The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Cognitive processing therapy (CPT) versus individual drug counseling (IDC) for PTSD for veterans with opioid use disorder maintained on buprenorphine.

BACKGROUND AND OBJECTIVES: There are high rates of comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD). Evidence-based trauma-focused psychotherapies such as Cognitive Processing Therapy (CPT) are a first-line treatment for PTSD. Veterans with OUD are treated primarily in substance use disorder (SUD) clinics where the standard of care is drug counseling; they often do not have access to first-line PTSD treatments. This study tested whether CPT can be conducted safely and effectively in veterans with comorbid OUD treated with buprenorphine. METHODS: This 12-week, 2-site, randomized clinical trial (RCT) included open-label randomization to two groups: (a) CPT versus (b) Individual Drug Counselling (IDC) in veterans with PTSD and comorbid OUD who were maintained on buprenorphine (N = 38). RESULTS: Veterans randomized to either IDC (n = 18) or CPT (n = 20) showed a significant reduction in self-reported PTSD symptoms over time as measured by the PTSD checklist (PCL-5) but there were no treatment group differences; there was some indication that reduction in PTSD symptoms in the CPT group were sustained in contrast to the IDC group. Recruitment was significantly impacted by COVID-19 pandemic, so this study serves as a proof-of-concept pilot study. DISCUSSION AND CONCLUSIONS: Veterans with OUD and PTSD can safely and effectively participate in evidence-based therapy for PTSD; further work should confirm that trauma-focused treatment may be more effective in leading to sustained remission of PTSD symptoms than drug counseling. SCIENTIFIC SIGNIFICANCE: This is the first study to evaluate CPT for PTSD in the context of buprenorphine treatment for OUD.

Progesterone Attenuates the Stress Response in Individuals with Alcohol Dependence and Post-Traumatic Stress Disorder - A Pilot Study.

OBJECTIVE: Evidence from laboratory studies suggests that progesterone may be effective in reducing stress and craving, and may improve cognitive performance in smokers and individuals with cocaine dependence. The objective of this study was to examine if progesterone would attenuate stress-induced craving, anxiety, affect and physiological measures, as well as improve stress-induced cognitive performance (processing speed and selective attention) in individuals diagnosed with alcohol use disorder (AUD) and post traumatic stress disorder (PTSD). METHODS: This laboratory study included (n = 13) participants who were diagnosed with current AUD and PTSD who were randomly assigned to recive either progesterone (200mg bid) or placebo in identical looking capsules for 3 days. On the fourth day they completed a laboratory session. In the morning of the test session, they received the last dose of medication and completed the rest of the laboratory procedures. The procedures included presentation in random order of personalized trauma and neutral scripts with relaxation in between. Main outcomes included measure of craving, anxiety, affect and cognitive performance. RESULTS: Consistent with other research, trauma scripts produced significantly greater increases in craving, anxiety and negative affect when compared with neutral scripts. Progesterone significantly reduced stress-induced symptoms of craving, anxiety, fear, anger and sadness but had no effect on positive emotions (joy, relaxation). Progesterone was effective in ameliorating stress-induced decreases in cognitive performance. CONCLUSIONS: The findings from this study demonstrate that progesterone can be effective in reducing stress-induced craving, anxiety and negative affect in a laboratory setting in individuals with comorbid AUD and PTSD. Interestingly, progesterone also improved cognitive performance. These findings require replication in a larger clinical trial and may have implications for treatment among individuals with AUD and PTSD.This study was registered as NCT02187224, at www.clinicaltrials.gov.

Ghrelin Predicts Stimulant and Sedative Effects of Alcohol in Heavy Drinkers.

AIM: The aim of this study was to examine the relationship between ghrelin levels and the subjective effects of alcohol in heavy drinkers, and to compare them to healthy controls. METHODS: Ghrelin levels were collected as part of two laboratory studies. Both groups received either IV infusion of saline or high dose of alcohol (100 mg%). In the study of heavy drinkers, ghrelin was gathered on all subjects, but data was analyzed only for participants who received placebo (N=12). Healthy controls (N=20) came from another study that collected data on family history. Ghrelin levels and measures of alcohol effects (BAES, VAS, NDS, YCS [see manuscript for details]) were collected at 4 timepoints: baseline, before infusion, during infusion and after infusion. RESULTS: IV alcohol significantly reduced ghrelin levels and higher fasting ghrelin levels were associated with more intense subjective alcohol effects. There were no differences in fasting ghrelin levels or subjective effects between heavy drinkers and controls. However, while both groups showed similar decline in ghrelin levels following alcohol infusion, on the placebo day, ghrelin levels in the healthy subjects increased significantly and exponentially over time while for the heavy drinkers ghrelin levels remained flat. CONCLUSIONS: Our findings support the role of ghrelin in reward mechanisms for alcohol. Contrary to others, we found no differences in fasting ghrelin levels or subjective experiences of alcohol between heavy drinkers and healthy controls. However, the group differences on the IV placebo day may be a possible indication of ghrelin abnormalities in heavy drinkers.

Thiopental Does Not Produce Hyperalgesia: A Laboratory Study Using Two Human Experimental Pain Models.

OBJECTIVE: Past investigations assessing the effects of thiopental on pain are conflicting. Although several studies demonstrate hyperalgesia as a result of barbiturate administration, others show analgesia. Our objective was to assess the effects of an infusion of the GABAA agonist thiopental, compared with placebo, in healthy participants on two subjective experimental pain paradigms: noxious electrical stimulation and intradermal capsaicin. METHODS: For electrical stimulation, the milliamps required to achieve pain threshold and tolerance were recorded, and the percent change from baseline was determined for each infusion condition. In the intradermal capsaicin condition, the area of hyperalgesia was determined by von Frey technique pre- and postinfusion, and the percent change in the area of hyperalgesia was calculated. RESULTS: Though thiopental infusion resulted in an increase in the electrical stimulation current required to elicit pain threshold or reach pain tolerance when compared with baseline, this finding was not statistically significant. In the intradermal capsaicin condition, there was a statistically significant difference in overall pre- and postinfusion pain interpretation, as measured by the McGill Pain Questionnaire (P < 0.05), but there was no significant difference in area of hyperalgesia. CONCLUSIONS: In this human study of thiopental's effects on two experimental pain models, our results show that thiopental does not induce hyperalgesia.

Trauma- and Stress-Induced Craving for Alcohol in Individuals Without PTSD.

AIMS: The main objective of the study was to compare the differences in craving following trauma and stress scripts in individuals with alcohol dependence (AD) who have experienced trauma but did not meet criteria for post-traumatic stress disorder (PTSD). METHODS: Twenty-eight men and women who participated in a treatment trial were included in this study before starting treatment. All had to meet criteria for AD and had experienced trauma at some point of their lives but were never diagnosed with PTSD. All participants had one laboratory session and were exposed to stress, trauma and neutral scripts randomly assigned. Main measures of craving, anxiety and mood were administered before, during and after each script. RESULTS: Stress and trauma scripts induced significantly more craving and anxiety than the neutral scripts. Interestingly, stress scripts produced stronger craving and anxiety than the trauma scripts but only with some measures. Stress and trauma scripts produced significantly more fear, anger and sadness and significantly lower ratings of joy and relaxation than the neutral script. Again, there were no differences between stress and trauma scripts for any of the emotional subscales. CONCLUSIONS: Trauma scripts did not result in stronger craving than stress scripts. These findings suggest that trauma in the absence of PTSD diagnosis does not lead to stronger craving for alcohol.

Zonisamide as an Adjunctive Treatment to Cognitive Processing Therapy for Veterans With Posttraumatic Stress Disorder and Comorbid Alcohol Use Disorder: A Pilot Study.

BACKGROUND AND OBJECTIVES: There are high rates of comorbid alcohol use disorder (AUD) among those who have posttraumatic stress disorder (PTSD). Ideally, treatment for comorbidity should address both disorders simultaneously. Zonisamide, an anticonvulsant, may be effective in decreasing alcohol use and may attenuate symptoms of PTSD. Treatment strategies can include medication in combination with a proven evidence-based psychotherapy designed to treat PTSD, such as cognitive processing therapy (CPT). METHODS: This 12-week pilot study was designed to test feasibility, acceptability, and preliminary efficacy of zonisamide (400 mg) as an adjunct to CPT for veterans with PTSD and comorbid AUD. Veterans (n = 24) with PTSD and current alcohol dependence were randomized in a 3:1 ratio to receive zonisamide or placebo in a double-blind fashion. All subjects received CPT enhanced to include sessions addressing drinking behavior. RESULTS: Subjects overall reported a significant decrease in drinking outcomes, craving, and symptoms of PTSD. Zonisamide was well-tolerated and easily administered with CPT, which was also well-tolerated. Exploratory analysis of comparison of groups suggests there was no advantage of zonisamide vs placebo in drinking or PTSD outcomes. There was a numeric but nonsignificant higher rate of abstinence with zonisamide (50%) vs placebo (33%). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: The interpretation of the results is limited by the pilot nature of this study. The combination of psychosocial treatment with medication management mimics real-world treatment. In order to isolate the individual contributions of medication vs psychotherapy a much larger study would need to be conducted. (Am J Addict 2020;29:515-524).

Alcohol Abstainer Status and Prazosin Treatment in Association with Changes in Posttraumatic Stress Disorder Symptoms in Veterans with Comorbid Alcohol Use Disorder and Posttraumatic Stress Disorder.

BACKGROUND: The noradrenergic system has been implicated in alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD), with adrenergic agents reducing drinking in individuals with AUD and improving sleep disturbances in individuals with PTSD. In a recent clinical trial, prazosin, an α1-adrenergic antagonist, was not superior to placebo in reducing PTSD symptoms, sleep problems, or alcohol consumption in a comorbid population; however, patients in both treatment conditions improved in all symptom domains over the course of treatment. It remains unknown whether alcohol abstinence is related to changes in PTSD symptoms and medication effects in individuals with this comorbidity. METHODS: Veterans with comorbid alcohol dependence and PTSD (n = 96) were randomized to prazosin (16 mg) or placebo in a 12-week outpatient, double-blind clinical trial. In this secondary data analysis, we examined main effects of alcohol abstainer status (abstainer vs. nonabstainer), treatment, and their interaction on changes in PTSD symptoms over time using linear mixed models. RESULTS: There was a main effect of alcohol abstainer status on symptoms of PTSD (p = 0.03), such that nonabstainers had lower total Clinician-Administered PTSD Scale (CAPS) scores than abstainers. There was a significant treatment by alcohol abstainer status interaction (p = 0.01); specifically, among placebo-treated individuals, those who did not abstain from alcohol had lower total CAPS scores compared to alcohol abstainers. Within the prazosin-treated group, abstainers and nonabstainers did not differ on total CAPS scores. Results were similar for the avoidance (p = 0.02), reexperiencing (p = 0.01), and hyperarousal (p = 0.04) subscales, such that placebo-treated nonabstainers had lower CAPS scores overall. CONCLUSIONS: Overall, prazosin treatment was not significantly related to changes in PTSD symptoms over the course of the 12-week clinical trial in a comorbid population. Interestingly, placebo-treated alcohol nonabstainers had a significant reduction in PTSD symptoms. Whether placebo-treated individuals continued to use alcohol because of ongoing symptoms of PTSD is not known.

A Pilot Randomized, Placebo-Controlled Trial of Glycine for Treatment of Schizophrenia and Alcohol Dependence.

Objectives: The hypofunctioning of N-methyl-D-aspartate (NMDA) receptors are thought to play an important role in the pathophysiology of schizophrenia. The augmentation of the glutamatergic system through the NMDA receptor may attenuate alcohol craving and use. This study was designed to evaluate the efficacy of glycine, an agonist of the glycine B co-agonist site of the NMDA receptor on alcohol consumption and cravings as well as on negative symptoms in schizophrenia. Methods: Participants (N = 20) were given 0.8 g/kg glycine or matching placebo (provided in bottles with mixed in solution) each week for the duration of the 12-week trial. Primary outcome measures included drinking, craving for alcohol, and symptoms of schizophrenia. Cognitive functioning (attention, concentration, and memory) was also evaluated. Results: Glycine showed no benefit over placebo in the reduction of heavy drinking days or craving for alcohol over a 12-week treatment period. Nor was there an effect on negative symptoms of schizophrenia or on cognitive functioning. Conclusions: Although our study showed no beneficial effect of glycine over placebo, our results are consistent with the largest trial of glycine treatment in schizophrenia. Diagnosed schizophrenia and alcohol dependence might be more difficult to treat because of more severe psychopathology. This is the first study to date to examine an innovative treatment approach with an amino acid, glycine, as potentially acting on both alcohol intake and negative symptoms of schizophrenia.

Ghrelin is Related to Personality Differences in Reward Sensitivity and Impulsivity.

AIMS: Ghrelin, a feeding-related peptide mainly produced in the stomach, has been linked to reward mechanisms for food and drugs of abuse in addition to traits of impulsivity. This study is a secondary analysis of an existing data set designed to examine the direct relationships between fasting ghrelin levels and reward sensitivity/impulsivity in healthy social drinkers. METHODS: Participants (n = 20) were recruited from an original study examining the subjective effects of alcohol among social drinkers. Fasting ghrelin levels were collected at baseline. Personality measures (Behavioral Inhibition, Behavioral Activation, and Affective Response to Impending Reward and Punishment and Barratt Impulsiveness Scale) were administered at baseline to evaluate sensitivity to reward and punishment, and measure traits of impulsivity, respectively. RESULTS: Fasting ghrelin levels were significantly related to reward sensitivity and impulsivity traits. Specifically, those with higher ghrelin levels were more sensitive to reward and were more impulsive (have lower self-control). CONCLUSIONS: The results indicate that individuals with higher levels of ghrelin are more sensitive to reward. In addition, they are less able to exercise self-control and to an extent more likely to act without thinking. This is the first study to report on the direct relationship between fasting ghrelin levels and personality characteristics such as reward sensitivity and aspects of impulsivity among healthy social drinkers. SHORT SUMMARY: Individuals with higher levels of fasting ghrelin are more sensitive to reward, but less sensitive to punishment. Higher ghrelin levels are also related to some aspects of impulsivity such as decreased self-control and increased likelihood of acting without thinking.

Suicidal ideation in military veterans with alcohol dependence and PTSD: The role of hostility.

BACKGROUND AND OBJECTIVES: Suicide is a significant public health problem among US military Veterans with rates exceeding civilian samples. Alcohol dependence (AD) and posttraumatic stress disorder (PTSD) are both associated with increases in suicidality. Given that risk of suicide is higher among those with both disorders, the study of relevant risk factors among those in this group is important. The current investigation focused on one such factor, hostility, and examined both overt hostility (ie, hostility that is more behavioral in nature and directed outwardly) and covert hostility (ie, hostility that is cognitive in nature and introspective) and their relationships to suicidal ideation. METHODS: Ninety-three Veterans participating in a randomized, double-blind, placebo-controlled treatment study evaluating the efficacy of the alpha-adrenergic agonist prazosin completed measures assessing overt hostility, covert hostility, and suicidal ideation at baseline. Depression symptoms and PTSD symptom severity also were assessed. RESULTS: Of the total sample, 60 participants (63.8%) indicated that they experienced suicidal ideation at some point in their lives. Covert hostility, in addition to PTSD symptom severity were found to be associated with the presence of lifetime suicidal ideation. Furthermore, depression symptoms were found to be associated with greater intensity of that ideation. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Findings highlight the importance of covert hostility as it relates to suicidal ideation among those with comorbid PTSD and AD and provides information which may help inform treatment approaches for high-risk military Veterans. (Am J Addict 2018;27:124-130).

Negative Affect Intensity and Hostility in Individuals With Alcohol Use Disorder With or Without Posttraumatic Stress Disorder.

OBJECTIVE: Negative affect intensity and hostility have both been implicated in alcohol use disorders (AUD) and posttraumatic stress disorder (PTSD) when they occur separately, but neither have been compared or explored among those with comorbid AUD and PTSD. This study is a secondary analysis designed to compare levels of negative affect intensity and hostility among those with AUD to those with comorbid AUD and PTSD. METHODS: Participants (n = 113) were recruited from the placebo-controlled groups of two distinct 12-week clinical trials (NCT00342563 and NCT00744055). The Short Affect Intensity Scale and Buss-Durkee Hostility Inventory were administered at weeks 0, 4, 8, and 12 to all study participants to assess negative affect intensity and hostility levels, respectively. RESULTS: Individuals with comorbid AUD and PTSD showed significantly higher levels of negative affect intensity and hostility than individuals with AUD only. These levels remained relatively stable over the course of the study in spite of all study participants showing clinically significant improvements in AUD severity and PTSD symptomatology (for those with dual diagnosis). CONCLUSIONS: Our results indicate that individuals with comorbid AUD and PTSD have higher levels of negative affect and higher levels of hostility compared to individuals with AUD alone. In addition, these heightened levels of negative affect intensity and hostility appear to function somewhat independently of diagnosis severity and symptomatology improvement. To our knowledge, this is the first study to compare negative affect intensity and hostility levels between individuals with AUD alone and those with comorbid AUD and PTSD.

Ghrelin is Supressed by Intravenous Alcohol and is Related to Stimulant and Sedative Effects of Alcohol.

AIMS: Evidence indicates that feeding-related peptides, such as ghrelin, have a role in the rewarding properties of addictive substances like alcohol. Oral alcohol administration significantly suppresses ghrelin. This study was designed to evaluate the effects of two doses of alcohol on ghrelin and examine if ghrelin levels predict the subjective effects of alcohol. METHODS: Healthy social drinkers (N = 20) participated in three, randomly assigned, and counterbalanced laboratory sessions. During each session they received a continuous IV infusion of either placebo (saline), low dose (40 mg%) or high dose (100 mg%) of alcohol. Participants were given a standardized, light breakfast 90 min before the start of the infusion. Ghrelin levels [acyl ghrelin (AG) and total ghrelin (TG)] were collected at four time points before, during and after the infusion. Subjective effects of alcohol, using the BAES, were evaluated before, during and after alcohol infusion. RESULTS: IV alcohol significantly reduced AG but not TG levels with no difference between the two doses of alcohol. The percent change (%∆) in AG suppression was substantial in both high dose (43.4%∆), and low dose (39.5%∆) of alcohol. Also, fasting AG and TG levels were significant predictors of alcohol stimulant and sedative effects. Higher fasting ghrelin levels were associated with longer and more intense subjective effects. CONCLUSIONS: The results provide evidence that IV alcohol suppresses ghrelin levels similarly to oral alcohol. This study is the first to show that ghrelin predicts subjective effects of alcohol, suggesting that ghrelin may have a role in the rewarding mechanisms for alcohol. SHORT SUMMARY: Intravenous alcohol infusion (low dose and high dose of alcohol) when compared to placebo (saline) significantly suppresses ghrelin in healthy social drinkers. Fasting ghrelin levels also predict subjective behavioral effects of alcohol. Those with higher fasting ghrelin levels tend to experience alcohol effects longer and more intensely.

Treatment of alcohol use disorder and co-occurring PTSD.

BACKGROUND: Alcohol use disorder (AUD) is a serious psychiatric disorder with medical, psychiatric, and social consequences. In individuals with comorbid post-traumatic stress disorder (PTSD), treatment outcomes are notably worse in comparison with treatment outcomes associated with either disorder occurring alone. There is a growing literature evaluating treatments, both pharmacotherapy and psychotherapy focused, in individuals with co-occurring AUD and PTSD. The main objective of this review was to evaluate pharmacotherapy and psychotherapy studies that were specifically designed to evaluate the treatment of individuals with comorbid AUD and PTSD. METHOD: MEDLINE and PUBMED databases were searched with no specific time period. Studies focusing on SUD treatments were excluded. Because the number of random clinical trial (RCT) studies was small, all publications (including open label, single case, and secondary analyses) were included. RESULTS: Sixteen studies met criteria and were organized based on whether they evaluated the efficacy of pharmacotherapy, psychotherapy, or both. Pharmacological interventions with either AUD or PTSD agents were mainly effective in reducing drinking outcomes; only one study using sertraline found that the active study medication was superior to placebo in reducing PTSD symptoms. Psychotherapies were not superior to a comparative treatment in reducing drinking outcomes. Only 1 study showed reduction in PTSD symptoms in a small sample of completers. The single RCT that evaluated the efficacy of naltrexone in combination with psychotherapies (prolonged exposure or supportive counseling) found that naltrexone in combination with prolonged exposure was better for drinking outcomes at follow-up. CONCLUSIONS: Although these studies represent a good start in terms of research in treatment interventions of co-occurring AUD and PTSD, the studies are very limited, most lack adequate power, and the majority suffer from inadequate control groups. In particular, there is a strong need to develop and evaluate the combined medication and psychological-based treatment interventions for those with comorbid AUD and PTSD.

A Comparison of Sexual Side Effects of Antidepressants With and Without Naltrexone.

OBJECTIVE: The aim of the study was to compare the rate of sexual side effects of the selective serotonin reuptake inhibitor paroxetine versus the tricyclic antidepressant desipramine and to examine the effect of co-prescription of naltrexone on sexual side effects among participants in a randomized clinical trial. METHODS: This was a secondary analysis (N = 88) of veterans who participated in a 12-week trial. All veterans were randomized into one of four treatment groups: (a) desipramine/naltrexone, (b) desipramine/placebo, (c) paroxetine/naltrexone, and (d) paroxetine/placebo. The main outcome measure was the frequency of sexual side effects consisting of "decreased sex drive" and/or "impotence" reported by veterans at each weekly visit. RESULTS: Approximately 61% of the veterans reported sexual side effects at least once during the trial, and 26.4% reported sexual side effects throughout the study. There were no significant differences in the frequency of sexual side effects among the four treatment groups. The results were similar when the comparison was made between the two antidepressant groups. There were no significant differences in the reporting of sexual side effects between those receiving desipramine and paroxetine. Also, the comparison between naltrexone and placebo did not alter the results. CONCLUSIONS: This is the first study to compare frequency of sexual side effect reporting between paroxetine and desipramine. We found no statistically significant differences in sexual side effect reporting between the two antidepressants. Also, the addition of naltrexone did not show any beneficial effect on the sexual side effect profile.

Trauma- and Stress-Induced Response in Veterans with Alcohol Dependence and Comorbid Post-Traumatic Stress Disorder.

BACKGROUND: Alcohol dependence (AD) and post-traumatic stress disorder (PTSD) commonly co-occur, and the co-occurrence is associated with worse prognosis than either disorder absent the other. Craving is an important construct related to relapse, but the relationship between PTSD symptoms, craving, and relapse is not well understood. Several studies have documented the relationship between stress and craving in individuals without comorbid PTSD, but the effect on those with comorbid PTSD is not well known. A small literature suggests that trauma imagery affects craving. This is the first study to explore the effects of trauma-induced and stress-induced scripts on alcohol craving, affect, cardiovascular, and cortisol responses in the laboratory. METHODS: Veterans (n = 25) diagnosed with AD and PTSD who were participating in a randomized clinical treatment trial took part in this laboratory study. Baseline assessment included PTSD symptoms and drinking quantity and frequency over 3 months before study initiation. In the laboratory, participants were exposed to neutral, stressful, and trauma scripts randomly assigned. Main outcomes included craving, anxiety, mood states, salivary cortisol, and cardiovascular responses. RESULTS: Both stress and trauma scripts produced greater increases in craving, negative affect, and cardiovascular reactivity, compared to neutral scripts. Trauma scripts produced significantly stronger craving for alcohol and greater cardiovascular reactivity than stress scripts. Also, trauma-induced but not stress-induced craving was positively correlated with baseline levels of drinking. There were no changes in cortisol levels from pre- to postexposure of any scripts. CONCLUSIONS: The results highlight that trauma cues are more salient in inducing alcohol craving than stress cues and higher reactivity is related to more baseline drinking. This finding is consistent with clinical observations that show an association between PTSD symptoms and alcohol relapse. It also underscores the importance of adequate treatment of PTSD as reactivity related to trauma cues and reminders may be an important factor in craving and relapse.

Effect of Intravenous Ethanol on Capsaicin-Induced Hyperalgesia in Human Subjects.

BACKGROUND: The objective of this study was to assess ethanol's (EtOH's) effects on capsaicin-induced hyperalgesia in healthy participants. Specifically, we investigated the change in area of capsaicin-induced hyperalgesia following 3 interventions: intravenous EtOH at 2 targeted breath alcohol concentrations (BrAC), or placebo. METHODS: Eighteen participants participated in 3 test days in a randomized order. Each test day, participants received an intradermal capsaicin injection on the volar surface of the forearm, followed by either infusion of high concentration EtOH (targeted BrAC = 0.100 g/dl), low concentration EtOH (targeted BrAC = 0.040 g/dl), or placebo. The area of hyperalgesia was determined by von Frey technique at 2 time points, prior to EtOH infusion, and again when target BrAC was reached. The primary outcome was the percent change in the area of capsaicin-induced hyperalgesia. Additional outcome measures included the visual analogue scale of mood states (VAS), which was administered at each time point. RESULTS: There was a marked 30% reduction in the area of capsaicin-induced hyperalgesia with infusion of a high concentration of EtOH (p < 0.05). Low concentration EtOH produced a 10% reduction in hyperalgesia area, although this finding did not reach significance. Further, participants reported significant feelings of euphoria and drowsiness at high concentrations of EtOH (p < 0.05), as measured by the VAS. CONCLUSIONS: In a human model examining pain phenomena related to central sensitization, this study is the first to demonstrate that capsaicin-induced hyperalgesia is markedly attenuated by EtOH. The capsaicin experimental pain paradigm employed provides a novel approach to evaluate EtOH's effects on pain processing. The antihyperalgesic effects of EtOH observed have important clinical implications for the converging fields of substance abuse and pain medicine and may inform why patients with chronic pain often report alcohol use as a form of self-medication.

Prazosin for Veterans with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence: A Clinical Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is an important and timely clinical issue particularly for combat veterans. Few pharmacologic options are available to treat PTSD, particularly among military personnel, and they are not based on rational neurobiology. The evidence for noradrenergic dysregulation in PTSD is strong, and the alpha-adrenergic agonist prazosin is one of the most promising medications to treat sleep disturbances associated with PTSD as well as PTSD symptoms among both veterans and civilians. Evidence also implicates noradrenergic dysregulation in the pathophysiology of alcohol dependence (AD); prazosin also may have efficacy in treating this disorder. The use of prazosin represents a rational and compelling approach for the treatment of PTSD and comorbid AD. Given the high rates of comorbid AD in trauma survivors with PTSD, and the enormous impact that these comorbid disorders have on psychosocial function and well-being, finding effective treatments for this population is of high clinical importance. METHODS: Ninety-six veterans with PTSD and comorbid AD were randomized to receive prazosin (16 mg) or placebo in an outpatient, randomized, double-blind, clinical trial for 13 weeks. Main outcomes included symptoms of PTSD, sleep disturbances, and alcohol use. RESULTS: Symptoms of PTSD improved over time, but contrary to the hypothesis, there was no medication effect on PTSD symptoms, or on sleep. Alcohol consumption also decreased over time, but there were no significant differences in outcomes between medication groups. CONCLUSIONS: Prazosin was not effective in treating PTSD symptoms, improving sleep, or reducing alcohol consumption overall in this dually diagnosed group. This does not support the use of prazosin in an actively drinking population and suggests that the presence of a comorbid condition affects the efficacy of this medication. This study highlights the importance of conducting clinical trials in "real-world" patients, as results may vary based on comorbid conditions.

Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials.

BACKGROUND: The ethanol metabolites, ethyl glucuronide (EtG) and ethyl sulfate (EtS), are biomarkers of recent alcohol consumption that provide objective measures of abstinence. Our goals are to better understand the impact of cutoff concentration on test interpretation, the need for measuring both metabolites, and how best to integrate test results with self-reports in clinical trials. METHODS: Subjects (n = 18) were administered, 1 week apart, 3 alcohol doses calibrated to achieve blood concentrations of 20, 80, and 120 mg/dl, respectively. Urinary EtG/EtS was measured at timed intervals during a 24-hour hospitalization and twice daily thereafter. In addition, participants from 2 clinical trials provided samples for EtG/EtS and drinking histories. Cutoffs for EtG/EtS of 100/50, 200/100, and 500/250 ng/ml were evaluated. RESULTS: Twelve hours following each challenge, EtG was always positive at the 100 and 200 cutoffs, but at 24 hours sensitivity was poor at all cutoffs following the low dose, and poor after 48 hours regardless of dose or cutoff. Similarly, in the clinical trials EtG sensitivity was good for detecting any drinking during the last 24 hours at the 2 lowest cutoffs, but under 40% during the last 24 to 48 hours. Sensitivity was reduced at the 500 ng/ml cutoff. Discrepancies between EtG and EtS were few. Comparison of self-reports of abstinence and EtG-confirmed abstinence indicated underreporting of drinking. CONCLUSIONS: Any drinking the night before should be detectable the following morning with EtG cutoffs of 100 or 200 ng/ml. Twenty-four hours after drinking, sensitivity is poor for light drinking, but good for heavier consumption. At 48 hours, sensitivity is low following 6 drinks or less. Increasing the cutoff to 500 ng/ml leads to substantially reduced sensitivity. Monitoring both EtG and EtS should usually be unnecessary. We recommend EtG-confirmed self-reports of abstinence for evaluation of outcomes in clinical trials.

Pharmacogenetics of naltrexone and disulfiram in alcohol dependent, dually diagnosed veterans.

BACKGROUND: Disulfiram and naltrexone were evaluated in treatment of individuals with co-occurring alcohol dependence and other Axis I disorders (e.g., Major Depression). We explored pharmacogenetic interactions in genotyped subjects. METHODS: Alcohol dependent (AD) subjects received naltrexone alone, placebo alone, disulfiram with placebo or disulfiram with naltrexone. They were genotyped for OPRM1 rs1799971 (Asn40Asp), and DBH rs1611115 (C-1021T). N = 107 male European-American subjects were included. RESULTS: There were no significant interactions with OPRM1. DBH interacted with naltrexone on the primary outcome of abstinence from heavy drinking (χ(2) (1) = 5.23, p = .02). "T" allele carriers on naltrexone had more abstinence compared to "CC" subjects on naltrexone (FET, p = .01). "T" allele carriers on naltrexone had the highest overall rates of abstinence from heavy drinking (>90%). Also, DBH genotype interacted with disulfram (F(1,17) = 7.52, p = .01) on drinks per drinking day with less drinking for subjects with the "CC" genotype than for T allele carriers on disulfiram. CONCLUSIONS: DBH*rs1611115*T associated with better response to naltrexone, while for those on disulfiram that drank, "CC" subjects drank less than T carriers. For rs1799971*G, we did not replicate findings from previous studies showing a more favorable response to NTX, possibly due to the small available sample. SCIENTIFIC SIGNIFICANCE: Genotyping rs1611115 may be useful in understanding inter-individual differences in AD treatment response. FUTURE DIRECTIONS: Further study of rs1611115 pharmacogenetics is warranted.