized therapy for alcohol dependence.
Expert opinion:
The opioid system is of crucial importance in the genesis and maintenance of alcohol dependence. Naltrexone- and to a lesser extent nalmefene- is an agent that modulates opioidergic transmission in the CNS and it shows a limited but well-studied efficacy in treating alcohol dependence. Several agents (LY2196044, ALKS-29, ALKS-33) that are currently undergoing Phase II and Phase III studies are of interest but first their efficacy must be proved in clinical practice.
Exenatide (also known as exendin-4) is a glucagon-like peptide-1 mimetic, which is indicated for the treatment of type 2 diabetes mellitus. The currently available formulation of this drug is a twice-daily exenatide (exenatide BID) injection that should be administered within 60 minutes of food. Once-weekly exenatide (exenatide QW) formulation is now being assessed in a clinical trial program. Exenatide QW has been shown to be the only noninsulin monotherapy to achieve glycosylated hemoglobin levels of <7% in >75% of treated patients. It has also demonstrated potential cardiovascular benefits by lowering total and low-density lipoprotein cholesterol concentrations, triglyceride levels, and both systolic and diastolic blood pressure. In addition, patients treated with exenatide QW achieved significant weight loss, which may also lead to significant cardiovascular risk reduction. Exenatide QW is associated with a lower incidence of gastrointestinal adverse effects compared with exenatide BID, and no patients treated with exenatide QW monotherapy experienced a confirmed hypoglycemic event. Exenatide QW results in 24-hour coverage with exenatide concentrations that are known to improve glycemic control and remain well tolerated in patients with type 2 diabetes mellitus. This review defines the state of play with exenatide QW by critically appraising its role in clinical practice.
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