Posttraumatic Stress Disorder and Alcohol Use Disorder: A Critical Review of Pharmacologic Treatments.

Treatment of alcohol use disorder (AUD) is complicated by the presence of psychiatric comorbidity including posttraumatic stress disorder (PTSD). This is a critical review of the literature to date on pharmacotherapy treatments of AUD and PTSD. A systematic literature search using PubMed MESH terms for alcohol and substance use disorders, PTSD, and treatment was undertaken to identify relevant randomized controlled trials (RCTs). The studies were independently evaluated (ILP and TLS) and those that evaluated the efficacy of a pharmacotherapy for individuals diagnosed with AUD and PTSD and were RCTs were selected. Studies were grouped in 3 categories: (i) those that evaluated first-line treatments for PTSD, (ii) those that evaluated medications to target AUD, and (iii) those that evaluated medications hypothesized to be effective in targeting alcohol consumption as well as PTSD symptoms. Nine RCTs were identified; 3 focused on medications to treat PTSD, 4 focused on AUD, and 3 to target both. One study included both a medication to treat PTSD and 1 to treat AUD so was discussed twice. All but 1 of the studies found that PTSD symptoms and drinking outcomes improved significantly over time. There is not 1 agent with clear evidence of efficacy in this comorbid group. The results for medications to treat PTSD are inconclusive because of contradictory results. There was weak evidence to support the use of medications to treat AUD among those with comorbidity with PTSD. Findings for medications that were hypothesized to treat both disorders were also contradictory. Most studies provided a combination of interventions to treat both disorders. Despite the contradictory results, this review suggests that individuals with AUD and comorbid PTSD can safely be prescribed medications used in noncomorbid populations and patients improve with treatment.

Medications for Alcohol Use Disorder.

The U.S. Preventive Services Task Force recommends that clinicians screen adults for alcohol misuse and provide persons engaged in risky or hazardous drinking behaviors with brief behavioral counseling to reduce alcohol misuse. However, only a minority of American adults with high-risk alcohol use receive treatment. Three medications are approved by the U.S. Food and Drug Administration to treat alcohol use disorder: acamprosate, disulfiram, and naltrexone. Acamprosate and naltrexone reduce alcohol consumption and increase abstinence rates, although the effects appear to be modest. Disulfiram has been used for years, but evidence supporting its effectiveness is inconsistent. Other medications may be beneficial to reduce heavy alcohol use. The anticonvulsants topiramate and gabapentin may reduce alcohol ingestion, although long-term studies are lacking. Antidepressants do not decrease alcohol use in patients without mood disorders, but sertraline and fluoxetine may help depressed patients decrease alcohol ingestion. Ondansetron may reduce alcohol use, particularly in selected subpopulations. Further study is needed for genetically targeted or as-needed medications to reduce alcohol use.

Alcohol-use disorders and depression: results from individual patient data meta-analysis of the acamprosate-controlled studies.

AIMS: To examine the predictors and correlates of depression in alcoholic patients following detoxification and during outpatient treatment, and the role of acamprosate. METHOD: The international research program of acamprosate has involved 6500 patients in randomized, placebo-controlled trials. Extensive baseline and follow-up data were documented for each patient. An individual patient data meta-analysis was conducted on a partial database. RESULTS: From 3354 patients in 11 studies (10 countries), we found 1120 (33.4% confidence intervals: 31.8-35.0) depressed patients (DPs). Among alcohol patients, the profile of DPs can be defined by five predictors: being female, younger, unemployed and living alone and being an episodic drinker. Compared with non-depressed patients (NDPs), their motivation to start a treatment and the compliance to treatment were lower. DPs performed less than NDPs in achieving abstinence. The acamprosate effect in increasing abstinence was similar for both DPs and NDPs patients. Abstinence during the trial was the key factor of depression remission: DPs were 7.58 times more likely to become NDPs if they were continuously abstinent. CONCLUSION: Our results justify the need to systematically identify depression among alcohol-dependent patients, but to treat the alcohol dependence as a first step, because enhancing abstinence will often involve remission of the depressive disorder.

Oxcarbazepine in combination with Tiaprid in inpatient alcohol-withdrawal--a RCT.

INTRODUCTION: Oxcarbazepine (OXC), a derivative of Carbamazepine (CBZ), may represent a solution to metabolic and side effects of CBZ treatment due to the fact that renal excretion is its major route of elimination. The goal of the study is to compare the efficacy and tolerability of OXC/Tiaprid (TIA) combination therapy to the well established Clomethiazole (CLO) therapy in an inpatient setting. METHODS: To investigate the efficacy of OXC/TIA in terms of lower alcohol withdrawal symptoms and better tolerability, 56 alcohol-dependent patients participated in a randomized open-label trial, where OXC/TIA and CLO treatments were compared. RESULTS: Following admission, we observed that severity of alcohol withdrawal syndrome was comparable between OXC/TIA and CLO-patients. Overall tolerability was good. However, significantly more patients in the OXC/TIA-group (48.1%) displayed no AE compared to the CLO-group (24.1%). We found no significant differences between groups regarding total number of recorded adverse events (AEs). DISCUSSION: OXC/TIA inpatient therapy proved to be as effective and participants demonstrated the same tolerance as with CLO. In medication-based alcohol withdrawal, OXC/TIA could have the potential to become a promising alternative for alcohol dependent patients unable to undergo inpatient withdrawal therapy with CLO. Our findings further indicate that it could be worthwhile testing OXC/TIA in alcohol withdrawal in daily care units and outpatient settings. This is an important question for national health care services, since outpatient therapy is more and more asked for as alternative to inpatient settings.

Prospects for pharmacotherapies to treat alcohol use disorder: an update on recent human studies.

PURPOSE OF REVIEW: The aim of this study was to provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past 2 years) human studies that evaluated medications' effects on alcohol-related outcomes. RECENT FINDINGS: Forty-five publications were found suitable for this review. A variety of compounds have been tested in the past 2 years as potential pharmacological options for AUD, including medications that act on multiple targets (topiramate, aripiprazole, quetiapine), calcium channels (gabapentin), gamma-Aminobutyric acid receptors (baclofen, diazepam), glutamate receptors (ifenprodil, memantine, glycine), nicotinic acetylcholine receptors (varenicline, mecamylamine), α1 adrenergic receptors (prazosin, doxazosin), neuroendocrine pathways (oxytocin, a vasopressin receptor 1b antagonist, a ghrelin receptor inverse agonist) and others (samidorphan, ibudilast, N-acetylcysteine, citoline). Important findings and limitations regarding the effects of these medications on alcohol-related outcomes are discussed. SUMMARY: There is a critical need to increase the armamentarium of medications for AUD. Human laboratory studies may help screen and prioritize promising targets and compounds before running large clinical trials. Given the complexity of AUD and the heterogeneity of afflicted patients, future studies should also investigate potential moderators and predictors of response to each pharmacological intervention.

Gambling disorder: a side effect of an off-label prescription of baclofen-literature review.

The use of high-dose baclofen emerged in 2008 in the treatment of alcohol-use disorders. Its prescription is still off-label in France, but recent trials have suggested the interest of using high doses for alcohol dependence, so we have to deal with an increase in its use. However, we still have few data about the adverse effects of a high-dose baclofen prescription, especially in complex addictive disorders. We present a case of a 32-year-old man who sought treatment for gambling disorders (GDs). He had complex addictive disorders, including alcohol-use disorders and GDs. He developed a severe GD, after treatment with a high dose of baclofen. The maximum dose was 160 mg/day, prescribed for his alcohol-use disorders. According to the Naranjo algorithm, the score was +7, it enabled to conclude that problem of gambling was probably imputable to baclofen. We discuss this case with reference to literature.

Sex Differences in Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) is a common and disabling mental disorder associated with a significant burden of medical consequences and high socioeconomic costs. Although a growing number of studies support the existence of sex differences in several aspects of alcohol consumption and AUD, the majority of investigations have been conducted in men. OBJECTIVE: This article was aimed at reviewing sex differences in AUD, focusing on epidemiology, neurobiology, pharmacokinetics, susceptibility to medical consequences, and treatment. RESULTS: Although AUD is more prevalent in men, the number of women with AUD is rapidly increasing, especially in adolescents. Women show a higher vulnerability to medical consequences induced by alcohol consumption, including alcohol-related liver disease, cardiomyopathy, and breast cancer. This observation is only partly explained by the sex differences observed in the pharmacokinetics of alcohol. Women also show an accelerated progression from the first use of alcohol to the onset of AUD and appear to be at higher risk of alcohol- medication interactions. Although AUD women are less likely to seek treatment than men, they achieve better results through dedicated programs taking into account the special needs of female patients. However, findings on the efficacy and safety of medications used to treat AUD mostly come from studies in which women were largely underrepresented. CONCLUSION: The sex differences observed suggest the urgent need to conduct studies recruiting adequate numbers of female subjects, to increase knowledge of sex differences in AUD, and to develop personalized and evidence-based approaches of prevention and treatment of AUD in women.

Pharmacotherapy used for alcohol and cocaine use disorders in a CAPS-AD of Minas Gerais

Abstract Substance use disorder is one of the major social and public health problems in the world. The present study analyzed the pharmacoepidemiological profile of patients treated at the Psychosocial Treatment Center for Alcohol and Substance Use Disorders (CAPS-AD) for treatment of alcohol use disorders (AUD), cocaine use disorders (CUD) and concomitant alcohol and cocaine use disorders (A-CUD) in the city of Betim-MG. The study used quantitative and descriptive data and was based on the evaluation of medical records of patients attended from January to December 2016. After analyzing 295 medical records, the majority of study participants were male (83.7 %) with an average age of 46.26 for AUD, 28.88 for CUD and 34.29 for A-CUD. The most prescribed drugs for AUD were diazepam (54.1 %), thiamine (37 %), complex B vitamins (29.5 %), and disulfiram (2.7 %); for CUD, diazepam (26.9 %) and haloperidol (23.1 %). It should be noticed that although contraindicated by the guidelines, chlorpromazine (42.3 %, 25.3 %, 20.3 %) was prescribed for CUD, AUD, and A-CUD respectively. Knowing the pharmacoepidemiological profile of CAPS-AD patients is extremely important for making decisions regarding which medicines to make available to the population.

Multifaceted academic detailing program to increase pharmacotherapy for alcohol use disorder: interrupted time series evaluation of effectiveness.

BACKGROUND: Active consideration of effective medications to treat alcohol use disorder (AUD) is a consensus standard of care, yet knowledge and use of these medications are very low across diverse settings. This study evaluated the overall effectiveness a multifaceted academic detailing program to address this persistent quality problem in the US Veterans Health Administration (VHA), as well as the context and process factors that explained variation in effectiveness across sites. METHODS: An interrupted time series design, analyzed with mixed-effects segmented logistic regression, was used to evaluate changes in level and rate of change in the monthly percent of patients with a clinically documented AUD who received naltrexone, acamprosate, disulfiram, or topiramate. Using data from a 20 month post-implementation period, intervention sites (n = 37) were compared to their own 16 month pre-implementation performance and separately to the rest of VHA. RESULTS: From immediately pre-intervention to the end of the observation period, the percent of patients in the intervention sites with AUD who received medication increased over 3.4 % in absolute terms and 68 % in relative terms (i.e., 4.9-8.3 %). This change was significant compared to the pre-implementation period in the intervention sites and secular trends in control sites. Sites with lower pre-implementation adoption, more person hours of detailing, but fewer people detailed, had larger immediate increases in medication receipt after implementation. The average number of detailing encounters per person was associated with steeper increases in slope over time. CONCLUSIONS: This study found empirical support for a multifaceted quality improvement strategy aimed at increasing access to and utilization of pharmacotherapy for AUD. Future studies should focus on determining how to enhance the programs effects, especially in non-responsive locations.

Sodium oxybate plus nalmefene for the treatment of alcohol use disorder: A case series.

The treatment of alcohol use disorder still remains a challenge. The efficacy of the combined pharmacological treatment for alcohol use disorder has been widely investigated with controversial results. The aim of our case series was to investigate the effect of nalmefene in patients not responding to sodium oxybate therapy. We describe seven cases of consecutive patients affected by alcohol use disorder, and treated with sodium oxybate (50 mg/kg per day) who did not achieve complete alcohol abstinence after at least one month of pharmacological treatment. Then, in partial- and non-responder patients to sodium oxybate treatment, administration of nalmefene, 18 mg as needed, was commenced. Our data show that, during the first month of the combined treatment of sodium oxybate plus nalmefene, patients were able to achieve alcohol abstinence (two patients), to suppress (five cases) or reduce (two patients) episodes of heavy drinking days, and to suppress the onset of craving for sodium oxybate (one patient). Likely, nalmefene may act in modulating the excessive reward effect of sodium oxybate, which may be responsible for the persistence of alcohol intake and for the onset of craving for sodium oxybate. However, controlled clinical trials to confirm the safety and efficacy of sodium oxybate plus nalmefene in treating alcohol use disorder are warranted.

Pharmacological treatments in alcohol use disorders: state of art and new perspectives.

The main focus of this narrative review is to present and discuss the most relevant clinical data about the pharmacological therapy for alcohol use disorders. By using PubMed we conducted a review of the clinical literature on drugs related to alcohol use disorders. All data are presented following the three phases of treatment: a) from withdrawal to abstinence; b) abstinence and relapse prevention; c) reduction of alcohol consumption. Historical evidence shows that in addition to the drugs already approved for the treatment of alcoholism, there are some off-label medications as effective as the approved ones which deserve therefore further study. The treatment of the alcoholic patient always requires a multidimensional and multidisciplinary approach, directed to the specific needs of each subject in order to achieve a correct care personalization. The study of the cognitive effects of each drug and pharmacogenetics will allow us to increasingly customize therapy for each individual patient.

Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects.

Acamprosate has been widely used since the Food and Drug Administration approved the medication for treatment of alcohol use disorders (AUDs) in 2004. Although the detailed molecular mechanism of acamprosate remains unclear, it has been largely known that acamprosate inhibits glutamate action in the brain. However, AUD is a complex and heterogeneous disorder. Thus, biomarkers are required to prescribe this medication to patients who will have the highest likelihood of responding positively. To identify pharmacometabolomic biomarkers of acamprosate response, we utilized serum samples from 120 alcohol-dependent subjects, including 71 responders (maintained continuous abstinence) and 49 non-responders (any alcohol use) during 12 weeks of acamprosate treatment. Notably, baseline serum glutamate levels were significantly higher in responders compared with non-responders. Importantly, serum glutamate levels of responders are normalized after acamprosate treatment, whereas there was no significant glutamate change in non-responders. Subsequent functional studies in animal models revealed that, in the absence of alcohol, acamprosate activates glutamine synthetase, which synthesizes glutamine from glutamate and ammonia. These results suggest that acamprosate reduces serum glutamate levels for those who have elevated baseline serum glutamate levels among responders. Taken together, our findings demonstrate that elevated baseline serum glutamate levels are a potential biomarker associated with positive acamprosate response, which is an important step towards development of a personalized approach to treatment for AUD.

Combining seeking safety with sertraline for PTSD and alcohol use disorders: A randomized controlled trial.

OBJECTIVE: The current study marks the first randomized controlled trial to test the benefit of combining Seeking Safety (SS), a present-focused cognitive-behavioral therapy for co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD), with sertraline, a front-line medication for PTSD shown to also impact drinking outcomes. METHOD: Sixty-nine participants (81% female; 59% African American) with primarily childhood sexual (46%) and physical (39%) trauma exposure, and drug dependence in addition to AUD were randomized to receive a partial-dose (12 sessions) of SS with either sertraline (n = 32; M = 7 sessions) or placebo (n = 37; M = 6 sessions). Assessments conducted at baseline, end-of-treatment, 6- and 12-months posttreatment measured PTSD and AUD symptom severity. RESULTS: Both groups demonstrated significant improvement in PTSD symptoms. The SS plus sertraline group exhibited a significantly greater reduction in PTSD symptoms than the SS plus placebo group at end-of-treatment (M difference = -16.15, p = .04, d = 0.83), which was sustained at 6- and 12-month follow-up (M difference = -13.81, p = .04, d = 0.71, and M difference = -12.72, p = .05, d = 0.65, respectively). Both SS groups improved significantly on AUD severity at all posttreatment time points with no significant differences between SS plus sertraline and SS plus placebo. CONCLUSION: Results support the combining of a cognitive-behavioral therapy and sertraline for PTSD/AUD. Clinically significant reductions in both PTSD and AUD severity were achieved and sustained through 12-months follow-up, Moreover, greater mean improvement in PTSD symptoms was observed across all follow-up assessments in the SS plus sertraline group. (PsycINFO Database Record

Effect of patient choice in an adaptive sequential randomization trial of treatment for alcohol and cocaine dependence.

OBJECTIVE: To evaluate the effect of providing choice of treatment alternatives to patients who fail to engage in or drop out of intensive outpatient programs (IOPs) for substance dependence. METHOD: Alcohol- and/or cocaine-dependent patients (N = 500) participated in a sequential, multiple-assignment, randomized trial (SMART). Those who failed to engage in an IOP at Week 2 (N = 189) or who dropped out after engagement (N = 84) were randomized for motivational-interviewing (MI) telephone calls that focused on engagement in an IOP (MI-IOP) or provided a choice of IOP type or 3 treatment options (MI-PC, or patient choice). Those not engaged at both 2 and 8 weeks (N = 102) were re-randomized either to MI-PC or no further outreach. Outcomes were treatment attendance and measures of alcohol and cocaine use obtained at 1, 2, 3, and 6 months. RESULTS: MI-PC produced better attendance than comparison conditions in patients who dropped out after initial engagement and in those re-randomized at 8 weeks. However, contrary to study hypotheses, MI-IOP produced significantly better alcohol-use outcomes than MI-PC in alcohol-dependent patients not engaged at Week 2. There were no other significant differences between treatment conditions on other main-effect analyses with alcohol- or cocaine-outcome measures. CONCLUSION: Providing treatment options via telephone calls to patients who failed to engage in IOP did not produce better substance-use outcomes than outreach calls focused on engagement in IOP. Future researchers should investigate the potential benefits of choice at other points in treatment (e.g., at intake) as well as choice of other combinations of treatments.

Donepezil for alcohol-related dementia: a case report.

A 75-year old man with a 40-year history of alcoholism was admitted to the hospital for intoxication and inability to care for himself. He had been admitted frequently in the past for detoxification and rehabilitation. The patient had no family history of Alzheimer's disease, no history of head injury, and single-photon emission computed tomography showed no typical findings of Alzheimer's disease. His cognitive function was impaired. He was treated with donepezil for alcohol-related dementia, and 3 months later, his cognitive function had improved. More research is needed to confirm donepezil's role in treating alcohol-related dementia.

Fluoxetine in adolescents with major depression and an alcohol use disorder: an open-label trial.

Recently, a first placebo-controlled study of an selective serotonin reuptake inhibitor (SSRI) medication was conducted among a sample of adolescents with major depression by Emslie et al. [Arch. Gen. Psychiatry 54 (1997) 1031.]. That study demonstrated efficacy for fluoxetine vs. placebo for treating adolescents with major depression. However, to date, no studies have been conducted to assess the efficacy of fluoxetine or any other SSRI medication in adolescents with major depression in combination with an alcohol use disorder (AUD). In this study, the authors investigated whether fluoxetine decreases the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD. The authors conducted a 12-week open-label study of fluoxetine (20 mg) in 13 adolescents with current comorbid major depression and an AUD. A significant within-group decrease (improvement) was found for both depressive symptoms and drinking during the course of the study. The fluoxetine was well tolerated during the study. These data suggest promise for fluoxetine for decreasing both the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD.

Treatment of opioid dependence in the setting of pregnancy.

Opioid dependence in the setting of pregnancy provides a distinct set of challenges for providers. Treatment plans must take into consideration psychiatric and medical comorbidities while balancing risks and benefits for the maternal-fetal dyad. Treatment is best offered through a comprehensive treatment program designed to effectively deliver opioid agonist maintenance treatment along with psychosocial and obstetric care. As misuse of prescription analgesics increases in the United States, identification of the problem in pregnancy will become more important because this misuse is expected to lead to an increased prevalence of opioid dependence in pregnancy. Buprenorphine as maintenance treatment of opioid dependence during pregnancy has promise and may offer some benefits, but more research is needed, especially regarding induction of actively addicted women during pregnancy. For the present, methadone maintenance remains the standard of care for agonist treatment of opioid dependence in pregnancy against which other treatments must be compared.

Pharmaceutical approaches of binge drinking.

Binge Drinking (BD) is often considered to be recurrent alcohol abuse amongst adolescents and young adults. However, the close link between adolescence and impulsivity has led many authors to define BD as intoxication-seeking behaviour. Medications may sometimes be justified because of the major short-term and long-term risks that underlie the most severe BD-related behaviours. The most common consequences in the long run are the occurrence of alcohol dependence, psycho- and neurodevelopmental disruptions and alcohol liver disease. To understand the specificities of BD among other forms of alcohol addiction, this article is based on a two-headed conception of alcohol dependence: on one hand, psychological dependence, which refers to the behavioural habituation of alcohol intake, clinically results in craving and is neurobiologically supported by the reward system, particularly the dopaminergic mesolimbic pathway (MLP); on the other hand, physical dependence, which refers to the pharmacological tolerance induced by chronic alcohol intake, results in Alcohol Withdrawal Syndrome (AWS) and is neurobiologically supported by the imbalance between GABA and Glutamate-NMDA neurotransmission. Medications for psychological dependence include anticraving drugs, which all act by regulating MLP. Medications for physical dependence on alcohol include GABA-A and perhaps GABA-B agonists and some NMDA antagonists. In practice, many alcohol-dependence treatments seem to have a dual action. This article proposes an attempt to classify current and forthcoming medications for alcohol addiction based on this two-headed approach to treating alcohol dependence. Drawing from this classification, specific therapeutic schemes for treating BD are proposed, with currently approved alcohol medications and possible future treatments. These schemes are justified by recent literature on the subject and propose to prioritize pure anticraving medications, taking into account the clinical specificities of BD. Furthermore, these schemes also mention harm-reductive neuroprotective and hepatoprotective strategies, which could be included in the arsenal of possible medications for BD in the near future.

Intramuscular extended-release naltrexone: current evidence.

Extended-release naltrexone (XR-NTX; Vivitrol), developed to address poor adherence in addictive disorders, is approved for use in alcohol and opioid-dependence disorders. In alcohol-dependent adults with ≥ 4-day initial abstinence, XR-NTX increased initial and 6-month abstinence. An fMRI study found that XR-NTX attenuated the salience of alcohol visual and olfactory cues in the absence of alcohol, and post hoc analyses demonstrated efficacy even during high cue-exposure holiday periods. Safety and tolerability have generally been good, without adverse hepatic impact or intractable acute pain management. XR-NTX use appears feasible in primary care and public systems, and retrospective claims analyses have found cost savings and decreased intensive service utilization relative to oral agents. In opioid dependence, following detoxification, XR-NTX shows efficacy for maintaining abstinence, improving retention, decreasing craving, and preventing relapse. Trials are also exploring its use for the treatment of stimulant dependence. XR-NTX appears compatible with counseling and self-help attendance. While more research is needed, current findings suggest that a formulation of naltrexone that was sought beginning over three decades ago is fulfilling its promise as an extended-release pharmacotherapeutic.